Bruce Jancin

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

RALEIGH, N.C. – Current screening instruments that are designed to identify the 20%-30% of psoriasis patients who have psoriatic arthritis leave much to be desired, Dr. Jessica A. Walsh asserted at the annual meeting of the Society for Investigative Dermatology.

She asked 189 psoriasis patients who are enrolled in the Utah Psoriasis Initiative to take three of the most popular psoriatic arthritis self-administered screening questionnaires. The tests’ sensitivities and specificities proved markedly lower than previously reported in the instruments’ validation studies.

Moreover, all three tests – the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Project (PEST), and the Toronto Psoriatic Arthritis Screen (ToPAS) – differentiated only poorly among psoriatic arthritis, other types of arthritis, and fibromyalgia.

And the tests had other weak points: "The instruments were less sensitive in patients with lower psoriatic arthritis disease activity, fewer disease features, and shorter disease duration. This is suboptimal because these instruments were designed to help capture early disease," said Dr. Walsh, a rheumatologist at the University of Utah, Salt Lake City.

She is involved in a project aimed at reducing delays in diagnosis of psoriatic arthritis, an underdiagnosed condition in psoriasis patients. According to a 2011 National Psoriasis Foundation survey, 29% of psoriatic arthritis patients don’t receive their diagnosis until 2 years or more after onset of symptoms. That’s bad news, because early diagnosis and treatment help minimize symptoms, enhance quality of life, and prevent joint damage. Studies show that nearly one-half of psoriatic arthritis patients develop radiographic evidence of erosive damage within 2 years of symptom onset. Treatment can slow that progressive erosion.

All 189 psoriasis patients in Dr. Walsh’s study had musculoskeletal complaints of sufficient magnitude that they were willing to take the three screening tests in order to receive a free rheumatologic evaluation. A total of 137 patients had psoriatic arthritis, and two-thirds of them had already been diagnosed with the disease prior to participation in her study.

The gold standard to which the screening tests were compared was Dr. Walsh’s diagnostic evaluation, which included laboratory testing and imaging as warranted. When there was a discrepancy between any of the screening tests and her diagnosis, as occurred in 138 cases, a second rheumatologist with expertise in psoriatic arthritis was called in as a tiebreaker.

The sensitivities of PACE, PEST, and ToPAS were 68%, 85%, and 75%, respectively. The specificities were worse, at 50%, 45%, and 55%. These are in sharp contrast to previous studies, in which the test sensitivities were 88%-97%, with reported specificities of 79%-95%, she noted.

The frequency of discrepancies between patient responses to specific screening questions and the rheumatologic exam findings varied among the test instruments in a way that caused Dr. Walsh to believe that combining selected questions from each test and, in some cases, modifying the wording might result in a hybrid-screening instrument with improved performance. She plans to test that hypothesis.

Dr. Abrar A. Qureshi, one of the developers of PASE, said he and his coworkers have been thinking along the same lines.

"We’re working on a shorter version of PASE that might work better. Nine of the 15 questions on PASE seem to track well with inflammatory arthritis," commented Dr. Qureshi, vice chairman of the department of dermatology at Brigham and Women’s Hospital, Boston.

The Utah Psoriasis Initiative is funded by the University of Utah department of dermatology. Dr. Walsh reported having no financial conflicts.

RALEIGH, N.C. – Current screening instruments that are designed to identify the 20%-30% of psoriasis patients who have psoriatic arthritis leave much to be desired, Dr. Jessica A. Walsh asserted at the annual meeting of the Society for Investigative Dermatology.

She asked 189 psoriasis patients who are enrolled in the Utah Psoriasis Initiative to take three of the most popular psoriatic arthritis self-administered screening questionnaires. The tests’ sensitivities and specificities proved markedly lower than previously reported in the instruments’ validation studies.

Moreover, all three tests – the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Project (PEST), and the Toronto Psoriatic Arthritis Screen (ToPAS) – differentiated only poorly among psoriatic arthritis, other types of arthritis, and fibromyalgia.

And the tests had other weak points: "The instruments were less sensitive in patients with lower psoriatic arthritis disease activity, fewer disease features, and shorter disease duration. This is suboptimal because these instruments were designed to help capture early disease," said Dr. Walsh, a rheumatologist at the University of Utah, Salt Lake City.

She is involved in a project aimed at reducing delays in diagnosis of psoriatic arthritis, an underdiagnosed condition in psoriasis patients. According to a 2011 National Psoriasis Foundation survey, 29% of psoriatic arthritis patients don’t receive their diagnosis until 2 years or more after onset of symptoms. That’s bad news, because early diagnosis and treatment help minimize symptoms, enhance quality of life, and prevent joint damage. Studies show that nearly one-half of psoriatic arthritis patients develop radiographic evidence of erosive damage within 2 years of symptom onset. Treatment can slow that progressive erosion.

All 189 psoriasis patients in Dr. Walsh’s study had musculoskeletal complaints of sufficient magnitude that they were willing to take the three screening tests in order to receive a free rheumatologic evaluation. A total of 137 patients had psoriatic arthritis, and two-thirds of them had already been diagnosed with the disease prior to participation in her study.

The gold standard to which the screening tests were compared was Dr. Walsh’s diagnostic evaluation, which included laboratory testing and imaging as warranted. When there was a discrepancy between any of the screening tests and her diagnosis, as occurred in 138 cases, a second rheumatologist with expertise in psoriatic arthritis was called in as a tiebreaker.

The sensitivities of PACE, PEST, and ToPAS were 68%, 85%, and 75%, respectively. The specificities were worse, at 50%, 45%, and 55%. These are in sharp contrast to previous studies, in which the test sensitivities were 88%-97%, with reported specificities of 79%-95%, she noted.

The frequency of discrepancies between patient responses to specific screening questions and the rheumatologic exam findings varied among the test instruments in a way that caused Dr. Walsh to believe that combining selected questions from each test and, in some cases, modifying the wording might result in a hybrid-screening instrument with improved performance. She plans to test that hypothesis.

Dr. Abrar A. Qureshi, one of the developers of PASE, said he and his coworkers have been thinking along the same lines.

"We’re working on a shorter version of PASE that might work better. Nine of the 15 questions on PASE seem to track well with inflammatory arthritis," commented Dr. Qureshi, vice chairman of the department of dermatology at Brigham and Women’s Hospital, Boston.

The Utah Psoriasis Initiative is funded by the University of Utah department of dermatology. Dr. Walsh reported having no financial conflicts.

RALEIGH, N.C. – Current screening instruments that are designed to identify the 20%-30% of psoriasis patients who have psoriatic arthritis leave much to be desired, Dr. Jessica A. Walsh asserted at the annual meeting of the Society for Investigative Dermatology.

She asked 189 psoriasis patients who are enrolled in the Utah Psoriasis Initiative to take three of the most popular psoriatic arthritis self-administered screening questionnaires. The tests’ sensitivities and specificities proved markedly lower than previously reported in the instruments’ validation studies.

Moreover, all three tests – the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Project (PEST), and the Toronto Psoriatic Arthritis Screen (ToPAS) – differentiated only poorly among psoriatic arthritis, other types of arthritis, and fibromyalgia.

And the tests had other weak points: "The instruments were less sensitive in patients with lower psoriatic arthritis disease activity, fewer disease features, and shorter disease duration. This is suboptimal because these instruments were designed to help capture early disease," said Dr. Walsh, a rheumatologist at the University of Utah, Salt Lake City.

She is involved in a project aimed at reducing delays in diagnosis of psoriatic arthritis, an underdiagnosed condition in psoriasis patients. According to a 2011 National Psoriasis Foundation survey, 29% of psoriatic arthritis patients don’t receive their diagnosis until 2 years or more after onset of symptoms. That’s bad news, because early diagnosis and treatment help minimize symptoms, enhance quality of life, and prevent joint damage. Studies show that nearly one-half of psoriatic arthritis patients develop radiographic evidence of erosive damage within 2 years of symptom onset. Treatment can slow that progressive erosion.

