ACR Winter Rheumatology Symposium 2014

SNOWMASS, COLO. – During a recent 15-year period in which the annual arthroplasty rate for osteoarthritis and other noninflammatory arthritides doubled, the arthroplasty rate for rheumatoid arthritis actually declined. Moreover, the mean age at the time of arthroplasty for RA rose.

"In a time frame when utilization of total knee and total hip replacement for osteoarthritis is really skyrocketing, with younger and younger patients, I think this speaks to something pretty good going on with our RA patients," Dr. Susan M. Goodman observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

She presented data from a soon to be published study of nearly 2.8 million arthroplasties included in 10 state databases. The arthroplasty rate for noninflammatory arthritis – the great majority of which is osteoarthritis (OA) – zoomed from 124.5/100,000 population in 1991 to 247.5/100,000 in 2005.

Meanwhile the rate of arthroplasty for RA fell slightly, albeit statistically significantly, from 4.6 to 4.5 per 100,000. The mean age at the time of arthroplasty for RA rose from 63.4 years in 1991 to 64.9 years in 2005, reported Dr. Goodman, a rheumatologist at the Hospital for Special Surgery in New York.

She turned to data from other sources to address issues related to the morbidity of arthroplasty for RA.

For example, it’s well documented that rheumatoid arthritis is associated with elevated cardiovascular risk, such that the typical RA patient has a cardiovascular morbidity burden comparable to that of someone without RA who’s 5 years older. So what does this mean for the many RA patients who come into the hospital for total hip or knee replacement?

Surprisingly, nothing. That is, data from multiple sources indicate RA patients are at no greater perioperative risk of cardiovascular events than are patients with OA undergoing the same procedures.

The take-away message? "Clearly we’re doing something right in managing our patients with RA," Dr. Goodman commented.

Similarly, an analysis of 7.75 million patients in the Nationwide Inpatient Sample database found that among RA patients undergoing intermediate-risk noncardiac surgery, such as total joint arthroplasty, the perioperative cardiovascular event rate was 0.34%, significantly less than the 1.07% rate in diabetic patients undergoing intermediate-risk surgeries. Moreover, perioperative mortality was 0.30% in the RA patients, less than half the 0.65% figure in diabetics (Arthritis Rheum. 2012;64:2429-37). These findings disproved the study hypothesis, which was that the two groups would have similar cardiovascular event rates, since both diseases are – unlike osteoarthritis – systemic inflammatory conditions associated with increased cardiovascular mortality.

"I think this means that we as rheumatologists are taking better care of our patients than the endocrinologists next door whose patients have a similar atherosclerotic burden," she continued.

Dr. Goodman was a coinvestigator in a population-based study of 351,103 total knee replacements and 157,775 total hip replacements done at 400 hospitals during 2006-2010. This retrospective analysis of an administrative database included 11,755 total knee and 5,400 total hip replacements for RA.

The prevalence of a prior history of MI, peripheral vascular disease, or cerebrovascular disease was closely similar in the RA and OA patients undergoing surgery. However, the prevalence of baseline COPD was significantly greater in the RA patients, at roughly 17.5%, or an absolute 3%-4% more than in the osteoarthritis patients.

The 30-day rates of cardiac events, venous thromboembolism, and cerebrovascular events were closely similar in the RA and OA arthroplasty patients. The RA patients undergoing total hip replacement had significantly higher rates of pulmonary compromise, infections, blood product transfusions, mechanical ventilation, and length of stay than did OA patients (Clin. Exp. Rheumatol. 2013;31:889-95). The RA patients with total knee replacement differed from their OA counterparts only in terms of greater need for transfusions and lengthier hospital stays (J. Arthroplasty 2014;29:308-13).

However, an analysis of the Hospital for Special Surgery experience failed to confirm the increased complication risks found in this study of a large administrative database. This retrospective review of adverse events within 6 months of total knee replacement in 156 RA patients and 318 OA controls showed no differences between the two groups in pneumonia, other infections, or venous thromboembolism. Moreover, the reoperation rate was 2.5% in the RA patients, compared with 8.8% in the OA group.

"The advantage of a smaller study like this is you really know who has RA and you have a lot of very granular information about the drugs they’re taking. The disadvantage, of course, is that you’re really not powered to look at major adverse events. But boy, there wasn’t even a hint of an increase in the complication rate amongst these RA patients," according to Dr. Goodman.

In a study she presented at the 2013 European Congress of Rheumatology, she compared 2-year outcomes post arthroplasty in RA and OA patients in the contemporary era of high use of biologic agents and traditional DMARDs for RA. The 178 RA patients who had total knee replacement had significantly greater comorbidities preoperatively than the 5,206 OA patients. Yet by 2 years postoperatively, they had fully caught up in terms of improved Western Ontario and McMaster Osteoarthritis Index (WOMAC) function and pain scores.

Total hip replacement was a very different story. The 202 RA patients were four times more likely to have poor WOMAC functional outcome and three times more likely to have poor pain outcome scores at 2 years, compared with 5,810 OA patients. In a multivariate analysis, higher expectations for surgery, better preoperative mental health, and more advanced education were associated with better 2-year outcomes.

"I’m not sure why our hip replacement patients with RA aren’t doing as well as the knee replacement patients, but they’re clearly not," according to the rheumatologist.

She reported having no financial disclosures.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – During a recent 15-year period in which the annual arthroplasty rate for osteoarthritis and other noninflammatory arthritides doubled, the arthroplasty rate for rheumatoid arthritis actually declined. Moreover, the mean age at the time of arthroplasty for RA rose.

"In a time frame when utilization of total knee and total hip replacement for osteoarthritis is really skyrocketing, with younger and younger patients, I think this speaks to something pretty good going on with our RA patients," Dr. Susan M. Goodman observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

She presented data from a soon to be published study of nearly 2.8 million arthroplasties included in 10 state databases. The arthroplasty rate for noninflammatory arthritis – the great majority of which is osteoarthritis (OA) – zoomed from 124.5/100,000 population in 1991 to 247.5/100,000 in 2005.

Meanwhile the rate of arthroplasty for RA fell slightly, albeit statistically significantly, from 4.6 to 4.5 per 100,000. The mean age at the time of arthroplasty for RA rose from 63.4 years in 1991 to 64.9 years in 2005, reported Dr. Goodman, a rheumatologist at the Hospital for Special Surgery in New York.

She turned to data from other sources to address issues related to the morbidity of arthroplasty for RA.

For example, it’s well documented that rheumatoid arthritis is associated with elevated cardiovascular risk, such that the typical RA patient has a cardiovascular morbidity burden comparable to that of someone without RA who’s 5 years older. So what does this mean for the many RA patients who come into the hospital for total hip or knee replacement?

Surprisingly, nothing. That is, data from multiple sources indicate RA patients are at no greater perioperative risk of cardiovascular events than are patients with OA undergoing the same procedures.

The take-away message? "Clearly we’re doing something right in managing our patients with RA," Dr. Goodman commented.

Similarly, an analysis of 7.75 million patients in the Nationwide Inpatient Sample database found that among RA patients undergoing intermediate-risk noncardiac surgery, such as total joint arthroplasty, the perioperative cardiovascular event rate was 0.34%, significantly less than the 1.07% rate in diabetic patients undergoing intermediate-risk surgeries. Moreover, perioperative mortality was 0.30% in the RA patients, less than half the 0.65% figure in diabetics (Arthritis Rheum. 2012;64:2429-37). These findings disproved the study hypothesis, which was that the two groups would have similar cardiovascular event rates, since both diseases are – unlike osteoarthritis – systemic inflammatory conditions associated with increased cardiovascular mortality.

"I think this means that we as rheumatologists are taking better care of our patients than the endocrinologists next door whose patients have a similar atherosclerotic burden," she continued.

Dr. Goodman was a coinvestigator in a population-based study of 351,103 total knee replacements and 157,775 total hip replacements done at 400 hospitals during 2006-2010. This retrospective analysis of an administrative database included 11,755 total knee and 5,400 total hip replacements for RA.

The prevalence of a prior history of MI, peripheral vascular disease, or cerebrovascular disease was closely similar in the RA and OA patients undergoing surgery. However, the prevalence of baseline COPD was significantly greater in the RA patients, at roughly 17.5%, or an absolute 3%-4% more than in the osteoarthritis patients.

The 30-day rates of cardiac events, venous thromboembolism, and cerebrovascular events were closely similar in the RA and OA arthroplasty patients. The RA patients undergoing total hip replacement had significantly higher rates of pulmonary compromise, infections, blood product transfusions, mechanical ventilation, and length of stay than did OA patients (Clin. Exp. Rheumatol. 2013;31:889-95). The RA patients with total knee replacement differed from their OA counterparts only in terms of greater need for transfusions and lengthier hospital stays (J. Arthroplasty 2014;29:308-13).

However, an analysis of the Hospital for Special Surgery experience failed to confirm the increased complication risks found in this study of a large administrative database. This retrospective review of adverse events within 6 months of total knee replacement in 156 RA patients and 318 OA controls showed no differences between the two groups in pneumonia, other infections, or venous thromboembolism. Moreover, the reoperation rate was 2.5% in the RA patients, compared with 8.8% in the OA group.

"The advantage of a smaller study like this is you really know who has RA and you have a lot of very granular information about the drugs they’re taking. The disadvantage, of course, is that you’re really not powered to look at major adverse events. But boy, there wasn’t even a hint of an increase in the complication rate amongst these RA patients," according to Dr. Goodman.

In a study she presented at the 2013 European Congress of Rheumatology, she compared 2-year outcomes post arthroplasty in RA and OA patients in the contemporary era of high use of biologic agents and traditional DMARDs for RA. The 178 RA patients who had total knee replacement had significantly greater comorbidities preoperatively than the 5,206 OA patients. Yet by 2 years postoperatively, they had fully caught up in terms of improved Western Ontario and McMaster Osteoarthritis Index (WOMAC) function and pain scores.

Total hip replacement was a very different story. The 202 RA patients were four times more likely to have poor WOMAC functional outcome and three times more likely to have poor pain outcome scores at 2 years, compared with 5,810 OA patients. In a multivariate analysis, higher expectations for surgery, better preoperative mental health, and more advanced education were associated with better 2-year outcomes.

"I’m not sure why our hip replacement patients with RA aren’t doing as well as the knee replacement patients, but they’re clearly not," according to the rheumatologist.

She reported having no financial disclosures.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – During a recent 15-year period in which the annual arthroplasty rate for osteoarthritis and other noninflammatory arthritides doubled, the arthroplasty rate for rheumatoid arthritis actually declined. Moreover, the mean age at the time of arthroplasty for RA rose.