All 189 psoriasis patients in Dr. Walsh’s study had musculoskeletal complaints of sufficient magnitude that they were willing to take the three screening tests in order to receive a free rheumatologic evaluation. A total of 137 patients had psoriatic arthritis, and two-thirds of them had already been diagnosed with the disease prior to participation in her study.

The gold standard to which the screening tests were compared was Dr. Walsh’s diagnostic evaluation, which included laboratory testing and imaging as warranted. When there was a discrepancy between any of the screening tests and her diagnosis, as occurred in 138 cases, a second rheumatologist with expertise in psoriatic arthritis was called in as a tiebreaker.

The sensitivities of PACE, PEST, and ToPAS were 68%, 85%, and 75%, respectively. The specificities were worse, at 50%, 45%, and 55%. These are in sharp contrast to previous studies, in which the test sensitivities were 88%-97%, with reported specificities of 79%-95%, she noted.

The frequency of discrepancies between patient responses to specific screening questions and the rheumatologic exam findings varied among the test instruments in a way that caused Dr. Walsh to believe that combining selected questions from each test and, in some cases, modifying the wording might result in a hybrid-screening instrument with improved performance. She plans to test that hypothesis.

Dr. Abrar A. Qureshi, one of the developers of PASE, said he and his coworkers have been thinking along the same lines.

"We’re working on a shorter version of PASE that might work better. Nine of the 15 questions on PASE seem to track well with inflammatory arthritis," commented Dr. Qureshi, vice chairman of the department of dermatology at Brigham and Women’s Hospital, Boston.

The Utah Psoriasis Initiative is funded by the University of Utah department of dermatology. Dr. Walsh reported having no financial conflicts.

BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.

Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.

During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.

After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.

The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.

Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.

In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.

The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.

Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.

Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.

BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.

Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.

During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.

After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.

The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.

Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.

In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.

The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.

Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.

Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.

BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.

Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.

During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.

After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.

The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.

Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.

In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.

The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.

Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.

Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.

RALEIGH, N.C. – Atopic dermatitis patients who possess a filaggrin loss-of-function mutation are not likely to be clear of the skin disease for longer than 5 months at a time, according to study results.

The prospective cohort PEER (Pediatric Eczema Elective Registry) study also found that the four most prevalent filaggrin mutations in white patients do not respond similarly to atopic dermatitis medications.

For example, patients with at least one null allele for R501X – the most prevalent filaggrin mutation in the PEER cohort – were 55% less likely than the group as a whole to report being symptom free for 6 months while off all medications for atopic dermatitis. In contrast, those with an S3247X mutation were 3.7-fold more likely to be both symptom and medication free for a 6-month period, according to Dr. David J. Margolis, professor of dermatology at the University of Pennsylvania, Philadelphia.

He presented a study involving 857 PEER participants who underwent DNA analysis screening for the four most common filaggrin mutations in white patients (R501X, 2282del4, R2247X, and S3247X). A total of 28% of white patients had at least one of the mutations, as did 5% of black patients. An R501X mutation was present in 12.2% of white patients and 3.3% of black patients. The second most common mutation (2282del4) was noted in 11.8% of white patients and 0.6% of black patients.

The ongoing Valeant Pharmaceutical–funded PEER study involves children with atopic dermatitis who used topical pimecrolimus (Elidel) for at least 6 weeks during the 6 months immediately prior to enrollment. Their average age at diagnosis was 2.1 years. Participants have been prospectively followed in the registry for a mean of roughly 5 years. They can use any form of treatment they choose. Data on the status of their skin disease are collected at 6-month intervals, allowing for the characteristic waxing and waning of atopic dermatitis.

In all, 81% of PEER participants have been symptom free for at least 6 months on at least one occasion during the 5 years of follow-up. However, only 25.6% were both symptom free and not using an eczema medication.

In a cross-sectional snapshot obtained at 3 years of follow-up, 62% of patients were still using a topical calcineurin inhibitor, 58% were on topical steroids, and 35% were on both forms of therapy.

Patients with any of the four filaggrin mutations were 50% as likely as those without a mutation to be symptom free for a 6-month period, after adjustment for age, sex, and ancestry.

Participants with an R501X mutation were an adjusted 55% less likely than the overall PEER cohort to be symptom free for 6 months while off medications; hence, they could be said to have significantly more persistent or severe disease, Dr. Margolis noted.

In contrast, patients with a 2282del4 mutation were 1.7-fold more likely than the overall group to be symptom free while off therapy for 6 months, whereas those with an R2247X mutation were about equally likely as the patients with none of the filaggrin mutations to enjoy such a period.

The filaggrin gene, which is located on chromosome 1, codes for filament-aggregating protein. It is thought that filaggrin loss-of-function mutations promote breakdown of the skin barrier, allowing a more aggressive immunologic response to antigens and irritants. In 2006, it was demonstrated that filaggrin loss-of-function mutations increase an individual’s risk of developing atopic dermatitis threefold.

That being said, the PEER analysis demonstrates that different filaggrin mutations vary considerably in the degree to which their associated skin disease is treatment-refractory. One reasonable hypothesis is that these differences in treatment responsiveness are related to mutation penetrance.

A limitation of this PEER analysis is that it screened only for the four most prevalent filaggrin mutations, he noted. Roughly 30-40 mutations have been reported thus far.

This study was funded by the National Institutes of Health. Dr. Margolis reported having no financial conflicts.

RALEIGH, N.C. – Atopic dermatitis patients who possess a filaggrin loss-of-function mutation are not likely to be clear of the skin disease for longer than 5 months at a time, according to study results.

The prospective cohort PEER (Pediatric Eczema Elective Registry) study also found that the four most prevalent filaggrin mutations in white patients do not respond similarly to atopic dermatitis medications.

For example, patients with at least one null allele for R501X – the most prevalent filaggrin mutation in the PEER cohort – were 55% less likely than the group as a whole to report being symptom free for 6 months while off all medications for atopic dermatitis. In contrast, those with an S3247X mutation were 3.7-fold more likely to be both symptom and medication free for a 6-month period, according to Dr. David J. Margolis, professor of dermatology at the University of Pennsylvania, Philadelphia.

He presented a study involving 857 PEER participants who underwent DNA analysis screening for the four most common filaggrin mutations in white patients (R501X, 2282del4, R2247X, and S3247X). A total of 28% of white patients had at least one of the mutations, as did 5% of black patients. An R501X mutation was present in 12.2% of white patients and 3.3% of black patients. The second most common mutation (2282del4) was noted in 11.8% of white patients and 0.6% of black patients.

The ongoing Valeant Pharmaceutical–funded PEER study involves children with atopic dermatitis who used topical pimecrolimus (Elidel) for at least 6 weeks during the 6 months immediately prior to enrollment. Their average age at diagnosis was 2.1 years. Participants have been prospectively followed in the registry for a mean of roughly 5 years. They can use any form of treatment they choose. Data on the status of their skin disease are collected at 6-month intervals, allowing for the characteristic waxing and waning of atopic dermatitis.

In all, 81% of PEER participants have been symptom free for at least 6 months on at least one occasion during the 5 years of follow-up. However, only 25.6% were both symptom free and not using an eczema medication.

In a cross-sectional snapshot obtained at 3 years of follow-up, 62% of patients were still using a topical calcineurin inhibitor, 58% were on topical steroids, and 35% were on both forms of therapy.

Patients with any of the four filaggrin mutations were 50% as likely as those without a mutation to be symptom free for a 6-month period, after adjustment for age, sex, and ancestry.

Participants with an R501X mutation were an adjusted 55% less likely than the overall PEER cohort to be symptom free for 6 months while off medications; hence, they could be said to have significantly more persistent or severe disease, Dr. Margolis noted.

In contrast, patients with a 2282del4 mutation were 1.7-fold more likely than the overall group to be symptom free while off therapy for 6 months, whereas those with an R2247X mutation were about equally likely as the patients with none of the filaggrin mutations to enjoy such a period.

The filaggrin gene, which is located on chromosome 1, codes for filament-aggregating protein. It is thought that filaggrin loss-of-function mutations promote breakdown of the skin barrier, allowing a more aggressive immunologic response to antigens and irritants. In 2006, it was demonstrated that filaggrin loss-of-function mutations increase an individual’s risk of developing atopic dermatitis threefold.

That being said, the PEER analysis demonstrates that different filaggrin mutations vary considerably in the degree to which their associated skin disease is treatment-refractory. One reasonable hypothesis is that these differences in treatment responsiveness are related to mutation penetrance.

A limitation of this PEER analysis is that it screened only for the four most prevalent filaggrin mutations, he noted. Roughly 30-40 mutations have been reported thus far.

This study was funded by the National Institutes of Health. Dr. Margolis reported having no financial conflicts.

RALEIGH, N.C. – Atopic dermatitis patients who possess a filaggrin loss-of-function mutation are not likely to be clear of the skin disease for longer than 5 months at a time, according to study results.

The prospective cohort PEER (Pediatric Eczema Elective Registry) study also found that the four most prevalent filaggrin mutations in white patients do not respond similarly to atopic dermatitis medications.

For example, patients with at least one null allele for R501X – the most prevalent filaggrin mutation in the PEER cohort – were 55% less likely than the group as a whole to report being symptom free for 6 months while off all medications for atopic dermatitis. In contrast, those with an S3247X mutation were 3.7-fold more likely to be both symptom and medication free for a 6-month period, according to Dr. David J. Margolis, professor of dermatology at the University of Pennsylvania, Philadelphia.

He presented a study involving 857 PEER participants who underwent DNA analysis screening for the four most common filaggrin mutations in white patients (R501X, 2282del4, R2247X, and S3247X). A total of 28% of white patients had at least one of the mutations, as did 5% of black patients. An R501X mutation was present in 12.2% of white patients and 3.3% of black patients. The second most common mutation (2282del4) was noted in 11.8% of white patients and 0.6% of black patients.

The ongoing Valeant Pharmaceutical–funded PEER study involves children with atopic dermatitis who used topical pimecrolimus (Elidel) for at least 6 weeks during the 6 months immediately prior to enrollment. Their average age at diagnosis was 2.1 years. Participants have been prospectively followed in the registry for a mean of roughly 5 years. They can use any form of treatment they choose. Data on the status of their skin disease are collected at 6-month intervals, allowing for the characteristic waxing and waning of atopic dermatitis.

In all, 81% of PEER participants have been symptom free for at least 6 months on at least one occasion during the 5 years of follow-up. However, only 25.6% were both symptom free and not using an eczema medication.

In a cross-sectional snapshot obtained at 3 years of follow-up, 62% of patients were still using a topical calcineurin inhibitor, 58% were on topical steroids, and 35% were on both forms of therapy.

Patients with any of the four filaggrin mutations were 50% as likely as those without a mutation to be symptom free for a 6-month period, after adjustment for age, sex, and ancestry.

Participants with an R501X mutation were an adjusted 55% less likely than the overall PEER cohort to be symptom free for 6 months while off medications; hence, they could be said to have significantly more persistent or severe disease, Dr. Margolis noted.

In contrast, patients with a 2282del4 mutation were 1.7-fold more likely than the overall group to be symptom free while off therapy for 6 months, whereas those with an R2247X mutation were about equally likely as the patients with none of the filaggrin mutations to enjoy such a period.

The filaggrin gene, which is located on chromosome 1, codes for filament-aggregating protein. It is thought that filaggrin loss-of-function mutations promote breakdown of the skin barrier, allowing a more aggressive immunologic response to antigens and irritants. In 2006, it was demonstrated that filaggrin loss-of-function mutations increase an individual’s risk of developing atopic dermatitis threefold.

That being said, the PEER analysis demonstrates that different filaggrin mutations vary considerably in the degree to which their associated skin disease is treatment-refractory. One reasonable hypothesis is that these differences in treatment responsiveness are related to mutation penetrance.

A limitation of this PEER analysis is that it screened only for the four most prevalent filaggrin mutations, he noted. Roughly 30-40 mutations have been reported thus far.

This study was funded by the National Institutes of Health. Dr. Margolis reported having no financial conflicts.

RALEIGH, N.C. – At 2 weeks after psoriasis patients received their first dose of the investigational interleukin-17 inhibitor ixekizumab, their gene expression pattern resembled that of healthy controls.

At the annual meeting of the Society for Investigative Dermatology, Dr. James G. Krueger presented a translational medicine study aimed at defining the impact that turning off IL-17 signaling has on pathological tissue structures, molecular pathways, and biomarkers.

His conclusion: "I think these data suggest IL-17 is the central cytokine driving pathogenesis in psoriasis," said Dr. Krueger of Rockefeller University in New York.

Eight psoriasis patients received a subcutaneous 150-mg dose of ixekizumab at weeks 0, 2, and 4 and underwent skin biopsies at weeks 0, 2, and 6. He compared their inflammatory gene expression profiles 2 weeks into treatment vs. those obtained from 15 psoriasis patients 2 weeks after beginning treatment with etanercept (at 50 mg twice weekly for 12 weeks).

IL-17 blockade with ixekizumab proved to have a greater impact on the expression of inflammatory genes known to be associated with psoriasis than did tumor necrosis factor inhibition via etanercept. Ixekizumab resulted in greater-than-75% normalization of expression of 643 of these inflammatory genes, compared with 104 with etanercept.

The structural result of IL-17 blockade was reversal by week 6 of the epidermal hyperplasia that is the hallmark of psoriasis, he added.

Two of the eight patients on the ixekizumab 150-mg regimen achieved PASI 75 (that is, a 75% improvement from baseline on the Psoriasis Area and Severity Index) in 2 weeks. That’s remarkably fast improvement, Dr. Krueger noted. By week 6, all eight patients had achieved PASI 75.

Another point in favor of IL-17’s being a central cytokine driving psoriasis is that ixekizumab shut down not only the IL-17A target genes downstream, but also genes controlling the production of key cytokines located upstream, including interferon-gamma and IL-22, he noted.

Phase III trials investigating ixekizumab for psoriasis are underway. The drug is also being investigated for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Dr. Krueger is a consultant to Eli Lilly, which funded the study and is developing ixekizumab as a treatment for psoriasis.

RALEIGH, N.C. – At 2 weeks after psoriasis patients received their first dose of the investigational interleukin-17 inhibitor ixekizumab, their gene expression pattern resembled that of healthy controls.

At the annual meeting of the Society for Investigative Dermatology, Dr. James G. Krueger presented a translational medicine study aimed at defining the impact that turning off IL-17 signaling has on pathological tissue structures, molecular pathways, and biomarkers.

His conclusion: "I think these data suggest IL-17 is the central cytokine driving pathogenesis in psoriasis," said Dr. Krueger of Rockefeller University in New York.

Eight psoriasis patients received a subcutaneous 150-mg dose of ixekizumab at weeks 0, 2, and 4 and underwent skin biopsies at weeks 0, 2, and 6. He compared their inflammatory gene expression profiles 2 weeks into treatment vs. those obtained from 15 psoriasis patients 2 weeks after beginning treatment with etanercept (at 50 mg twice weekly for 12 weeks).