"In a time frame when utilization of total knee and total hip replacement for osteoarthritis is really skyrocketing, with younger and younger patients, I think this speaks to something pretty good going on with our RA patients," Dr. Susan M. Goodman observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

She presented data from a soon to be published study of nearly 2.8 million arthroplasties included in 10 state databases. The arthroplasty rate for noninflammatory arthritis – the great majority of which is osteoarthritis (OA) – zoomed from 124.5/100,000 population in 1991 to 247.5/100,000 in 2005.

Meanwhile the rate of arthroplasty for RA fell slightly, albeit statistically significantly, from 4.6 to 4.5 per 100,000. The mean age at the time of arthroplasty for RA rose from 63.4 years in 1991 to 64.9 years in 2005, reported Dr. Goodman, a rheumatologist at the Hospital for Special Surgery in New York.

She turned to data from other sources to address issues related to the morbidity of arthroplasty for RA.

For example, it’s well documented that rheumatoid arthritis is associated with elevated cardiovascular risk, such that the typical RA patient has a cardiovascular morbidity burden comparable to that of someone without RA who’s 5 years older. So what does this mean for the many RA patients who come into the hospital for total hip or knee replacement?

Surprisingly, nothing. That is, data from multiple sources indicate RA patients are at no greater perioperative risk of cardiovascular events than are patients with OA undergoing the same procedures.

The take-away message? "Clearly we’re doing something right in managing our patients with RA," Dr. Goodman commented.

Similarly, an analysis of 7.75 million patients in the Nationwide Inpatient Sample database found that among RA patients undergoing intermediate-risk noncardiac surgery, such as total joint arthroplasty, the perioperative cardiovascular event rate was 0.34%, significantly less than the 1.07% rate in diabetic patients undergoing intermediate-risk surgeries. Moreover, perioperative mortality was 0.30% in the RA patients, less than half the 0.65% figure in diabetics (Arthritis Rheum. 2012;64:2429-37). These findings disproved the study hypothesis, which was that the two groups would have similar cardiovascular event rates, since both diseases are – unlike osteoarthritis – systemic inflammatory conditions associated with increased cardiovascular mortality.

"I think this means that we as rheumatologists are taking better care of our patients than the endocrinologists next door whose patients have a similar atherosclerotic burden," she continued.

Dr. Goodman was a coinvestigator in a population-based study of 351,103 total knee replacements and 157,775 total hip replacements done at 400 hospitals during 2006-2010. This retrospective analysis of an administrative database included 11,755 total knee and 5,400 total hip replacements for RA.

The prevalence of a prior history of MI, peripheral vascular disease, or cerebrovascular disease was closely similar in the RA and OA patients undergoing surgery. However, the prevalence of baseline COPD was significantly greater in the RA patients, at roughly 17.5%, or an absolute 3%-4% more than in the osteoarthritis patients.

The 30-day rates of cardiac events, venous thromboembolism, and cerebrovascular events were closely similar in the RA and OA arthroplasty patients. The RA patients undergoing total hip replacement had significantly higher rates of pulmonary compromise, infections, blood product transfusions, mechanical ventilation, and length of stay than did OA patients (Clin. Exp. Rheumatol. 2013;31:889-95). The RA patients with total knee replacement differed from their OA counterparts only in terms of greater need for transfusions and lengthier hospital stays (J. Arthroplasty 2014;29:308-13).

However, an analysis of the Hospital for Special Surgery experience failed to confirm the increased complication risks found in this study of a large administrative database. This retrospective review of adverse events within 6 months of total knee replacement in 156 RA patients and 318 OA controls showed no differences between the two groups in pneumonia, other infections, or venous thromboembolism. Moreover, the reoperation rate was 2.5% in the RA patients, compared with 8.8% in the OA group.

"The advantage of a smaller study like this is you really know who has RA and you have a lot of very granular information about the drugs they’re taking. The disadvantage, of course, is that you’re really not powered to look at major adverse events. But boy, there wasn’t even a hint of an increase in the complication rate amongst these RA patients," according to Dr. Goodman.

In a study she presented at the 2013 European Congress of Rheumatology, she compared 2-year outcomes post arthroplasty in RA and OA patients in the contemporary era of high use of biologic agents and traditional DMARDs for RA. The 178 RA patients who had total knee replacement had significantly greater comorbidities preoperatively than the 5,206 OA patients. Yet by 2 years postoperatively, they had fully caught up in terms of improved Western Ontario and McMaster Osteoarthritis Index (WOMAC) function and pain scores.

Total hip replacement was a very different story. The 202 RA patients were four times more likely to have poor WOMAC functional outcome and three times more likely to have poor pain outcome scores at 2 years, compared with 5,810 OA patients. In a multivariate analysis, higher expectations for surgery, better preoperative mental health, and more advanced education were associated with better 2-year outcomes.

"I’m not sure why our hip replacement patients with RA aren’t doing as well as the knee replacement patients, but they’re clearly not," according to the rheumatologist.

She reported having no financial disclosures.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Whether a woman with antiphospholipid antibodies meets diagnostic criteria for antiphospholipid syndrome makes a huge difference in her risk of pregnancy failure.

Having antiphospholipid antibodies alone confers only a modest increase in the risks of thrombosis and/or pregnancy mishap, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium, sponsored by the American College of Rheumatology.

"You don’t have to jump all over these patients and get them worked up into a tizzy that they’re going to have blood clots or major pregnancy problems if they’ve never had them before," said Dr. Clowse, director of the Duke University Autoimmunity in Pregnancy registry in Durham, N.C.

The published experience indicates that women with antiphospholipid antibodies (aPL) but not antiphospholipid syndrome (APS) have roughly a 15% rate of pregnancy loss in their first pregnancy, not much different than the 11% rate in the general population. In contrast, women with untreated APS have up to a 90% pregnancy loss rate. With aspirin at 81 mg/day, this rate drops to 50%, and with dual therapy of low-dose aspirin plus either low-molecular-weight (LMW) or unfractionated heparin, the risk falls further to 25%, still twice that of the general population.

Thus, the distinction between aPL and APS is key. In addition to its implications for pregnancy outcome, it also guides the duration of anticoagulation following thrombosis. Anticoagulation needs to continue indefinitely in patients with APS because of their high risk of another clotting event. Indeed, patients with APS, if left untreated after a thrombotic event, have a 25% chance of another event within the next year, the rheumatologist noted.

"The diagnosis of APS is actually straightforward, but in patients referred to our lupus clinic from outside I see the term being used pretty fast and loose, and I think it’s somewhat inappropriate to do so. There are many patients with antiphospholipid antibodies who don’t have APS," she continued.

The current diagnostic criteria for APS – the so-called Sydney criteria (J. Thromb. Haemost. 2006;4:295-306) – require both laboratory and clinical findings. The laboratory criteria require a finding of lupus anticoagulant, medium- or high-titer IgG or IgM anticardiolipin antibodies, and/or medium- or high-titer anti-beta2-glycoprotein-1 antibody. The test results need to be positive on two occasions 12 weeks apart, although treatment for presumptive APS can start after tentative diagnosis based upon the first positive test.

To meet the vascular criteria for APS, a patient simply has to have had an arterial, venous, or small vessel thrombosis in any tissue or organ. The pregnancy criteria are more elaborate. To qualify, a woman must have had spontaneous abortions at less than 10 weeks’ gestation in at least three or more consecutive pregnancies, or a second- or third-trimester pregnancy loss of a normal fetus, or premature birth of a morphologically normal fetus before week 34 due to preeclampsia or placental insufficiency.

In women with full-blown APS, antibody titers matter quite a bit in terms of pregnancy outcome. In a study of 51 women with APS who were treated with LMW heparin and aspirin throughout 55 pregnancies, the 20 women with antibody titers greater than four times the upper limit of normal had a 35% rate of delivering an appropriately grown baby after 32 weeks’ gestation. The 35 antibody-positive women with titers less than four times the upper limit of normal had a 77% rate of normal delivery (Acta Obstet. Gynecol. Scand. 2011;90:1428-33).

In women with aPL only, the risk of pregnancy loss may be so low that aspirin isn’t protective. In an intriguing Italian study of 139 pregnancies in 114 women with aPL but not APS, the pregnancy loss rate in 104 pregnancies treated throughout with low-dose aspirin was 7.7%, while in 35 untreated pregnancies the rate was 2.9% (J. Rheumatol. 2013;40:425-9).

"The conclusion here is you can go ahead and use aspirin, but we don’t know that it’s doing a whole lot. Maybe we’re really just treating ourselves," Dr. Clowse mused.

Evidence from the PROMISSE trial, the largest-ever U.S. study of pregnancy loss in lupus patients, points to lupus anticoagulant as the main driver of pregnancy morbidity in patients with aPL. Thirty-nine percent of lupus anticoagulant–positive patients had adverse pregnancy outcomes, compared with just 3% of those without lupus anticoagulant. Unfortunately, treatment with heparin, aspirin, prednisone, or hydroxychloroquine didn’t mitigate the risk (Arthritis Rheum. 2012;64:2311-8).

While pregnancy loss is the biggest concern among most women with APS, it’s important to watch for maternal complications, including early severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and thrombotic events.

"It’s worth talking to the woman before pregnancy and explaining that, unfortunately, pregnancy loss is not necessarily the worst thing that can happen. Her health can also be at risk," Dr. Clowse observed.

In her own practice, everybody with APS goes on aspirin at 81 mg/day throughout pregnancy, even if there has been no prior pregnancy loss. With a history of three or more consecutive pregnancy losses, the treatment is low-dose LMW heparin plus low-dose aspirin. In women with a history of pregnancy loss that doesn’t reach that level, there is no good evidence to provide guidance as to whether to use low-dose LMW heparin plus aspirin or aspirin alone; however, she tends to be more aggressive in women with lupus anticoagulant or very high titers of the other aPLs. Women with a history of thrombosis, whether arterial or venous, are encouraged to remain on full-dose LMW heparin plus low-dose aspirin throughout pregnancy.

Dr. Clowse reported serving as a consultant to UCB.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Whether a woman with antiphospholipid antibodies meets diagnostic criteria for antiphospholipid syndrome makes a huge difference in her risk of pregnancy failure.

Having antiphospholipid antibodies alone confers only a modest increase in the risks of thrombosis and/or pregnancy mishap, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium, sponsored by the American College of Rheumatology.

"You don’t have to jump all over these patients and get them worked up into a tizzy that they’re going to have blood clots or major pregnancy problems if they’ve never had them before," said Dr. Clowse, director of the Duke University Autoimmunity in Pregnancy registry in Durham, N.C.

The published experience indicates that women with antiphospholipid antibodies (aPL) but not antiphospholipid syndrome (APS) have roughly a 15% rate of pregnancy loss in their first pregnancy, not much different than the 11% rate in the general population. In contrast, women with untreated APS have up to a 90% pregnancy loss rate. With aspirin at 81 mg/day, this rate drops to 50%, and with dual therapy of low-dose aspirin plus either low-molecular-weight (LMW) or unfractionated heparin, the risk falls further to 25%, still twice that of the general population.