IL-17 blockade with ixekizumab proved to have a greater impact on the expression of inflammatory genes known to be associated with psoriasis than did tumor necrosis factor inhibition via etanercept. Ixekizumab resulted in greater-than-75% normalization of expression of 643 of these inflammatory genes, compared with 104 with etanercept.

The structural result of IL-17 blockade was reversal by week 6 of the epidermal hyperplasia that is the hallmark of psoriasis, he added.

Two of the eight patients on the ixekizumab 150-mg regimen achieved PASI 75 (that is, a 75% improvement from baseline on the Psoriasis Area and Severity Index) in 2 weeks. That’s remarkably fast improvement, Dr. Krueger noted. By week 6, all eight patients had achieved PASI 75.

Another point in favor of IL-17’s being a central cytokine driving psoriasis is that ixekizumab shut down not only the IL-17A target genes downstream, but also genes controlling the production of key cytokines located upstream, including interferon-gamma and IL-22, he noted.

Phase III trials investigating ixekizumab for psoriasis are underway. The drug is also being investigated for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Dr. Krueger is a consultant to Eli Lilly, which funded the study and is developing ixekizumab as a treatment for psoriasis.

RALEIGH, N.C. – At 2 weeks after psoriasis patients received their first dose of the investigational interleukin-17 inhibitor ixekizumab, their gene expression pattern resembled that of healthy controls.

At the annual meeting of the Society for Investigative Dermatology, Dr. James G. Krueger presented a translational medicine study aimed at defining the impact that turning off IL-17 signaling has on pathological tissue structures, molecular pathways, and biomarkers.

His conclusion: "I think these data suggest IL-17 is the central cytokine driving pathogenesis in psoriasis," said Dr. Krueger of Rockefeller University in New York.

Eight psoriasis patients received a subcutaneous 150-mg dose of ixekizumab at weeks 0, 2, and 4 and underwent skin biopsies at weeks 0, 2, and 6. He compared their inflammatory gene expression profiles 2 weeks into treatment vs. those obtained from 15 psoriasis patients 2 weeks after beginning treatment with etanercept (at 50 mg twice weekly for 12 weeks).

IL-17 blockade with ixekizumab proved to have a greater impact on the expression of inflammatory genes known to be associated with psoriasis than did tumor necrosis factor inhibition via etanercept. Ixekizumab resulted in greater-than-75% normalization of expression of 643 of these inflammatory genes, compared with 104 with etanercept.

The structural result of IL-17 blockade was reversal by week 6 of the epidermal hyperplasia that is the hallmark of psoriasis, he added.

Two of the eight patients on the ixekizumab 150-mg regimen achieved PASI 75 (that is, a 75% improvement from baseline on the Psoriasis Area and Severity Index) in 2 weeks. That’s remarkably fast improvement, Dr. Krueger noted. By week 6, all eight patients had achieved PASI 75.

Another point in favor of IL-17’s being a central cytokine driving psoriasis is that ixekizumab shut down not only the IL-17A target genes downstream, but also genes controlling the production of key cytokines located upstream, including interferon-gamma and IL-22, he noted.

Phase III trials investigating ixekizumab for psoriasis are underway. The drug is also being investigated for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Dr. Krueger is a consultant to Eli Lilly, which funded the study and is developing ixekizumab as a treatment for psoriasis.

BERLIN – The proteasome inhibitor bortezomib shows considerable promise as a novel treatment for refractory SLE, according to Dr. Reinhard E. Voll.

"I think it’s useful as an induction therapy; then you can go on with regular maintenance therapy," he said at the annual European Congress of Rheumatology.

He presented a series of 13 patients with SLE refractory to conventional immunosuppressive drugs and antimalarials treated off label with bortezomib (Velcade) at three German university medical centers. Ten patients had refractory active lupus nephritis.

All patients responded to bortezomib with significant reductions in anti–double-stranded DNA antibody titers and SLE Disease Activity Index (SLEDAI) scores. Proteinuria decreased within 6 weeks in all patients with active lupus nephritis, one of whom achieved normal protein excretion by 4 months, according to Dr. Voll, a rheumatologist at the University of Freiburg (Germany).

The mean baseline SLEDAI score was 14.3, dropping to 5.2 after two to a maximum of four courses of bortezomib. In the three patients with the highest baseline SLEDAIs of 20 or 21, their scores at the end of bortezomib therapy were 4, 6, and 7.

Patients remained on mycophenolate mofetil and antimalarials during treatment with bortezomib. Once the patients displayed marked improvement, the proteasome inhibitor was stopped. During 6 months of follow-up post bortezomib, SLEDAIs remained the same as, and in some cases lower than, at the time bortezomib was stopped.

Bortezomib is approved for the treatment of relapsed multiple myeloma and for mantle cell lymphoma.

The SLE patients received bortezomib intravenously at a dose of 1.3 mg/m² of body surface area on days 1, 4, and 8, and in some cases also on day 11 of a given treatment cycle. Patients typically received 20 mg of dexamethasone together with bortezomib. Up to four cycles could be given, with 10-14 days in between.

Dr. Voll said he limits himself to three treatment days per cycle because three of the seven patients who got a fourth dose on day 11 at other centers developed peripheral polyneuropathies, the drug’s major side effect. Bortezomib-induced peripheral neuropathy resolves upon treatment discontinuation. But the problem didn’t occur in patients treated on three days per cycle.

One patient developed a moderate transient thrombocytopenia after four treatment cycles, but no other hematologic toxicities occurred.

Because of concern that a drug that depletes pathogenic antibodies might also lower protective vaccine antibody titers, the investigators measured titers to hepatitis B surface antigen and tetanus toxoid before and after bortezomib. Vaccine antibody titers dropped by up to 50% but still remained in the protective zone.

In an interview, Dr. Voll explained that he grew interested in investigating bortezomib because of a conviction he shares with others that one of the major reasons SLE and other antibody-mediated diseases can become highly refractory to conventional therapies is that affected patients have long-lived plasma cells secreting copious quantities of pathogenic antibodies. These self-perpetuating plasma cells are resistant to conventional SLE medications, including intravenous pulsed-dose cyclophosphamide, rituximab, and antimalarials (Nat. Rev. Rheumatol. 2011;7:170-8).

"We thought bortezomib might be toxic not only to myeloma cells, but to normal plasma cells. We moved to mouse models of lupus and found we could deplete the long-lived plasma cells very nicely with bortezomib. And we could also resolve lupus nephritis," he recalled, citing his earlier published study (Nat. Med. 2008;14:748-55).

The rheumatologist speculated that the proteasome inhibitor might also be useful in very severe cases of allergic disease. A colleague treated a patient with food allergies so severe that the patient had been unable to eat solid food for 2 years and was becoming suicidal as a result.

"After the second course of bortezomib, he could eat one solid meal per day, and his IgE antibody titers went way down. It was really amazing," Dr. Voll said.

In light of the highly promising 13-patient series, the next logical step would be a formal clinical trial of bortezomib in refractory SLE. Bortezomib’s manufacturer, Millenium Pharmaceuticals, has a related drug with less associated peripheral neuropathy that’s well along in development; the company has indicated interest in sponsoring a clinical trial of the new drug in refractory SLE, according to the rheumatologist.

The bortezomib used in the 13-patient series was paid for by the German health care system. Dr. Voll reported having no relevant financial conflicts.

BERLIN – The proteasome inhibitor bortezomib shows considerable promise as a novel treatment for refractory SLE, according to Dr. Reinhard E. Voll.

"I think it’s useful as an induction therapy; then you can go on with regular maintenance therapy," he said at the annual European Congress of Rheumatology.

He presented a series of 13 patients with SLE refractory to conventional immunosuppressive drugs and antimalarials treated off label with bortezomib (Velcade) at three German university medical centers. Ten patients had refractory active lupus nephritis.

All patients responded to bortezomib with significant reductions in anti–double-stranded DNA antibody titers and SLE Disease Activity Index (SLEDAI) scores. Proteinuria decreased within 6 weeks in all patients with active lupus nephritis, one of whom achieved normal protein excretion by 4 months, according to Dr. Voll, a rheumatologist at the University of Freiburg (Germany).

The mean baseline SLEDAI score was 14.3, dropping to 5.2 after two to a maximum of four courses of bortezomib. In the three patients with the highest baseline SLEDAIs of 20 or 21, their scores at the end of bortezomib therapy were 4, 6, and 7.

Patients remained on mycophenolate mofetil and antimalarials during treatment with bortezomib. Once the patients displayed marked improvement, the proteasome inhibitor was stopped. During 6 months of follow-up post bortezomib, SLEDAIs remained the same as, and in some cases lower than, at the time bortezomib was stopped.

Bortezomib is approved for the treatment of relapsed multiple myeloma and for mantle cell lymphoma.

The SLE patients received bortezomib intravenously at a dose of 1.3 mg/m² of body surface area on days 1, 4, and 8, and in some cases also on day 11 of a given treatment cycle. Patients typically received 20 mg of dexamethasone together with bortezomib. Up to four cycles could be given, with 10-14 days in between.

Dr. Voll said he limits himself to three treatment days per cycle because three of the seven patients who got a fourth dose on day 11 at other centers developed peripheral polyneuropathies, the drug’s major side effect. Bortezomib-induced peripheral neuropathy resolves upon treatment discontinuation. But the problem didn’t occur in patients treated on three days per cycle.

One patient developed a moderate transient thrombocytopenia after four treatment cycles, but no other hematologic toxicities occurred.

Because of concern that a drug that depletes pathogenic antibodies might also lower protective vaccine antibody titers, the investigators measured titers to hepatitis B surface antigen and tetanus toxoid before and after bortezomib. Vaccine antibody titers dropped by up to 50% but still remained in the protective zone.

In an interview, Dr. Voll explained that he grew interested in investigating bortezomib because of a conviction he shares with others that one of the major reasons SLE and other antibody-mediated diseases can become highly refractory to conventional therapies is that affected patients have long-lived plasma cells secreting copious quantities of pathogenic antibodies. These self-perpetuating plasma cells are resistant to conventional SLE medications, including intravenous pulsed-dose cyclophosphamide, rituximab, and antimalarials (Nat. Rev. Rheumatol. 2011;7:170-8).

"We thought bortezomib might be toxic not only to myeloma cells, but to normal plasma cells. We moved to mouse models of lupus and found we could deplete the long-lived plasma cells very nicely with bortezomib. And we could also resolve lupus nephritis," he recalled, citing his earlier published study (Nat. Med. 2008;14:748-55).

The rheumatologist speculated that the proteasome inhibitor might also be useful in very severe cases of allergic disease. A colleague treated a patient with food allergies so severe that the patient had been unable to eat solid food for 2 years and was becoming suicidal as a result.

"After the second course of bortezomib, he could eat one solid meal per day, and his IgE antibody titers went way down. It was really amazing," Dr. Voll said.

In light of the highly promising 13-patient series, the next logical step would be a formal clinical trial of bortezomib in refractory SLE. Bortezomib’s manufacturer, Millenium Pharmaceuticals, has a related drug with less associated peripheral neuropathy that’s well along in development; the company has indicated interest in sponsoring a clinical trial of the new drug in refractory SLE, according to the rheumatologist.

The bortezomib used in the 13-patient series was paid for by the German health care system. Dr. Voll reported having no relevant financial conflicts.

BERLIN – The proteasome inhibitor bortezomib shows considerable promise as a novel treatment for refractory SLE, according to Dr. Reinhard E. Voll.

"I think it’s useful as an induction therapy; then you can go on with regular maintenance therapy," he said at the annual European Congress of Rheumatology.

He presented a series of 13 patients with SLE refractory to conventional immunosuppressive drugs and antimalarials treated off label with bortezomib (Velcade) at three German university medical centers. Ten patients had refractory active lupus nephritis.

All patients responded to bortezomib with significant reductions in anti–double-stranded DNA antibody titers and SLE Disease Activity Index (SLEDAI) scores. Proteinuria decreased within 6 weeks in all patients with active lupus nephritis, one of whom achieved normal protein excretion by 4 months, according to Dr. Voll, a rheumatologist at the University of Freiburg (Germany).

The mean baseline SLEDAI score was 14.3, dropping to 5.2 after two to a maximum of four courses of bortezomib. In the three patients with the highest baseline SLEDAIs of 20 or 21, their scores at the end of bortezomib therapy were 4, 6, and 7.

Patients remained on mycophenolate mofetil and antimalarials during treatment with bortezomib. Once the patients displayed marked improvement, the proteasome inhibitor was stopped. During 6 months of follow-up post bortezomib, SLEDAIs remained the same as, and in some cases lower than, at the time bortezomib was stopped.

Bortezomib is approved for the treatment of relapsed multiple myeloma and for mantle cell lymphoma.

The SLE patients received bortezomib intravenously at a dose of 1.3 mg/m² of body surface area on days 1, 4, and 8, and in some cases also on day 11 of a given treatment cycle. Patients typically received 20 mg of dexamethasone together with bortezomib. Up to four cycles could be given, with 10-14 days in between.

Dr. Voll said he limits himself to three treatment days per cycle because three of the seven patients who got a fourth dose on day 11 at other centers developed peripheral polyneuropathies, the drug’s major side effect. Bortezomib-induced peripheral neuropathy resolves upon treatment discontinuation. But the problem didn’t occur in patients treated on three days per cycle.

One patient developed a moderate transient thrombocytopenia after four treatment cycles, but no other hematologic toxicities occurred.

Because of concern that a drug that depletes pathogenic antibodies might also lower protective vaccine antibody titers, the investigators measured titers to hepatitis B surface antigen and tetanus toxoid before and after bortezomib. Vaccine antibody titers dropped by up to 50% but still remained in the protective zone.

In an interview, Dr. Voll explained that he grew interested in investigating bortezomib because of a conviction he shares with others that one of the major reasons SLE and other antibody-mediated diseases can become highly refractory to conventional therapies is that affected patients have long-lived plasma cells secreting copious quantities of pathogenic antibodies. These self-perpetuating plasma cells are resistant to conventional SLE medications, including intravenous pulsed-dose cyclophosphamide, rituximab, and antimalarials (Nat. Rev. Rheumatol. 2011;7:170-8).

"We thought bortezomib might be toxic not only to myeloma cells, but to normal plasma cells. We moved to mouse models of lupus and found we could deplete the long-lived plasma cells very nicely with bortezomib. And we could also resolve lupus nephritis," he recalled, citing his earlier published study (Nat. Med. 2008;14:748-55).

The rheumatologist speculated that the proteasome inhibitor might also be useful in very severe cases of allergic disease. A colleague treated a patient with food allergies so severe that the patient had been unable to eat solid food for 2 years and was becoming suicidal as a result.

"After the second course of bortezomib, he could eat one solid meal per day, and his IgE antibody titers went way down. It was really amazing," Dr. Voll said.

In light of the highly promising 13-patient series, the next logical step would be a formal clinical trial of bortezomib in refractory SLE. Bortezomib’s manufacturer, Millenium Pharmaceuticals, has a related drug with less associated peripheral neuropathy that’s well along in development; the company has indicated interest in sponsoring a clinical trial of the new drug in refractory SLE, according to the rheumatologist.

The bortezomib used in the 13-patient series was paid for by the German health care system. Dr. Voll reported having no relevant financial conflicts.

BERLIN – A recently identified polymorphism in the fibroblast growth factor 23 gene may be a useful predictor of high risk for coronary artery damage in patients with Kawasaki disease.