Thus, the distinction between aPL and APS is key. In addition to its implications for pregnancy outcome, it also guides the duration of anticoagulation following thrombosis. Anticoagulation needs to continue indefinitely in patients with APS because of their high risk of another clotting event. Indeed, patients with APS, if left untreated after a thrombotic event, have a 25% chance of another event within the next year, the rheumatologist noted.

"The diagnosis of APS is actually straightforward, but in patients referred to our lupus clinic from outside I see the term being used pretty fast and loose, and I think it’s somewhat inappropriate to do so. There are many patients with antiphospholipid antibodies who don’t have APS," she continued.

The current diagnostic criteria for APS – the so-called Sydney criteria (J. Thromb. Haemost. 2006;4:295-306) – require both laboratory and clinical findings. The laboratory criteria require a finding of lupus anticoagulant, medium- or high-titer IgG or IgM anticardiolipin antibodies, and/or medium- or high-titer anti-beta2-glycoprotein-1 antibody. The test results need to be positive on two occasions 12 weeks apart, although treatment for presumptive APS can start after tentative diagnosis based upon the first positive test.

To meet the vascular criteria for APS, a patient simply has to have had an arterial, venous, or small vessel thrombosis in any tissue or organ. The pregnancy criteria are more elaborate. To qualify, a woman must have had spontaneous abortions at less than 10 weeks’ gestation in at least three or more consecutive pregnancies, or a second- or third-trimester pregnancy loss of a normal fetus, or premature birth of a morphologically normal fetus before week 34 due to preeclampsia or placental insufficiency.

In women with full-blown APS, antibody titers matter quite a bit in terms of pregnancy outcome. In a study of 51 women with APS who were treated with LMW heparin and aspirin throughout 55 pregnancies, the 20 women with antibody titers greater than four times the upper limit of normal had a 35% rate of delivering an appropriately grown baby after 32 weeks’ gestation. The 35 antibody-positive women with titers less than four times the upper limit of normal had a 77% rate of normal delivery (Acta Obstet. Gynecol. Scand. 2011;90:1428-33).

In women with aPL only, the risk of pregnancy loss may be so low that aspirin isn’t protective. In an intriguing Italian study of 139 pregnancies in 114 women with aPL but not APS, the pregnancy loss rate in 104 pregnancies treated throughout with low-dose aspirin was 7.7%, while in 35 untreated pregnancies the rate was 2.9% (J. Rheumatol. 2013;40:425-9).

"The conclusion here is you can go ahead and use aspirin, but we don’t know that it’s doing a whole lot. Maybe we’re really just treating ourselves," Dr. Clowse mused.

Evidence from the PROMISSE trial, the largest-ever U.S. study of pregnancy loss in lupus patients, points to lupus anticoagulant as the main driver of pregnancy morbidity in patients with aPL. Thirty-nine percent of lupus anticoagulant–positive patients had adverse pregnancy outcomes, compared with just 3% of those without lupus anticoagulant. Unfortunately, treatment with heparin, aspirin, prednisone, or hydroxychloroquine didn’t mitigate the risk (Arthritis Rheum. 2012;64:2311-8).

While pregnancy loss is the biggest concern among most women with APS, it’s important to watch for maternal complications, including early severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and thrombotic events.

"It’s worth talking to the woman before pregnancy and explaining that, unfortunately, pregnancy loss is not necessarily the worst thing that can happen. Her health can also be at risk," Dr. Clowse observed.

In her own practice, everybody with APS goes on aspirin at 81 mg/day throughout pregnancy, even if there has been no prior pregnancy loss. With a history of three or more consecutive pregnancy losses, the treatment is low-dose LMW heparin plus low-dose aspirin. In women with a history of pregnancy loss that doesn’t reach that level, there is no good evidence to provide guidance as to whether to use low-dose LMW heparin plus aspirin or aspirin alone; however, she tends to be more aggressive in women with lupus anticoagulant or very high titers of the other aPLs. Women with a history of thrombosis, whether arterial or venous, are encouraged to remain on full-dose LMW heparin plus low-dose aspirin throughout pregnancy.

Dr. Clowse reported serving as a consultant to UCB.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Whether a woman with antiphospholipid antibodies meets diagnostic criteria for antiphospholipid syndrome makes a huge difference in her risk of pregnancy failure.

Having antiphospholipid antibodies alone confers only a modest increase in the risks of thrombosis and/or pregnancy mishap, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium, sponsored by the American College of Rheumatology.

"You don’t have to jump all over these patients and get them worked up into a tizzy that they’re going to have blood clots or major pregnancy problems if they’ve never had them before," said Dr. Clowse, director of the Duke University Autoimmunity in Pregnancy registry in Durham, N.C.

The published experience indicates that women with antiphospholipid antibodies (aPL) but not antiphospholipid syndrome (APS) have roughly a 15% rate of pregnancy loss in their first pregnancy, not much different than the 11% rate in the general population. In contrast, women with untreated APS have up to a 90% pregnancy loss rate. With aspirin at 81 mg/day, this rate drops to 50%, and with dual therapy of low-dose aspirin plus either low-molecular-weight (LMW) or unfractionated heparin, the risk falls further to 25%, still twice that of the general population.

Thus, the distinction between aPL and APS is key. In addition to its implications for pregnancy outcome, it also guides the duration of anticoagulation following thrombosis. Anticoagulation needs to continue indefinitely in patients with APS because of their high risk of another clotting event. Indeed, patients with APS, if left untreated after a thrombotic event, have a 25% chance of another event within the next year, the rheumatologist noted.

"The diagnosis of APS is actually straightforward, but in patients referred to our lupus clinic from outside I see the term being used pretty fast and loose, and I think it’s somewhat inappropriate to do so. There are many patients with antiphospholipid antibodies who don’t have APS," she continued.

The current diagnostic criteria for APS – the so-called Sydney criteria (J. Thromb. Haemost. 2006;4:295-306) – require both laboratory and clinical findings. The laboratory criteria require a finding of lupus anticoagulant, medium- or high-titer IgG or IgM anticardiolipin antibodies, and/or medium- or high-titer anti-beta2-glycoprotein-1 antibody. The test results need to be positive on two occasions 12 weeks apart, although treatment for presumptive APS can start after tentative diagnosis based upon the first positive test.

To meet the vascular criteria for APS, a patient simply has to have had an arterial, venous, or small vessel thrombosis in any tissue or organ. The pregnancy criteria are more elaborate. To qualify, a woman must have had spontaneous abortions at less than 10 weeks’ gestation in at least three or more consecutive pregnancies, or a second- or third-trimester pregnancy loss of a normal fetus, or premature birth of a morphologically normal fetus before week 34 due to preeclampsia or placental insufficiency.

In women with full-blown APS, antibody titers matter quite a bit in terms of pregnancy outcome. In a study of 51 women with APS who were treated with LMW heparin and aspirin throughout 55 pregnancies, the 20 women with antibody titers greater than four times the upper limit of normal had a 35% rate of delivering an appropriately grown baby after 32 weeks’ gestation. The 35 antibody-positive women with titers less than four times the upper limit of normal had a 77% rate of normal delivery (Acta Obstet. Gynecol. Scand. 2011;90:1428-33).

In women with aPL only, the risk of pregnancy loss may be so low that aspirin isn’t protective. In an intriguing Italian study of 139 pregnancies in 114 women with aPL but not APS, the pregnancy loss rate in 104 pregnancies treated throughout with low-dose aspirin was 7.7%, while in 35 untreated pregnancies the rate was 2.9% (J. Rheumatol. 2013;40:425-9).

"The conclusion here is you can go ahead and use aspirin, but we don’t know that it’s doing a whole lot. Maybe we’re really just treating ourselves," Dr. Clowse mused.

Evidence from the PROMISSE trial, the largest-ever U.S. study of pregnancy loss in lupus patients, points to lupus anticoagulant as the main driver of pregnancy morbidity in patients with aPL. Thirty-nine percent of lupus anticoagulant–positive patients had adverse pregnancy outcomes, compared with just 3% of those without lupus anticoagulant. Unfortunately, treatment with heparin, aspirin, prednisone, or hydroxychloroquine didn’t mitigate the risk (Arthritis Rheum. 2012;64:2311-8).

While pregnancy loss is the biggest concern among most women with APS, it’s important to watch for maternal complications, including early severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and thrombotic events.

"It’s worth talking to the woman before pregnancy and explaining that, unfortunately, pregnancy loss is not necessarily the worst thing that can happen. Her health can also be at risk," Dr. Clowse observed.

In her own practice, everybody with APS goes on aspirin at 81 mg/day throughout pregnancy, even if there has been no prior pregnancy loss. With a history of three or more consecutive pregnancy losses, the treatment is low-dose LMW heparin plus low-dose aspirin. In women with a history of pregnancy loss that doesn’t reach that level, there is no good evidence to provide guidance as to whether to use low-dose LMW heparin plus aspirin or aspirin alone; however, she tends to be more aggressive in women with lupus anticoagulant or very high titers of the other aPLs. Women with a history of thrombosis, whether arterial or venous, are encouraged to remain on full-dose LMW heparin plus low-dose aspirin throughout pregnancy.

Dr. Clowse reported serving as a consultant to UCB.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Mounting circumstantial evidence points to perturbation of bacterial communities in the gut and skin as important environmental triggers for psoriasis and psoriatic arthritis.

A distinctive pattern of alterations in the skin microbiota, termed bacterial "cutaneotypes," has recently been documented in lesional and uninvolved skin of psoriasis patients. Similarly, psoriatic arthritis patients show decreased diversity of their intestinal bacterial community in a pattern similar to patients with inflammatory bowel disease, Dr. Jose U. Scher said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

The current working hypothesis of disease pathogenesis is that, in individuals genetically predisposed to psoriasis or psoriatic arthritis, this microbial dysbiosis at the cutaneous and gut levels provides an environmental trigger for overt expression of clinical disease.

"This dysbiosis is potentially relevant as a diagnostic and/or therapeutic target in psoriasis and psoriatic arthritis. For example, it may eventually become possible to assess the gut microbiota to predict which psoriasis patients will later develop psoriatic arthritis. And reconstituting the gut flora may turn out to have therapeutic benefit. But much more work is needed," explained Dr. Scher, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University.

About 25%-30% of psoriasis patients develop inflammatory psoriatic arthritis, most often roughly 7 years after onset of their skin disease. Genetics clearly plays a role, as shown in a classic Danish twin registry study with more than 21,000 subjects. Fifty-five percent of the siblings of monozygotic twins with psoriatic arthritis had skin psoriasis, but only 10% of the siblings had psoriatic arthritis, as did 3.8% of siblings of dizygotic twins with psoriatic arthritis. The lesser concordance rate seen for psoriatic arthritis hinted at the importance of environmental factors in disease genesis (Ann. Rheum. Dis. 2008;67:1417-21).