Fibroblast growth factor is a phosphorus-regulating hormone. Fibroblast growth factor 23 (FGF23) has previously been identified as a contributor to left ventricular hypertrophy in patients with chronic kidney disease (Circulation 2009;119:2545-52), and as having a possible role in the atherosclerotic process as well. There are FGF23 receptors in the vasculature and in the heart, Dr. Fernanda Falcini explained at the annual European Congress of Rheumatology.

She and her coinvestigators have recently identified an FGF23 polymorphism involving a C insertion in the intronic region between nucleotides 36 and 37. Now they have implicated the polymorphism as having a possible functional role in the predisposition to coronary artery disease in patients with Kawasaki disease.

First the investigators demonstrated that the polymorphism was present in 35% of 100 healthy Italian white subjects. Then they extended their DNA analysis to 118 white patients with Kawasaki disease and 76 age- and sex-matched healthy control children.

The Kawasaki disease patients (median age, 33 months) underwent two-dimensional echocardiography at hospital admission, at day 15, and at 2, 6, and 12 months. Coronary artery damage in the form of an aneurysm or global dilation developed in 28 of the 118 patients.

Of patients with Kawasaki disease, 31% possessed the FGF23 polymorphism. Strikingly, the polymorphism was present in 24 of the 28 patients (86%) with coronary artery disease, but in only 12 of 90 (13%) with normal arteries, reported Dr. Falcini, a rheumatologist at the University of Florence (Italy).

Moreover, Kawasaki disease patients with the FGF23 polymorphism had significantly higher serum FGF23 levels than those with the wildtype FGF23 gene: a mean of 120, compared with 38 pg/mL. How those substantially higher serum levels of the hormone relate to coronary artery damage in patients with Kawasaki disease is a top research priority.

Coronary artery involvement is the most serious and long-lasting complication of Kawasaki disease, and the biggest contributor to the disease’s increased mortality risk. The etiology of the coronary artery damage remains unknown. The leading theory is that an infectious agent elicits a massive systemic inflammatory response directed at cardiovascular tissues. The ability to identify the patient subgroup at high risk for coronary artery damage would enable physicians to develop an aggressive, selectively applied prevention strategy.

The study was funded by an Italian medical research foundation. Dr. Falcini reported having no relevant financial conflicts.

BERLIN – A recently identified polymorphism in the fibroblast growth factor 23 gene may be a useful predictor of high risk for coronary artery damage in patients with Kawasaki disease.

Fibroblast growth factor is a phosphorus-regulating hormone. Fibroblast growth factor 23 (FGF23) has previously been identified as a contributor to left ventricular hypertrophy in patients with chronic kidney disease (Circulation 2009;119:2545-52), and as having a possible role in the atherosclerotic process as well. There are FGF23 receptors in the vasculature and in the heart, Dr. Fernanda Falcini explained at the annual European Congress of Rheumatology.

She and her coinvestigators have recently identified an FGF23 polymorphism involving a C insertion in the intronic region between nucleotides 36 and 37. Now they have implicated the polymorphism as having a possible functional role in the predisposition to coronary artery disease in patients with Kawasaki disease.

First the investigators demonstrated that the polymorphism was present in 35% of 100 healthy Italian white subjects. Then they extended their DNA analysis to 118 white patients with Kawasaki disease and 76 age- and sex-matched healthy control children.

The Kawasaki disease patients (median age, 33 months) underwent two-dimensional echocardiography at hospital admission, at day 15, and at 2, 6, and 12 months. Coronary artery damage in the form of an aneurysm or global dilation developed in 28 of the 118 patients.

Of patients with Kawasaki disease, 31% possessed the FGF23 polymorphism. Strikingly, the polymorphism was present in 24 of the 28 patients (86%) with coronary artery disease, but in only 12 of 90 (13%) with normal arteries, reported Dr. Falcini, a rheumatologist at the University of Florence (Italy).

Moreover, Kawasaki disease patients with the FGF23 polymorphism had significantly higher serum FGF23 levels than those with the wildtype FGF23 gene: a mean of 120, compared with 38 pg/mL. How those substantially higher serum levels of the hormone relate to coronary artery damage in patients with Kawasaki disease is a top research priority.

Coronary artery involvement is the most serious and long-lasting complication of Kawasaki disease, and the biggest contributor to the disease’s increased mortality risk. The etiology of the coronary artery damage remains unknown. The leading theory is that an infectious agent elicits a massive systemic inflammatory response directed at cardiovascular tissues. The ability to identify the patient subgroup at high risk for coronary artery damage would enable physicians to develop an aggressive, selectively applied prevention strategy.

The study was funded by an Italian medical research foundation. Dr. Falcini reported having no relevant financial conflicts.

BERLIN – A recently identified polymorphism in the fibroblast growth factor 23 gene may be a useful predictor of high risk for coronary artery damage in patients with Kawasaki disease.

Fibroblast growth factor is a phosphorus-regulating hormone. Fibroblast growth factor 23 (FGF23) has previously been identified as a contributor to left ventricular hypertrophy in patients with chronic kidney disease (Circulation 2009;119:2545-52), and as having a possible role in the atherosclerotic process as well. There are FGF23 receptors in the vasculature and in the heart, Dr. Fernanda Falcini explained at the annual European Congress of Rheumatology.

She and her coinvestigators have recently identified an FGF23 polymorphism involving a C insertion in the intronic region between nucleotides 36 and 37. Now they have implicated the polymorphism as having a possible functional role in the predisposition to coronary artery disease in patients with Kawasaki disease.

First the investigators demonstrated that the polymorphism was present in 35% of 100 healthy Italian white subjects. Then they extended their DNA analysis to 118 white patients with Kawasaki disease and 76 age- and sex-matched healthy control children.

The Kawasaki disease patients (median age, 33 months) underwent two-dimensional echocardiography at hospital admission, at day 15, and at 2, 6, and 12 months. Coronary artery damage in the form of an aneurysm or global dilation developed in 28 of the 118 patients.

Of patients with Kawasaki disease, 31% possessed the FGF23 polymorphism. Strikingly, the polymorphism was present in 24 of the 28 patients (86%) with coronary artery disease, but in only 12 of 90 (13%) with normal arteries, reported Dr. Falcini, a rheumatologist at the University of Florence (Italy).

Moreover, Kawasaki disease patients with the FGF23 polymorphism had significantly higher serum FGF23 levels than those with the wildtype FGF23 gene: a mean of 120, compared with 38 pg/mL. How those substantially higher serum levels of the hormone relate to coronary artery damage in patients with Kawasaki disease is a top research priority.

Coronary artery involvement is the most serious and long-lasting complication of Kawasaki disease, and the biggest contributor to the disease’s increased mortality risk. The etiology of the coronary artery damage remains unknown. The leading theory is that an infectious agent elicits a massive systemic inflammatory response directed at cardiovascular tissues. The ability to identify the patient subgroup at high risk for coronary artery damage would enable physicians to develop an aggressive, selectively applied prevention strategy.

The study was funded by an Italian medical research foundation. Dr. Falcini reported having no relevant financial conflicts.

HOUSTON – Long-term testosterone replacement therapy in men with hypogonadism brought impressive reductions in body weight and waist circumference in a 5-year observational study.

"This is an amazing response. I don’t know of many other therapies where you have more than 90% of treated patients respond in a positive way," observed Farid Saad, Ph.D. He referred to the fact that 90% of the 255 men treated for hypogonadism lost at least 5 kg from their initial body weight and 97% experienced shrinkage in waist circumference, with a 10-cm or greater reduction in 46% of men. That’s a lot of belt notches.

This 5-year study of testosterone replacement in hypogonadal men features what’s easily the longest follow-up reported anywhere to date. The average 36-pound weight loss and substantial waist shrinkage were "unintended and unexpected," because prior 1- to 2-year-long studies showed less impressive changes, explained Dr. Saad, at the annual meeting of the Endocrine Society.