Subclinical gut inflammation is common in psoriatic arthritis. In one early study, histologic evidence of mild or moderate gut mucosal inflammation was detected in 45% of a group of psoriatic arthritis patients, compared with 15% of patients with rheumatoid arthritis and 0% of controls (Scand. J. Rheumatol. 1997;26:92-8).

Also, psoriasis patients are at a roughly 3.5-fold increased risk of developing Crohn’s disease. Among patients with established psoriatic arthritis, this risk climbs to 6.5-fold greater than in nonpsoriatic controls (Ann. Rheum. Dis. 2013;72:1200-5).

In a soon-to-be-published study, Dr. Scher and his coworkers have taken the field a step further, employing high-throughput gene sequencing to analyze the gut bacterial communities of psoriatic arthritis patients and controls. These were all new-onset psoriatic arthritis patients who had never been exposed to systemic corticosteroids, biologic agents, or conventional disease-modifying antirheumatic drugs.

Compared with the stool samples of healthy controls, several major bacterial species were underrepresented or absent in the gut microbiota of psoriatic arthritis patients. These included Akkermansia, the most common mucolytic bacterium in healthy subjects. Intriguingly, Akkermansia counts are decreased 15-fold in Crohn’s disease and 92-fold in ulcerative colitis, according to the rheumatologist.

Other bacterial species markedly less abundant in the psoriatic arthritis patients’ gut flora were Ruminoccocus, Alistipes, and Roseburia. Like Akkermansia, these are mucin-degrading bacteria that promote a healthy gut environment, and they, too, are reduced in inflammatory bowel disease, Dr. Scher said.

He theorized that these disruptions of the bacterial ecosystem might arise from a course of antibiotics, a change in diet, or other insults. The result is activation of dendritic cells to produce interleukin-23, which triggers a proinflammatory cascade including tumor necrosis factor-alpha, interleukin-22, and antimicrobial peptides.

As shown by other investigators (Mucosal Immunol. 2013;6:666-77), these proinflammatory cytokines inhibit RANK ligand, which is the critical factor for differentiation of microfold cells in the gut. These microfold cells, or M cells, are specialized epithelial cells that transport antigens across the gut epithelium and play an important role in maintenance of an efficient immune response. It’s plausible that, when these M cells are defective, the resultant loss of tolerance and chronic inflammatory state can result in psoriatic arthritis, he explained.

Dr. Scher’s colleagues at New York University have used high-throughput gene sequencing to analyze the cutaneous microbiota of lesional and nonlesional skin in psoriasis patients, as well as skin samples from the same sites in healthy controls. The impetus for this study was a hypothesis that psoriasis might represent an inappropriate cutaneous immune response directed against offending bacteria in the skin microbiota.

Sure enough, the bacterial community present in psoriatic lesions displayed a markedly decreased diversity, compared with controls. This decreased diversity also was present, albeit to a lesser extent, in the psoriasis patients’ nonlesional skin. Both the lesional and nonlesional skin of psoriasis patients contained an increased abundance of Corynebacterium, Staphylococcus, and Streptococcus, compared with controls.

In addition, the skin microbiota could be classified into one of two characteristic patterns, which the investigators termed "cutaneotypes." Cutaneotype 1, which predominated in the skin of normal controls, contained an abundance of Proteobacteria. In contrast, cutaneotype 2, which was 3.5-fold more prevalent in psoriatic lesions than in controls, was enriched in Firmicutes and Actinobacteria. The psoriatic patients’ nonlesional skin contained a balance of cutaneotypes 1 and 2 (Microbiome 2013 Dec. 23 [doi:10.1186/2049-2618-1-31]).

Dr. Scher said that the next step in his own research is to learn whether the gut microbiota of psoriasis patients differs from that of psoriatic arthritis patients.

"That’s to me the most important piece of data. I think there’s a lot of work to do, and we’re doing it now, in prospective fashion. We’re following patients with psoriasis, and for those who later convert to psoriatic arthritis we’ll want to know if there’s alteration of their bacterial immunity, both in the gut and the skin," he explained.

Dr. Scher reported having no financial conflicts.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Mounting circumstantial evidence points to perturbation of bacterial communities in the gut and skin as important environmental triggers for psoriasis and psoriatic arthritis.

A distinctive pattern of alterations in the skin microbiota, termed bacterial "cutaneotypes," has recently been documented in lesional and uninvolved skin of psoriasis patients. Similarly, psoriatic arthritis patients show decreased diversity of their intestinal bacterial community in a pattern similar to patients with inflammatory bowel disease, Dr. Jose U. Scher said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

The current working hypothesis of disease pathogenesis is that, in individuals genetically predisposed to psoriasis or psoriatic arthritis, this microbial dysbiosis at the cutaneous and gut levels provides an environmental trigger for overt expression of clinical disease.

"This dysbiosis is potentially relevant as a diagnostic and/or therapeutic target in psoriasis and psoriatic arthritis. For example, it may eventually become possible to assess the gut microbiota to predict which psoriasis patients will later develop psoriatic arthritis. And reconstituting the gut flora may turn out to have therapeutic benefit. But much more work is needed," explained Dr. Scher, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University.

About 25%-30% of psoriasis patients develop inflammatory psoriatic arthritis, most often roughly 7 years after onset of their skin disease. Genetics clearly plays a role, as shown in a classic Danish twin registry study with more than 21,000 subjects. Fifty-five percent of the siblings of monozygotic twins with psoriatic arthritis had skin psoriasis, but only 10% of the siblings had psoriatic arthritis, as did 3.8% of siblings of dizygotic twins with psoriatic arthritis. The lesser concordance rate seen for psoriatic arthritis hinted at the importance of environmental factors in disease genesis (Ann. Rheum. Dis. 2008;67:1417-21).

Subclinical gut inflammation is common in psoriatic arthritis. In one early study, histologic evidence of mild or moderate gut mucosal inflammation was detected in 45% of a group of psoriatic arthritis patients, compared with 15% of patients with rheumatoid arthritis and 0% of controls (Scand. J. Rheumatol. 1997;26:92-8).

Also, psoriasis patients are at a roughly 3.5-fold increased risk of developing Crohn’s disease. Among patients with established psoriatic arthritis, this risk climbs to 6.5-fold greater than in nonpsoriatic controls (Ann. Rheum. Dis. 2013;72:1200-5).

In a soon-to-be-published study, Dr. Scher and his coworkers have taken the field a step further, employing high-throughput gene sequencing to analyze the gut bacterial communities of psoriatic arthritis patients and controls. These were all new-onset psoriatic arthritis patients who had never been exposed to systemic corticosteroids, biologic agents, or conventional disease-modifying antirheumatic drugs.

Compared with the stool samples of healthy controls, several major bacterial species were underrepresented or absent in the gut microbiota of psoriatic arthritis patients. These included Akkermansia, the most common mucolytic bacterium in healthy subjects. Intriguingly, Akkermansia counts are decreased 15-fold in Crohn’s disease and 92-fold in ulcerative colitis, according to the rheumatologist.

Other bacterial species markedly less abundant in the psoriatic arthritis patients’ gut flora were Ruminoccocus, Alistipes, and Roseburia. Like Akkermansia, these are mucin-degrading bacteria that promote a healthy gut environment, and they, too, are reduced in inflammatory bowel disease, Dr. Scher said.

He theorized that these disruptions of the bacterial ecosystem might arise from a course of antibiotics, a change in diet, or other insults. The result is activation of dendritic cells to produce interleukin-23, which triggers a proinflammatory cascade including tumor necrosis factor-alpha, interleukin-22, and antimicrobial peptides.

As shown by other investigators (Mucosal Immunol. 2013;6:666-77), these proinflammatory cytokines inhibit RANK ligand, which is the critical factor for differentiation of microfold cells in the gut. These microfold cells, or M cells, are specialized epithelial cells that transport antigens across the gut epithelium and play an important role in maintenance of an efficient immune response. It’s plausible that, when these M cells are defective, the resultant loss of tolerance and chronic inflammatory state can result in psoriatic arthritis, he explained.

Dr. Scher’s colleagues at New York University have used high-throughput gene sequencing to analyze the cutaneous microbiota of lesional and nonlesional skin in psoriasis patients, as well as skin samples from the same sites in healthy controls. The impetus for this study was a hypothesis that psoriasis might represent an inappropriate cutaneous immune response directed against offending bacteria in the skin microbiota.

Sure enough, the bacterial community present in psoriatic lesions displayed a markedly decreased diversity, compared with controls. This decreased diversity also was present, albeit to a lesser extent, in the psoriasis patients’ nonlesional skin. Both the lesional and nonlesional skin of psoriasis patients contained an increased abundance of Corynebacterium, Staphylococcus, and Streptococcus, compared with controls.

In addition, the skin microbiota could be classified into one of two characteristic patterns, which the investigators termed "cutaneotypes." Cutaneotype 1, which predominated in the skin of normal controls, contained an abundance of Proteobacteria. In contrast, cutaneotype 2, which was 3.5-fold more prevalent in psoriatic lesions than in controls, was enriched in Firmicutes and Actinobacteria. The psoriatic patients’ nonlesional skin contained a balance of cutaneotypes 1 and 2 (Microbiome 2013 Dec. 23 [doi:10.1186/2049-2618-1-31]).

Dr. Scher said that the next step in his own research is to learn whether the gut microbiota of psoriasis patients differs from that of psoriatic arthritis patients.

"That’s to me the most important piece of data. I think there’s a lot of work to do, and we’re doing it now, in prospective fashion. We’re following patients with psoriasis, and for those who later convert to psoriatic arthritis we’ll want to know if there’s alteration of their bacterial immunity, both in the gut and the skin," he explained.

Dr. Scher reported having no financial conflicts.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Mounting circumstantial evidence points to perturbation of bacterial communities in the gut and skin as important environmental triggers for psoriasis and psoriatic arthritis.

A distinctive pattern of alterations in the skin microbiota, termed bacterial "cutaneotypes," has recently been documented in lesional and uninvolved skin of psoriasis patients. Similarly, psoriatic arthritis patients show decreased diversity of their intestinal bacterial community in a pattern similar to patients with inflammatory bowel disease, Dr. Jose U. Scher said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

The current working hypothesis of disease pathogenesis is that, in individuals genetically predisposed to psoriasis or psoriatic arthritis, this microbial dysbiosis at the cutaneous and gut levels provides an environmental trigger for overt expression of clinical disease.

"This dysbiosis is potentially relevant as a diagnostic and/or therapeutic target in psoriasis and psoriatic arthritis. For example, it may eventually become possible to assess the gut microbiota to predict which psoriasis patients will later develop psoriatic arthritis. And reconstituting the gut flora may turn out to have therapeutic benefit. But much more work is needed," explained Dr. Scher, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University.