The 255 study participants averaged just under 61 years of age. Nearly all were obese or overweight, as is typical in male hypogonadism. All had a serum testosterone level below 350 ng/dL, along with testosterone deficiency–related symptoms. Serum testosterone levels normalized within the first 6-9 months of treatment with slow-acting intramuscular testosterone undecanoate and remained in the normal range thereafter.

"If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination."

The men went from a mean baseline body weight of 106 kg to 90 kg over the course of 5 years. A total of 76% of participants lost 10 kg or more of their initial body weight, 53% lost at least 15 kg, and 31% dropped at least 20 kg. The weight loss was continuous; the men lost a mean of 4% of their initial body weight at 1 year, 9% at 3 years, and 13.2% after 5 years. Only 5% of men gained weight during follow-up.

Waist circumference declined by a mean of 8.8 cm from 107.2 cm at baseline. And mean body mass index dropped from 34 to 29 kg/m².

Study participants were not placed on a structured diet or exercise program, although they did receive advice on the importance of making lifestyle changes.

Three men have developed prostate cancer, but that’s less than the background rate in the general population.

"I think now the general understanding at the major urologic conferences is that testosterone does not increase the risk of prostate cancer. And I wouldn’t expect other side effects because testosterone is a natural substance and we don’t use supraphysiologic doses, we just bring testosterone levels in these hypogonadal men back to normal. I say, in a maybe not very scientific way, that if testosterone [were] harmful to men, then nature would have made a major mistake," according to Dr. Saad, head of global medical affairs–andrology at Bayer Pharma in Berlin.

He added that it would be nice to confirm the findings of this observational study in a prospective randomized controlled trial, but no ethics committee in the world would approve such a study because testosterone deficiency carries elevated risks of osteoporosis, cardiovascular disease, and diabetes. And the treatment for testosterone deficiency as spelled out in Endocrine Society guidelines is testosterone replacement to normal physiologic levels.

Two other studies presented at the conference confirmed Dr. Saad’s weight loss and waist circumference shrinkage findings. Dr. Youssef El Douaihy of Maimonides Medical Center, New York, reported that during a median 6.7-year follow-up of 130 hypogonadal men on testosterone replacement therapy, the subjects lost a mean of 14.3 kg or 13% of their initial body weight. They also experienced a mean 11-cm decrease in waist circumference.

And Dr. Michael Zitzmann of the University of Munster, Germany, presented a series of 334 patients with male hypogonadism treated for up to 15 years with intramuscular testosterone undecanoate. The prevalence of metabolic syndrome dropped from 88% to 52% within the first 2 years. Highly significant reductions in blood pressure, resting heart rate, body weight, body mass index, waist circumference, fasting blood glucose, LDL cholesterol, and triglycerides were documented, all highly significant differences.

Why the big weight loss in patients on long-term testosterone replacement therapy? Dr. Saad speculated that the explanation might lie in the combined improvements in vitality, virility, and motivation to change, all of which in recent studies have been shown to be triggered by normalization of testosterone levels.

"Testosterone may be of value as a facilitator of lifestyle change," he asserted.

Dr. Gary Wittert concurred.

"It’s extremely motivating to men to see their testosterone level come up to normal and the associated improvement in body weight, erectile dysfunction, and the significant improvement in lower urinary tract symptoms. So the message is quite clear: If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination," declared Dr. Wittert, professor of medicine at the University of Adelaide, Australia, who is a testosterone clinical trialist not involved in these studies.

Dr. Saad noted that another attribute of testosterone normalization that may be highly relevant to progressive long-term weight loss is that testosterone increases fat-free mass. He cited a recent pilot study in which hypogonadal men with spinal cord injury received transdermal testosterone replacement. In 1 year, their fat-free mass increased by an average of 3.5 kg and their resting energy expenditure rose by 112 kcal/day (Horm. Metab. Res. 2011;43:574-9).

"If you accumulate that over 5 years, it could be a major contributor to the weight loss the men in our study experienced," Dr. Saad observed.

Dr. Vineeth Mohan, who chaired a session where Dr. Saad presented his findings, said the new data raise the possibility that a large weight loss in a patient treated for male hypogonadism could be an indicator that natural testosterone production has recovered and replacement therapy is no longer needed. That would make sense, since adipose tissue is a powerful suppressor of testosterone production.

"I might look at that loss of a significant amount of body weight as a signal that the testosterone axis has improved, and perhaps as an opportunity for reassessment," said Dr. Mohan, an endocrinologist at the Cleveland Clinic Foundation in Weston, Fla.

He reported having no financial conflicts.

HOUSTON – Long-term testosterone replacement therapy in men with hypogonadism brought impressive reductions in body weight and waist circumference in a 5-year observational study.

"This is an amazing response. I don’t know of many other therapies where you have more than 90% of treated patients respond in a positive way," observed Farid Saad, Ph.D. He referred to the fact that 90% of the 255 men treated for hypogonadism lost at least 5 kg from their initial body weight and 97% experienced shrinkage in waist circumference, with a 10-cm or greater reduction in 46% of men. That’s a lot of belt notches.

This 5-year study of testosterone replacement in hypogonadal men features what’s easily the longest follow-up reported anywhere to date. The average 36-pound weight loss and substantial waist shrinkage were "unintended and unexpected," because prior 1- to 2-year-long studies showed less impressive changes, explained Dr. Saad, at the annual meeting of the Endocrine Society.

The 255 study participants averaged just under 61 years of age. Nearly all were obese or overweight, as is typical in male hypogonadism. All had a serum testosterone level below 350 ng/dL, along with testosterone deficiency–related symptoms. Serum testosterone levels normalized within the first 6-9 months of treatment with slow-acting intramuscular testosterone undecanoate and remained in the normal range thereafter.

"If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination."

The men went from a mean baseline body weight of 106 kg to 90 kg over the course of 5 years. A total of 76% of participants lost 10 kg or more of their initial body weight, 53% lost at least 15 kg, and 31% dropped at least 20 kg. The weight loss was continuous; the men lost a mean of 4% of their initial body weight at 1 year, 9% at 3 years, and 13.2% after 5 years. Only 5% of men gained weight during follow-up.

Waist circumference declined by a mean of 8.8 cm from 107.2 cm at baseline. And mean body mass index dropped from 34 to 29 kg/m².

Study participants were not placed on a structured diet or exercise program, although they did receive advice on the importance of making lifestyle changes.

Three men have developed prostate cancer, but that’s less than the background rate in the general population.

"I think now the general understanding at the major urologic conferences is that testosterone does not increase the risk of prostate cancer. And I wouldn’t expect other side effects because testosterone is a natural substance and we don’t use supraphysiologic doses, we just bring testosterone levels in these hypogonadal men back to normal. I say, in a maybe not very scientific way, that if testosterone [were] harmful to men, then nature would have made a major mistake," according to Dr. Saad, head of global medical affairs–andrology at Bayer Pharma in Berlin.

He added that it would be nice to confirm the findings of this observational study in a prospective randomized controlled trial, but no ethics committee in the world would approve such a study because testosterone deficiency carries elevated risks of osteoporosis, cardiovascular disease, and diabetes. And the treatment for testosterone deficiency as spelled out in Endocrine Society guidelines is testosterone replacement to normal physiologic levels.

Two other studies presented at the conference confirmed Dr. Saad’s weight loss and waist circumference shrinkage findings. Dr. Youssef El Douaihy of Maimonides Medical Center, New York, reported that during a median 6.7-year follow-up of 130 hypogonadal men on testosterone replacement therapy, the subjects lost a mean of 14.3 kg or 13% of their initial body weight. They also experienced a mean 11-cm decrease in waist circumference.

And Dr. Michael Zitzmann of the University of Munster, Germany, presented a series of 334 patients with male hypogonadism treated for up to 15 years with intramuscular testosterone undecanoate. The prevalence of metabolic syndrome dropped from 88% to 52% within the first 2 years. Highly significant reductions in blood pressure, resting heart rate, body weight, body mass index, waist circumference, fasting blood glucose, LDL cholesterol, and triglycerides were documented, all highly significant differences.

Why the big weight loss in patients on long-term testosterone replacement therapy? Dr. Saad speculated that the explanation might lie in the combined improvements in vitality, virility, and motivation to change, all of which in recent studies have been shown to be triggered by normalization of testosterone levels.

"Testosterone may be of value as a facilitator of lifestyle change," he asserted.

Dr. Gary Wittert concurred.

"It’s extremely motivating to men to see their testosterone level come up to normal and the associated improvement in body weight, erectile dysfunction, and the significant improvement in lower urinary tract symptoms. So the message is quite clear: If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination," declared Dr. Wittert, professor of medicine at the University of Adelaide, Australia, who is a testosterone clinical trialist not involved in these studies.

Dr. Saad noted that another attribute of testosterone normalization that may be highly relevant to progressive long-term weight loss is that testosterone increases fat-free mass. He cited a recent pilot study in which hypogonadal men with spinal cord injury received transdermal testosterone replacement. In 1 year, their fat-free mass increased by an average of 3.5 kg and their resting energy expenditure rose by 112 kcal/day (Horm. Metab. Res. 2011;43:574-9).

"If you accumulate that over 5 years, it could be a major contributor to the weight loss the men in our study experienced," Dr. Saad observed.

Dr. Vineeth Mohan, who chaired a session where Dr. Saad presented his findings, said the new data raise the possibility that a large weight loss in a patient treated for male hypogonadism could be an indicator that natural testosterone production has recovered and replacement therapy is no longer needed. That would make sense, since adipose tissue is a powerful suppressor of testosterone production.

"I might look at that loss of a significant amount of body weight as a signal that the testosterone axis has improved, and perhaps as an opportunity for reassessment," said Dr. Mohan, an endocrinologist at the Cleveland Clinic Foundation in Weston, Fla.

He reported having no financial conflicts.

HOUSTON – Long-term testosterone replacement therapy in men with hypogonadism brought impressive reductions in body weight and waist circumference in a 5-year observational study.

"This is an amazing response. I don’t know of many other therapies where you have more than 90% of treated patients respond in a positive way," observed Farid Saad, Ph.D. He referred to the fact that 90% of the 255 men treated for hypogonadism lost at least 5 kg from their initial body weight and 97% experienced shrinkage in waist circumference, with a 10-cm or greater reduction in 46% of men. That’s a lot of belt notches.

This 5-year study of testosterone replacement in hypogonadal men features what’s easily the longest follow-up reported anywhere to date. The average 36-pound weight loss and substantial waist shrinkage were "unintended and unexpected," because prior 1- to 2-year-long studies showed less impressive changes, explained Dr. Saad, at the annual meeting of the Endocrine Society.

The 255 study participants averaged just under 61 years of age. Nearly all were obese or overweight, as is typical in male hypogonadism. All had a serum testosterone level below 350 ng/dL, along with testosterone deficiency–related symptoms. Serum testosterone levels normalized within the first 6-9 months of treatment with slow-acting intramuscular testosterone undecanoate and remained in the normal range thereafter.

"If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination."

The men went from a mean baseline body weight of 106 kg to 90 kg over the course of 5 years. A total of 76% of participants lost 10 kg or more of their initial body weight, 53% lost at least 15 kg, and 31% dropped at least 20 kg. The weight loss was continuous; the men lost a mean of 4% of their initial body weight at 1 year, 9% at 3 years, and 13.2% after 5 years. Only 5% of men gained weight during follow-up.

Waist circumference declined by a mean of 8.8 cm from 107.2 cm at baseline. And mean body mass index dropped from 34 to 29 kg/m².

Study participants were not placed on a structured diet or exercise program, although they did receive advice on the importance of making lifestyle changes.

Three men have developed prostate cancer, but that’s less than the background rate in the general population.

"I think now the general understanding at the major urologic conferences is that testosterone does not increase the risk of prostate cancer. And I wouldn’t expect other side effects because testosterone is a natural substance and we don’t use supraphysiologic doses, we just bring testosterone levels in these hypogonadal men back to normal. I say, in a maybe not very scientific way, that if testosterone [were] harmful to men, then nature would have made a major mistake," according to Dr. Saad, head of global medical affairs–andrology at Bayer Pharma in Berlin.

He added that it would be nice to confirm the findings of this observational study in a prospective randomized controlled trial, but no ethics committee in the world would approve such a study because testosterone deficiency carries elevated risks of osteoporosis, cardiovascular disease, and diabetes. And the treatment for testosterone deficiency as spelled out in Endocrine Society guidelines is testosterone replacement to normal physiologic levels.

Two other studies presented at the conference confirmed Dr. Saad’s weight loss and waist circumference shrinkage findings. Dr. Youssef El Douaihy of Maimonides Medical Center, New York, reported that during a median 6.7-year follow-up of 130 hypogonadal men on testosterone replacement therapy, the subjects lost a mean of 14.3 kg or 13% of their initial body weight. They also experienced a mean 11-cm decrease in waist circumference.

And Dr. Michael Zitzmann of the University of Munster, Germany, presented a series of 334 patients with male hypogonadism treated for up to 15 years with intramuscular testosterone undecanoate. The prevalence of metabolic syndrome dropped from 88% to 52% within the first 2 years. Highly significant reductions in blood pressure, resting heart rate, body weight, body mass index, waist circumference, fasting blood glucose, LDL cholesterol, and triglycerides were documented, all highly significant differences.

Why the big weight loss in patients on long-term testosterone replacement therapy? Dr. Saad speculated that the explanation might lie in the combined improvements in vitality, virility, and motivation to change, all of which in recent studies have been shown to be triggered by normalization of testosterone levels.

"Testosterone may be of value as a facilitator of lifestyle change," he asserted.

Dr. Gary Wittert concurred.

"It’s extremely motivating to men to see their testosterone level come up to normal and the associated improvement in body weight, erectile dysfunction, and the significant improvement in lower urinary tract symptoms. So the message is quite clear: If you can’t motivate men to deal with their subclinical coronary artery disease, they will definitely be motivated to deal with their erections and their frequent night urination," declared Dr. Wittert, professor of medicine at the University of Adelaide, Australia, who is a testosterone clinical trialist not involved in these studies.

Dr. Saad noted that another attribute of testosterone normalization that may be highly relevant to progressive long-term weight loss is that testosterone increases fat-free mass. He cited a recent pilot study in which hypogonadal men with spinal cord injury received transdermal testosterone replacement. In 1 year, their fat-free mass increased by an average of 3.5 kg and their resting energy expenditure rose by 112 kcal/day (Horm. Metab. Res. 2011;43:574-9).

"If you accumulate that over 5 years, it could be a major contributor to the weight loss the men in our study experienced," Dr. Saad observed.

Dr. Vineeth Mohan, who chaired a session where Dr. Saad presented his findings, said the new data raise the possibility that a large weight loss in a patient treated for male hypogonadism could be an indicator that natural testosterone production has recovered and replacement therapy is no longer needed. That would make sense, since adipose tissue is a powerful suppressor of testosterone production.

"I might look at that loss of a significant amount of body weight as a signal that the testosterone axis has improved, and perhaps as an opportunity for reassessment," said Dr. Mohan, an endocrinologist at the Cleveland Clinic Foundation in Weston, Fla.

He reported having no financial conflicts.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.