About 25%-30% of psoriasis patients develop inflammatory psoriatic arthritis, most often roughly 7 years after onset of their skin disease. Genetics clearly plays a role, as shown in a classic Danish twin registry study with more than 21,000 subjects. Fifty-five percent of the siblings of monozygotic twins with psoriatic arthritis had skin psoriasis, but only 10% of the siblings had psoriatic arthritis, as did 3.8% of siblings of dizygotic twins with psoriatic arthritis. The lesser concordance rate seen for psoriatic arthritis hinted at the importance of environmental factors in disease genesis (Ann. Rheum. Dis. 2008;67:1417-21).

Subclinical gut inflammation is common in psoriatic arthritis. In one early study, histologic evidence of mild or moderate gut mucosal inflammation was detected in 45% of a group of psoriatic arthritis patients, compared with 15% of patients with rheumatoid arthritis and 0% of controls (Scand. J. Rheumatol. 1997;26:92-8).

Also, psoriasis patients are at a roughly 3.5-fold increased risk of developing Crohn’s disease. Among patients with established psoriatic arthritis, this risk climbs to 6.5-fold greater than in nonpsoriatic controls (Ann. Rheum. Dis. 2013;72:1200-5).

In a soon-to-be-published study, Dr. Scher and his coworkers have taken the field a step further, employing high-throughput gene sequencing to analyze the gut bacterial communities of psoriatic arthritis patients and controls. These were all new-onset psoriatic arthritis patients who had never been exposed to systemic corticosteroids, biologic agents, or conventional disease-modifying antirheumatic drugs.

Compared with the stool samples of healthy controls, several major bacterial species were underrepresented or absent in the gut microbiota of psoriatic arthritis patients. These included Akkermansia, the most common mucolytic bacterium in healthy subjects. Intriguingly, Akkermansia counts are decreased 15-fold in Crohn’s disease and 92-fold in ulcerative colitis, according to the rheumatologist.

Other bacterial species markedly less abundant in the psoriatic arthritis patients’ gut flora were Ruminoccocus, Alistipes, and Roseburia. Like Akkermansia, these are mucin-degrading bacteria that promote a healthy gut environment, and they, too, are reduced in inflammatory bowel disease, Dr. Scher said.

He theorized that these disruptions of the bacterial ecosystem might arise from a course of antibiotics, a change in diet, or other insults. The result is activation of dendritic cells to produce interleukin-23, which triggers a proinflammatory cascade including tumor necrosis factor-alpha, interleukin-22, and antimicrobial peptides.

As shown by other investigators (Mucosal Immunol. 2013;6:666-77), these proinflammatory cytokines inhibit RANK ligand, which is the critical factor for differentiation of microfold cells in the gut. These microfold cells, or M cells, are specialized epithelial cells that transport antigens across the gut epithelium and play an important role in maintenance of an efficient immune response. It’s plausible that, when these M cells are defective, the resultant loss of tolerance and chronic inflammatory state can result in psoriatic arthritis, he explained.

Dr. Scher’s colleagues at New York University have used high-throughput gene sequencing to analyze the cutaneous microbiota of lesional and nonlesional skin in psoriasis patients, as well as skin samples from the same sites in healthy controls. The impetus for this study was a hypothesis that psoriasis might represent an inappropriate cutaneous immune response directed against offending bacteria in the skin microbiota.

Sure enough, the bacterial community present in psoriatic lesions displayed a markedly decreased diversity, compared with controls. This decreased diversity also was present, albeit to a lesser extent, in the psoriasis patients’ nonlesional skin. Both the lesional and nonlesional skin of psoriasis patients contained an increased abundance of Corynebacterium, Staphylococcus, and Streptococcus, compared with controls.

In addition, the skin microbiota could be classified into one of two characteristic patterns, which the investigators termed "cutaneotypes." Cutaneotype 1, which predominated in the skin of normal controls, contained an abundance of Proteobacteria. In contrast, cutaneotype 2, which was 3.5-fold more prevalent in psoriatic lesions than in controls, was enriched in Firmicutes and Actinobacteria. The psoriatic patients’ nonlesional skin contained a balance of cutaneotypes 1 and 2 (Microbiome 2013 Dec. 23 [doi:10.1186/2049-2618-1-31]).

Dr. Scher said that the next step in his own research is to learn whether the gut microbiota of psoriasis patients differs from that of psoriatic arthritis patients.

"That’s to me the most important piece of data. I think there’s a lot of work to do, and we’re doing it now, in prospective fashion. We’re following patients with psoriasis, and for those who later convert to psoriatic arthritis we’ll want to know if there’s alteration of their bacterial immunity, both in the gut and the skin," he explained.

Dr. Scher reported having no financial conflicts.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The prospect of preventing fetal heart block from neonatal lupus by using hydroxychloroquine to treat women with systemic lupus erythematosus and other anti-Ro antibody-positive rheumatologic diseases throughout pregnancy is drawing mounting physician interest.

"I think these new data are exciting. I actually now have changed my practice as a result of these two studies. I don’t think these studies demand that everybody else change what they’re doing, but I now give hydroxychloroquine to our pregnant patients who have anti-Ro antibodies," Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Maternal anti-Ro antibodies readily transfer across the placenta starting at about week 16 of gestation. Roughly 2% of fetuses whose mothers are positive for these antibodies develop congenital complete heart block caused by inflammation at the atrioventricular node. It’s an irreversible condition with significant morbidity and even mortality.

Moreover, if the mother has previously given birth to a baby with any manifestation of neonatal lupus – even if limited to neonatal rash – the risk of congenital complete heart block in subsequent pregnancies climbs to about 15%, according to Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C.

She and her coinvestigators at Duke conducted one of the two studies that have led to her change in practice. It was a retrospective observational study of the recent Duke experience with pregnancies complicated by the presence of maternal anti-Ro antibodies. Twenty of the 33 subjects had systemic lupus erythematosus (SLE); most of the rest had unspecified rheumatologic disease or Sjögren’s syndrome.

Only 1 of 14 women treated with 200-400 mg/day of hydroxychloroquine throughout pregnancy had a baby with congenital heart block, while 7 of 19 pregnancies where hydroxychloroquine wasn’t prescribed resulted in this fetal cardiac disorder. This translated into an 86% relative risk reduction of fetal congenital complete heart block in hydroxychloroquine recipients (Am. J. Obstet. Gynecol. 2013;208:64.e1-7).

Dr. Clowse noted that the Duke study confirms a recent report by investigators at New York University, who searched three databases in the United States, France, and England and identified 257 pregnancies involving mothers positive for anti-Ro antibodies, all of whom had previously given birth to a child with cardiac neonatal lupus. Forty of the women were on hydroxychloroquine starting before 10 weeks of gestation and continued throughout pregnancy; the other 217 didn’t take hydroxychloroquine during the pregnancy. The incidence of recurrent neonatal congenital heart block was 7.5% in the hydroxychloroquine group, compared with 21.2% in mothers who didn’t receive the drug, for a 77% relative risk reduction (Circulation 2012;126:76-82).

The New York University researchers are in the midst of a confirmatory prospective nonrandomized study in women with a history of pregnancy complicated by fetal complete heart block who are on hydroxychloroquine in a subsequent pregnancy. But because it will probably take several more years to accumulate sufficient pregnancies to draw statistically significant conclusions, and in light of hydroxychloroquine’s favorable risk: benefit ratio in pregnancy, Dr. Clowse has decided to change her own practice.

Hydroxychloroquine is rated Pregnancy Class C by the Food and Drug Administration. It readily crosses the placenta. It has not been associated with pregnancy loss, prematurity, congenital anomalies, or any other adverse fetal effects. Dr. Clowse considers hydroxychloroquine to be the best medication for prevention of SLE flares in pregnancy.

She reported serving as a consultant to UCB.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The prospect of preventing fetal heart block from neonatal lupus by using hydroxychloroquine to treat women with systemic lupus erythematosus and other anti-Ro antibody-positive rheumatologic diseases throughout pregnancy is drawing mounting physician interest.

"I think these new data are exciting. I actually now have changed my practice as a result of these two studies. I don’t think these studies demand that everybody else change what they’re doing, but I now give hydroxychloroquine to our pregnant patients who have anti-Ro antibodies," Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Maternal anti-Ro antibodies readily transfer across the placenta starting at about week 16 of gestation. Roughly 2% of fetuses whose mothers are positive for these antibodies develop congenital complete heart block caused by inflammation at the atrioventricular node. It’s an irreversible condition with significant morbidity and even mortality.

Moreover, if the mother has previously given birth to a baby with any manifestation of neonatal lupus – even if limited to neonatal rash – the risk of congenital complete heart block in subsequent pregnancies climbs to about 15%, according to Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C.

She and her coinvestigators at Duke conducted one of the two studies that have led to her change in practice. It was a retrospective observational study of the recent Duke experience with pregnancies complicated by the presence of maternal anti-Ro antibodies. Twenty of the 33 subjects had systemic lupus erythematosus (SLE); most of the rest had unspecified rheumatologic disease or Sjögren’s syndrome.

Only 1 of 14 women treated with 200-400 mg/day of hydroxychloroquine throughout pregnancy had a baby with congenital heart block, while 7 of 19 pregnancies where hydroxychloroquine wasn’t prescribed resulted in this fetal cardiac disorder. This translated into an 86% relative risk reduction of fetal congenital complete heart block in hydroxychloroquine recipients (Am. J. Obstet. Gynecol. 2013;208:64.e1-7).

Dr. Clowse noted that the Duke study confirms a recent report by investigators at New York University, who searched three databases in the United States, France, and England and identified 257 pregnancies involving mothers positive for anti-Ro antibodies, all of whom had previously given birth to a child with cardiac neonatal lupus. Forty of the women were on hydroxychloroquine starting before 10 weeks of gestation and continued throughout pregnancy; the other 217 didn’t take hydroxychloroquine during the pregnancy. The incidence of recurrent neonatal congenital heart block was 7.5% in the hydroxychloroquine group, compared with 21.2% in mothers who didn’t receive the drug, for a 77% relative risk reduction (Circulation 2012;126:76-82).

The New York University researchers are in the midst of a confirmatory prospective nonrandomized study in women with a history of pregnancy complicated by fetal complete heart block who are on hydroxychloroquine in a subsequent pregnancy. But because it will probably take several more years to accumulate sufficient pregnancies to draw statistically significant conclusions, and in light of hydroxychloroquine’s favorable risk: benefit ratio in pregnancy, Dr. Clowse has decided to change her own practice.

Hydroxychloroquine is rated Pregnancy Class C by the Food and Drug Administration. It readily crosses the placenta. It has not been associated with pregnancy loss, prematurity, congenital anomalies, or any other adverse fetal effects. Dr. Clowse considers hydroxychloroquine to be the best medication for prevention of SLE flares in pregnancy.

She reported serving as a consultant to UCB.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The prospect of preventing fetal heart block from neonatal lupus by using hydroxychloroquine to treat women with systemic lupus erythematosus and other anti-Ro antibody-positive rheumatologic diseases throughout pregnancy is drawing mounting physician interest.

"I think these new data are exciting. I actually now have changed my practice as a result of these two studies. I don’t think these studies demand that everybody else change what they’re doing, but I now give hydroxychloroquine to our pregnant patients who have anti-Ro antibodies," Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Maternal anti-Ro antibodies readily transfer across the placenta starting at about week 16 of gestation. Roughly 2% of fetuses whose mothers are positive for these antibodies develop congenital complete heart block caused by inflammation at the atrioventricular node. It’s an irreversible condition with significant morbidity and even mortality.

Moreover, if the mother has previously given birth to a baby with any manifestation of neonatal lupus – even if limited to neonatal rash – the risk of congenital complete heart block in subsequent pregnancies climbs to about 15%, according to Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C.

She and her coinvestigators at Duke conducted one of the two studies that have led to her change in practice. It was a retrospective observational study of the recent Duke experience with pregnancies complicated by the presence of maternal anti-Ro antibodies. Twenty of the 33 subjects had systemic lupus erythematosus (SLE); most of the rest had unspecified rheumatologic disease or Sjögren’s syndrome.

Only 1 of 14 women treated with 200-400 mg/day of hydroxychloroquine throughout pregnancy had a baby with congenital heart block, while 7 of 19 pregnancies where hydroxychloroquine wasn’t prescribed resulted in this fetal cardiac disorder. This translated into an 86% relative risk reduction of fetal congenital complete heart block in hydroxychloroquine recipients (Am. J. Obstet. Gynecol. 2013;208:64.e1-7).

Dr. Clowse noted that the Duke study confirms a recent report by investigators at New York University, who searched three databases in the United States, France, and England and identified 257 pregnancies involving mothers positive for anti-Ro antibodies, all of whom had previously given birth to a child with cardiac neonatal lupus. Forty of the women were on hydroxychloroquine starting before 10 weeks of gestation and continued throughout pregnancy; the other 217 didn’t take hydroxychloroquine during the pregnancy. The incidence of recurrent neonatal congenital heart block was 7.5% in the hydroxychloroquine group, compared with 21.2% in mothers who didn’t receive the drug, for a 77% relative risk reduction (Circulation 2012;126:76-82).

The New York University researchers are in the midst of a confirmatory prospective nonrandomized study in women with a history of pregnancy complicated by fetal complete heart block who are on hydroxychloroquine in a subsequent pregnancy. But because it will probably take several more years to accumulate sufficient pregnancies to draw statistically significant conclusions, and in light of hydroxychloroquine’s favorable risk: benefit ratio in pregnancy, Dr. Clowse has decided to change her own practice.

Hydroxychloroquine is rated Pregnancy Class C by the Food and Drug Administration. It readily crosses the placenta. It has not been associated with pregnancy loss, prematurity, congenital anomalies, or any other adverse fetal effects. Dr. Clowse considers hydroxychloroquine to be the best medication for prevention of SLE flares in pregnancy.

She reported serving as a consultant to UCB.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.

"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.

Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.

The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).

The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).

Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.

In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).

Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.

Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.

"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.

Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.

The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).

The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).

Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.

In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).

Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.

Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.

"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.

Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.

The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).

The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).

Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.

In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).

Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.

Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.

It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).

"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.

Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.

"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.

Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.

"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.

"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.

Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.

Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.

"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.

Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.

Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.

"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.

There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.

"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.

Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.

It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).

"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.

Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.

"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.

Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.

"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.

"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.

Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.

Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.

"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.

Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.

Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.

"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.

There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.

"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.

Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.

It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).

"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.

Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.

"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.

Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.

"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.

"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.

Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.

Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.

"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.

Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.

Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.

"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.

There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.

"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.

Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Most rheumatologists view their patients’ vaccination status as a matter within the sphere of primary care medicine, but payers and health policy makers see things otherwise.

"You and I will soon be judged as to whether we’re good rheumatologists on the basis of whether our patients have gotten vaccinated, with almost complete certainty in my mind. This as a quality measure – ‘Are your patients getting vaccinated?’ – is undergoing measure-specification testing now by the American College of Rheumatology," Dr. Jeffrey R. Curtis said at the Winter Rheumatology Symposium sponsored by the ACR.

Flu, pneumococcal, HPV vaccines underused

Vaccination rates in patients with rheumatic diseases are unacceptably low, as highlighted in a study by Dr. Curtis and coinvestigators. They looked retrospectively at vaccination rates over a 5-year period in 141,140 rheumatoid arthritis (RA) patients, 6,300 others with psoriatic arthritis, and 770,520 osteoarthritis patients. Only 19%-22% of patients in the three groups received the influenza vaccine in all 5 years, and 29%-33% were vaccinated against pneumococcus.

Patients with RA or systemic lupus erythematosus (SLE) have been shown to be at 1.5-fold increased risk of high-grade cervical dysplasia, compared with the general population, yet less than 14% of females and less than 1% of males with autoimmune diseases have received the three-dose recombinant human papillomavirus (HPV) vaccine, as reported by Dr. Seoyoung C. Kim of Brigham and Women’s Hospital, Boston, and coworkers at the ACR 2013 annual meeting.

"My point is that we keep seeing this recurring theme: Our patients are at higher risk for infections and cervical cancer, we have vaccines that work to prevent those things, but we’re not using them and in most cases neither is primary care," said Dr. Curtis, director of the arthritis clinical intervention program and associate director of the Center for Education and Research on Therapeutics of Musculoskeletal Disorders at the University of Alabama, Birmingham.

"Regardless of whether you say this is a primary care thing and work with primary care to make sure it gets done, or you help enfranchise patients so they take control over this, or you’re going to do it your own self, you and I are going to be judged on this. It will be part of the new quality measures. This is happening," he emphasized.

One strategy Dr. Curtis said has been shown to be "reasonably effective" in several studies is to delegate responsibility for vaccinations to a mid-level practitioner, not on a patient-by-patient basis, but for the whole rheumatology practice.

Most studies indicate that long-term efficacy of vaccines is generally adequate in patients on methotrexate and/or biologics, albeit not as good as in the general population. The exception is rituximab (Rituxan): Patients on this drug have a greatly diminished humoral response to the PPSV-23 pneumococcal vaccine (Pneumovax) as well as to trivalent influenza vaccine. However, Dutch investigators showed that while the humoral response was seriously reduced in RA patients who got the flu vaccine 4-8 weeks after receiving rituximab, the immune response was modestly better when patients got the vaccine 6-10 months post rituximab (Arthritis Rheum. 2010;62:75-81).

"It matters when you got rituximab. If a patient got it a month or two ago, I wouldn’t bother vaccinating against influenza. Patients will have no response. But if it has been 6 or more months, it probably is worth doing," Dr. Curtis said.

Herpes zoster vaccination

RA patients are at 1.5- to 2-fold increased risk for herpes zoster, compared with the age-matched general population. The risk in lupus patients is even greater. Yet very few patients with these diseases get the live-virus herpes zoster vaccine.

The jury is still out as to whether anti–tumor necrosis factor therapies further raise that risk; the evidence is mixed. However, a particularly large study conducted by Dr. Curtis and coworkers in 24,000 older RA patients who were new users of anti-TNF biologics and nearly 12,000 who were new users of methotrexate and other nonbiologic DMARDs found that the rate of herpes zoster in the new users was 12.6 cases per 1,000 person-years, no higher than in those starting on nonbiologic DMARDs (JAMA 2013;309:887-95).

In contrast, a consistent finding in multiple studies is that the risk of herpes zoster is nearly twofold greater in RA patients receiving prednisone at greater than 7.5-10 mg/day. For example, the JAMA study by Dr. Curtis and coinvestigators found that baseline use of prednisone at more than 10 mg/day was independently associated with a 1.87-fold increased risk of zoster.

Tofacitinib (Xeljanz) clearly confers an increased risk of herpes zoster. At last fall’s annual ACR meeting, Dr. Curtis presented highlights of the worldwide clinical trial experience with tofacitinib in RA, totaling five phase III and six phase II randomized trials as well as two long-term extension studies. Tofacitinib was associated with a herpes zoster rate of 40-50 cases per 1,000 person-years, which is more than threefold higher than the rate with any anti-TNF agent.

"I think from a clinical perspective this definitely needs to be on our radar screen. Hopefully it makes the case that vaccination with the live-virus zoster vaccine, Zostavax, is compelling. I suspect that it’s not tofacitinib in particular, because early data for some of the other janus kinase inhibitors has suggested this problem is a class effect," Dr. Curtis said.

In vaccinating patients with RA and other rheumatic diseases, the recommended approach is whenever possible to give the vaccines before starting methotrexate or a biologic agent. That’s going to result in the greatest possible protection. The humoral response won’t be as robust if vaccines are given to patients already on treatment, but it’s still probably worth doing, except if they’ve recently received rituximab, he continued.

Vaccination guidelines not necessarily correct

Dr. Curtis cautioned that the major guidelines regarding vaccination of adults with rheumatic diseases should not automatically be taken as truth. For example, the ACR recommends against giving the live-virus herpes zoster vaccine to patients who are taking a biologic agent (Arthritis Care Res. 2012;64:625-39). But the European League Against Rheumatism (EULAR) guidelines state that the vaccine "may be considered" in such patients (Ann. Rheum. Dis. 2011;70:414-22).

Consistent with the EULAR stance, a study conducted by Dr. Curtis and coworkers in more than 463,000 elderly patients with RA or one of four other autoimmune diseases found that no safety issues arose in patients who were given the herpes zoster vaccine while on a TNF antagonist, a non-TNF biologic, or a nonbiologic DMARD. Moreover, the vaccine’s protective effect in RA patients on an anti-TNF biologic was similar to that seen in individuals without RA, with a 39% relative risk reduction, compared with unvaccinated individuals (JAMA 2012;308:43-9).

Here’s another point of contention regarding major practice guidelines: Recommendations from the Centers for Disease Control and Prevention state that glucocorticoid therapy is not a contraindication to administering live-virus vaccine to immunocompromised patients provided they are on low- to moderate-dose prednisone, which the CDC defines as less than 20 mg/day of prednisone for less than 14 days. Dr. Curtis disagrees.

"I consider 15 mg of prednisone more immunosuppressive than the biologics that we give," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Most rheumatologists view their patients’ vaccination status as a matter within the sphere of primary care medicine, but payers and health policy makers see things otherwise.

"You and I will soon be judged as to whether we’re good rheumatologists on the basis of whether our patients have gotten vaccinated, with almost complete certainty in my mind. This as a quality measure – ‘Are your patients getting vaccinated?’ – is undergoing measure-specification testing now by the American College of Rheumatology," Dr. Jeffrey R. Curtis said at the Winter Rheumatology Symposium sponsored by the ACR.

Flu, pneumococcal, HPV vaccines underused

Vaccination rates in patients with rheumatic diseases are unacceptably low, as highlighted in a study by Dr. Curtis and coinvestigators. They looked retrospectively at vaccination rates over a 5-year period in 141,140 rheumatoid arthritis (RA) patients, 6,300 others with psoriatic arthritis, and 770,520 osteoarthritis patients. Only 19%-22% of patients in the three groups received the influenza vaccine in all 5 years, and 29%-33% were vaccinated against pneumococcus.

Patients with RA or systemic lupus erythematosus (SLE) have been shown to be at 1.5-fold increased risk of high-grade cervical dysplasia, compared with the general population, yet less than 14% of females and less than 1% of males with autoimmune diseases have received the three-dose recombinant human papillomavirus (HPV) vaccine, as reported by Dr. Seoyoung C. Kim of Brigham and Women’s Hospital, Boston, and coworkers at the ACR 2013 annual meeting.

"My point is that we keep seeing this recurring theme: Our patients are at higher risk for infections and cervical cancer, we have vaccines that work to prevent those things, but we’re not using them and in most cases neither is primary care," said Dr. Curtis, director of the arthritis clinical intervention program and associate director of the Center for Education and Research on Therapeutics of Musculoskeletal Disorders at the University of Alabama, Birmingham.

"Regardless of whether you say this is a primary care thing and work with primary care to make sure it gets done, or you help enfranchise patients so they take control over this, or you’re going to do it your own self, you and I are going to be judged on this. It will be part of the new quality measures. This is happening," he emphasized.

One strategy Dr. Curtis said has been shown to be "reasonably effective" in several studies is to delegate responsibility for vaccinations to a mid-level practitioner, not on a patient-by-patient basis, but for the whole rheumatology practice.

Most studies indicate that long-term efficacy of vaccines is generally adequate in patients on methotrexate and/or biologics, albeit not as good as in the general population. The exception is rituximab (Rituxan): Patients on this drug have a greatly diminished humoral response to the PPSV-23 pneumococcal vaccine (Pneumovax) as well as to trivalent influenza vaccine. However, Dutch investigators showed that while the humoral response was seriously reduced in RA patients who got the flu vaccine 4-8 weeks after receiving rituximab, the immune response was modestly better when patients got the vaccine 6-10 months post rituximab (Arthritis Rheum. 2010;62:75-81).

"It matters when you got rituximab. If a patient got it a month or two ago, I wouldn’t bother vaccinating against influenza. Patients will have no response. But if it has been 6 or more months, it probably is worth doing," Dr. Curtis said.

Herpes zoster vaccination

RA patients are at 1.5- to 2-fold increased risk for herpes zoster, compared with the age-matched general population. The risk in lupus patients is even greater. Yet very few patients with these diseases get the live-virus herpes zoster vaccine.

The jury is still out as to whether anti–tumor necrosis factor therapies further raise that risk; the evidence is mixed. However, a particularly large study conducted by Dr. Curtis and coworkers in 24,000 older RA patients who were new users of anti-TNF biologics and nearly 12,000 who were new users of methotrexate and other nonbiologic DMARDs found that the rate of herpes zoster in the new users was 12.6 cases per 1,000 person-years, no higher than in those starting on nonbiologic DMARDs (JAMA 2013;309:887-95).

In contrast, a consistent finding in multiple studies is that the risk of herpes zoster is nearly twofold greater in RA patients receiving prednisone at greater than 7.5-10 mg/day. For example, the JAMA study by Dr. Curtis and coinvestigators found that baseline use of prednisone at more than 10 mg/day was independently associated with a 1.87-fold increased risk of zoster.

Tofacitinib (Xeljanz) clearly confers an increased risk of herpes zoster. At last fall’s annual ACR meeting, Dr. Curtis presented highlights of the worldwide clinical trial experience with tofacitinib in RA, totaling five phase III and six phase II randomized trials as well as two long-term extension studies. Tofacitinib was associated with a herpes zoster rate of 40-50 cases per 1,000 person-years, which is more than threefold higher than the rate with any anti-TNF agent.

"I think from a clinical perspective this definitely needs to be on our radar screen. Hopefully it makes the case that vaccination with the live-virus zoster vaccine, Zostavax, is compelling. I suspect that it’s not tofacitinib in particular, because early data for some of the other janus kinase inhibitors has suggested this problem is a class effect," Dr. Curtis said.

In vaccinating patients with RA and other rheumatic diseases, the recommended approach is whenever possible to give the vaccines before starting methotrexate or a biologic agent. That’s going to result in the greatest possible protection. The humoral response won’t be as robust if vaccines are given to patients already on treatment, but it’s still probably worth doing, except if they’ve recently received rituximab, he continued.

Vaccination guidelines not necessarily correct

Dr. Curtis cautioned that the major guidelines regarding vaccination of adults with rheumatic diseases should not automatically be taken as truth. For example, the ACR recommends against giving the live-virus herpes zoster vaccine to patients who are taking a biologic agent (Arthritis Care Res. 2012;64:625-39). But the European League Against Rheumatism (EULAR) guidelines state that the vaccine "may be considered" in such patients (Ann. Rheum. Dis. 2011;70:414-22).

Consistent with the EULAR stance, a study conducted by Dr. Curtis and coworkers in more than 463,000 elderly patients with RA or one of four other autoimmune diseases found that no safety issues arose in patients who were given the herpes zoster vaccine while on a TNF antagonist, a non-TNF biologic, or a nonbiologic DMARD. Moreover, the vaccine’s protective effect in RA patients on an anti-TNF biologic was similar to that seen in individuals without RA, with a 39% relative risk reduction, compared with unvaccinated individuals (JAMA 2012;308:43-9).

Here’s another point of contention regarding major practice guidelines: Recommendations from the Centers for Disease Control and Prevention state that glucocorticoid therapy is not a contraindication to administering live-virus vaccine to immunocompromised patients provided they are on low- to moderate-dose prednisone, which the CDC defines as less than 20 mg/day of prednisone for less than 14 days. Dr. Curtis disagrees.

"I consider 15 mg of prednisone more immunosuppressive than the biologics that we give," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – Most rheumatologists view their patients’ vaccination status as a matter within the sphere of primary care medicine, but payers and health policy makers see things otherwise.

"You and I will soon be judged as to whether we’re good rheumatologists on the basis of whether our patients have gotten vaccinated, with almost complete certainty in my mind. This as a quality measure – ‘Are your patients getting vaccinated?’ – is undergoing measure-specification testing now by the American College of Rheumatology," Dr. Jeffrey R. Curtis said at the Winter Rheumatology Symposium sponsored by the ACR.

Flu, pneumococcal, HPV vaccines underused

Vaccination rates in patients with rheumatic diseases are unacceptably low, as highlighted in a study by Dr. Curtis and coinvestigators. They looked retrospectively at vaccination rates over a 5-year period in 141,140 rheumatoid arthritis (RA) patients, 6,300 others with psoriatic arthritis, and 770,520 osteoarthritis patients. Only 19%-22% of patients in the three groups received the influenza vaccine in all 5 years, and 29%-33% were vaccinated against pneumococcus.

Patients with RA or systemic lupus erythematosus (SLE) have been shown to be at 1.5-fold increased risk of high-grade cervical dysplasia, compared with the general population, yet less than 14% of females and less than 1% of males with autoimmune diseases have received the three-dose recombinant human papillomavirus (HPV) vaccine, as reported by Dr. Seoyoung C. Kim of Brigham and Women’s Hospital, Boston, and coworkers at the ACR 2013 annual meeting.

"My point is that we keep seeing this recurring theme: Our patients are at higher risk for infections and cervical cancer, we have vaccines that work to prevent those things, but we’re not using them and in most cases neither is primary care," said Dr. Curtis, director of the arthritis clinical intervention program and associate director of the Center for Education and Research on Therapeutics of Musculoskeletal Disorders at the University of Alabama, Birmingham.

"Regardless of whether you say this is a primary care thing and work with primary care to make sure it gets done, or you help enfranchise patients so they take control over this, or you’re going to do it your own self, you and I are going to be judged on this. It will be part of the new quality measures. This is happening," he emphasized.

One strategy Dr. Curtis said has been shown to be "reasonably effective" in several studies is to delegate responsibility for vaccinations to a mid-level practitioner, not on a patient-by-patient basis, but for the whole rheumatology practice.

Most studies indicate that long-term efficacy of vaccines is generally adequate in patients on methotrexate and/or biologics, albeit not as good as in the general population. The exception is rituximab (Rituxan): Patients on this drug have a greatly diminished humoral response to the PPSV-23 pneumococcal vaccine (Pneumovax) as well as to trivalent influenza vaccine. However, Dutch investigators showed that while the humoral response was seriously reduced in RA patients who got the flu vaccine 4-8 weeks after receiving rituximab, the immune response was modestly better when patients got the vaccine 6-10 months post rituximab (Arthritis Rheum. 2010;62:75-81).

"It matters when you got rituximab. If a patient got it a month or two ago, I wouldn’t bother vaccinating against influenza. Patients will have no response. But if it has been 6 or more months, it probably is worth doing," Dr. Curtis said.

Herpes zoster vaccination

RA patients are at 1.5- to 2-fold increased risk for herpes zoster, compared with the age-matched general population. The risk in lupus patients is even greater. Yet very few patients with these diseases get the live-virus herpes zoster vaccine.

The jury is still out as to whether anti–tumor necrosis factor therapies further raise that risk; the evidence is mixed. However, a particularly large study conducted by Dr. Curtis and coworkers in 24,000 older RA patients who were new users of anti-TNF biologics and nearly 12,000 who were new users of methotrexate and other nonbiologic DMARDs found that the rate of herpes zoster in the new users was 12.6 cases per 1,000 person-years, no higher than in those starting on nonbiologic DMARDs (JAMA 2013;309:887-95).

In contrast, a consistent finding in multiple studies is that the risk of herpes zoster is nearly twofold greater in RA patients receiving prednisone at greater than 7.5-10 mg/day. For example, the JAMA study by Dr. Curtis and coinvestigators found that baseline use of prednisone at more than 10 mg/day was independently associated with a 1.87-fold increased risk of zoster.

Tofacitinib (Xeljanz) clearly confers an increased risk of herpes zoster. At last fall’s annual ACR meeting, Dr. Curtis presented highlights of the worldwide clinical trial experience with tofacitinib in RA, totaling five phase III and six phase II randomized trials as well as two long-term extension studies. Tofacitinib was associated with a herpes zoster rate of 40-50 cases per 1,000 person-years, which is more than threefold higher than the rate with any anti-TNF agent.

"I think from a clinical perspective this definitely needs to be on our radar screen. Hopefully it makes the case that vaccination with the live-virus zoster vaccine, Zostavax, is compelling. I suspect that it’s not tofacitinib in particular, because early data for some of the other janus kinase inhibitors has suggested this problem is a class effect," Dr. Curtis said.

In vaccinating patients with RA and other rheumatic diseases, the recommended approach is whenever possible to give the vaccines before starting methotrexate or a biologic agent. That’s going to result in the greatest possible protection. The humoral response won’t be as robust if vaccines are given to patients already on treatment, but it’s still probably worth doing, except if they’ve recently received rituximab, he continued.

Vaccination guidelines not necessarily correct

Dr. Curtis cautioned that the major guidelines regarding vaccination of adults with rheumatic diseases should not automatically be taken as truth. For example, the ACR recommends against giving the live-virus herpes zoster vaccine to patients who are taking a biologic agent (Arthritis Care Res. 2012;64:625-39). But the European League Against Rheumatism (EULAR) guidelines state that the vaccine "may be considered" in such patients (Ann. Rheum. Dis. 2011;70:414-22).

Consistent with the EULAR stance, a study conducted by Dr. Curtis and coworkers in more than 463,000 elderly patients with RA or one of four other autoimmune diseases found that no safety issues arose in patients who were given the herpes zoster vaccine while on a TNF antagonist, a non-TNF biologic, or a nonbiologic DMARD. Moreover, the vaccine’s protective effect in RA patients on an anti-TNF biologic was similar to that seen in individuals without RA, with a 39% relative risk reduction, compared with unvaccinated individuals (JAMA 2012;308:43-9).

Here’s another point of contention regarding major practice guidelines: Recommendations from the Centers for Disease Control and Prevention state that glucocorticoid therapy is not a contraindication to administering live-virus vaccine to immunocompromised patients provided they are on low- to moderate-dose prednisone, which the CDC defines as less than 20 mg/day of prednisone for less than 14 days. Dr. Curtis disagrees.

"I consider 15 mg of prednisone more immunosuppressive than the biologics that we give," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The use of anti–tumor necrosis factor biologics in patients with rheumatoid arthritis, psoriasis, and other serious autoimmune diseases is not associated with increased risk of most forms of cancer, with two highly visible and important exceptions: nonmelanoma skin cancer and malignant melanoma.

That’s the largely reassuring conclusion to be drawn from two large studies conducted by researchers at Stockholm’s Karolinska Institute, according to Dr. Jeffrey R. Curtis, director of the arthritis clinical intervention program at the University of Alabama, Birmingham.

The Swedish group conducted a comprehensive meta-analysis of all 74 pharmaceutical company–sponsored randomized controlled trials of anti-TNF biologics lasting at least 4 weeks. The investigators used individual patient data for 15,418 anti-TNF recipients and 7,486 subjects randomized to methotrexate and other comparators. About half of the randomized trials focused on rheumatoid arthritis (RA) patients; the other half involved patients with the other approved indications for anti-TNF therapy.

The use of individual patient data was a nuance of the meta-analysis that wowed Dr. Curtis.

"This is a really great paper. One of the reasons I was very impressed with it is that getting drug companies to give up any raw person-level data to anybody is difficult. The European Medicines Agency requested it, and that’s probably the only reason it happened," Dr. Curtis observed at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The overall relative risk for all forms of cancer, excluding nonmelanoma skin cancer, in patients on anti-TNF biologics was 0.99. Their cancer rate was 641 per 100,000 person-years (Pharmacoepidemiol. Drug Saf. 2011;20:119-30).

"You can tell your patients the risk for cancer is less than 1 in 100 – it’s about 6 per 1,000 – and it’s not increased compared to background therapy," the rheumatologist said.

The exception was nonmelanoma skin cancer. The relative risk for this malignancy among users of all anti-TNF biologics was increased twofold.

In a separate study, the same group used prospectively recorded data from Swedish national registries to investigate the association between anti-TNF therapy and melanoma. This analysis involved 10,878 RA patients treated with anti-TNF biologics, 42,198 others who were not, and 162,743 matched controls from the general population.

Compared with controls, RA patients not on anti-TNF biologics did not have a significantly increased risk of malignant melanoma. However, the 38 first invasive melanomas that occurred in RA patients taking a TNF antagonist signified a 1.5-fold increased risk of this malignancy compared to the general population. This 50% increase in relative risk was statistically significant. The absolute increase in risk was quite small: 20 additional cases per 100,000 person-years. The number needed to harm – that is, the number of patients who needed to be treated with an anti-TNF biologic to cause one additional case of melanoma – was 50,000 (BMJ 2013;346:f1939 [doi: 10.1136/bmj.f1939]).

Dr. Curtis noted that patients who have been urged to consider going on a TNF antagonist often return to the office waving a printout of the product labeling that warns of the possibility of malignancy.

"The bottom line: I tell patients that based on the data that there doesn’t appear to be an increased risk for all types of cancer, including hematologic, with the exceptions of nonmelanoma skin cancer and melanoma. Those are the two we need to advise patients about," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The use of anti–tumor necrosis factor biologics in patients with rheumatoid arthritis, psoriasis, and other serious autoimmune diseases is not associated with increased risk of most forms of cancer, with two highly visible and important exceptions: nonmelanoma skin cancer and malignant melanoma.

That’s the largely reassuring conclusion to be drawn from two large studies conducted by researchers at Stockholm’s Karolinska Institute, according to Dr. Jeffrey R. Curtis, director of the arthritis clinical intervention program at the University of Alabama, Birmingham.

The Swedish group conducted a comprehensive meta-analysis of all 74 pharmaceutical company–sponsored randomized controlled trials of anti-TNF biologics lasting at least 4 weeks. The investigators used individual patient data for 15,418 anti-TNF recipients and 7,486 subjects randomized to methotrexate and other comparators. About half of the randomized trials focused on rheumatoid arthritis (RA) patients; the other half involved patients with the other approved indications for anti-TNF therapy.

The use of individual patient data was a nuance of the meta-analysis that wowed Dr. Curtis.

"This is a really great paper. One of the reasons I was very impressed with it is that getting drug companies to give up any raw person-level data to anybody is difficult. The European Medicines Agency requested it, and that’s probably the only reason it happened," Dr. Curtis observed at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The overall relative risk for all forms of cancer, excluding nonmelanoma skin cancer, in patients on anti-TNF biologics was 0.99. Their cancer rate was 641 per 100,000 person-years (Pharmacoepidemiol. Drug Saf. 2011;20:119-30).

"You can tell your patients the risk for cancer is less than 1 in 100 – it’s about 6 per 1,000 – and it’s not increased compared to background therapy," the rheumatologist said.

The exception was nonmelanoma skin cancer. The relative risk for this malignancy among users of all anti-TNF biologics was increased twofold.

In a separate study, the same group used prospectively recorded data from Swedish national registries to investigate the association between anti-TNF therapy and melanoma. This analysis involved 10,878 RA patients treated with anti-TNF biologics, 42,198 others who were not, and 162,743 matched controls from the general population.

Compared with controls, RA patients not on anti-TNF biologics did not have a significantly increased risk of malignant melanoma. However, the 38 first invasive melanomas that occurred in RA patients taking a TNF antagonist signified a 1.5-fold increased risk of this malignancy compared to the general population. This 50% increase in relative risk was statistically significant. The absolute increase in risk was quite small: 20 additional cases per 100,000 person-years. The number needed to harm – that is, the number of patients who needed to be treated with an anti-TNF biologic to cause one additional case of melanoma – was 50,000 (BMJ 2013;346:f1939 [doi: 10.1136/bmj.f1939]).

Dr. Curtis noted that patients who have been urged to consider going on a TNF antagonist often return to the office waving a printout of the product labeling that warns of the possibility of malignancy.

"The bottom line: I tell patients that based on the data that there doesn’t appear to be an increased risk for all types of cancer, including hematologic, with the exceptions of nonmelanoma skin cancer and melanoma. Those are the two we need to advise patients about," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – The use of anti–tumor necrosis factor biologics in patients with rheumatoid arthritis, psoriasis, and other serious autoimmune diseases is not associated with increased risk of most forms of cancer, with two highly visible and important exceptions: nonmelanoma skin cancer and malignant melanoma.

That’s the largely reassuring conclusion to be drawn from two large studies conducted by researchers at Stockholm’s Karolinska Institute, according to Dr. Jeffrey R. Curtis, director of the arthritis clinical intervention program at the University of Alabama, Birmingham.

The Swedish group conducted a comprehensive meta-analysis of all 74 pharmaceutical company–sponsored randomized controlled trials of anti-TNF biologics lasting at least 4 weeks. The investigators used individual patient data for 15,418 anti-TNF recipients and 7,486 subjects randomized to methotrexate and other comparators. About half of the randomized trials focused on rheumatoid arthritis (RA) patients; the other half involved patients with the other approved indications for anti-TNF therapy.

The use of individual patient data was a nuance of the meta-analysis that wowed Dr. Curtis.

"This is a really great paper. One of the reasons I was very impressed with it is that getting drug companies to give up any raw person-level data to anybody is difficult. The European Medicines Agency requested it, and that’s probably the only reason it happened," Dr. Curtis observed at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The overall relative risk for all forms of cancer, excluding nonmelanoma skin cancer, in patients on anti-TNF biologics was 0.99. Their cancer rate was 641 per 100,000 person-years (Pharmacoepidemiol. Drug Saf. 2011;20:119-30).

"You can tell your patients the risk for cancer is less than 1 in 100 – it’s about 6 per 1,000 – and it’s not increased compared to background therapy," the rheumatologist said.

The exception was nonmelanoma skin cancer. The relative risk for this malignancy among users of all anti-TNF biologics was increased twofold.

In a separate study, the same group used prospectively recorded data from Swedish national registries to investigate the association between anti-TNF therapy and melanoma. This analysis involved 10,878 RA patients treated with anti-TNF biologics, 42,198 others who were not, and 162,743 matched controls from the general population.

Compared with controls, RA patients not on anti-TNF biologics did not have a significantly increased risk of malignant melanoma. However, the 38 first invasive melanomas that occurred in RA patients taking a TNF antagonist signified a 1.5-fold increased risk of this malignancy compared to the general population. This 50% increase in relative risk was statistically significant. The absolute increase in risk was quite small: 20 additional cases per 100,000 person-years. The number needed to harm – that is, the number of patients who needed to be treated with an anti-TNF biologic to cause one additional case of melanoma – was 50,000 (BMJ 2013;346:f1939 [doi: 10.1136/bmj.f1939]).

Dr. Curtis noted that patients who have been urged to consider going on a TNF antagonist often return to the office waving a printout of the product labeling that warns of the possibility of malignancy.

"The bottom line: I tell patients that based on the data that there doesn’t appear to be an increased risk for all types of cancer, including hematologic, with the exceptions of nonmelanoma skin cancer and melanoma. Those are the two we need to advise patients about," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

bjancin@frontlinemedcom.com