Sara Freeman

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Stopping imatinib in patients who have achieved stable remission of chronic myeloid leukemia for at least 2 years appears to be a safe therapeutic strategy, according to updated results of the Australasian Leukemia and Lymphoma CML-8 trial.

"Approximately 40% of patients who had been in a stable complete molecular response and stopped their treatment are in a complete molecular response with a median follow-up of 3 years," said consultant hematologist Dr. David Ross in an interview at the annual congress of the European Hematology Association.

As of April 2012, 18 of 40 patients remained in stable complete molecular remission (CMR) while off treatment. Although 22 patients had a molecular recurrence at some point after imatinib (Gleevec) withdrawal, they all responded to the reintroduction of imatinib, with most patients rapidly regaining CMR.

These data build on those already released from the STIM (Stop Imatinib) trial (Lancet Oncol. 2010;11:1029-35) and the STOP 2G-TKI study, which have also shown that imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) withdrawal is a feasible therapeutic strategy for some patients with chronic myeloid leukemia (CML).

The CML-8 trial involved 40 adult patients who had been treated with imatinib for at least 3 years and were in CMR for at least 2 years. CMR was defined as no detectable BCR-ABL mRNA as determined by real-time quantitative polymerase chain reaction (RT-PCR) analysis. The latter was checked every month during the first year after imatinib withdrawal, every 2 months in the second year, and then every 3 months for up to 5 years of total follow-up. The last patient entered the trial in 2011, so further data from the trial are likely in the future.

"We’ve not seen any relapses later than 2 years," said Dr. Ross, of SA Pathology and Flinders Medical Centre in Adelaide, Australia.

"If I were designing the study again now, I would only do the monthly testing for 6 months because all of the action is in the first 6 months," Dr. Ross said.

The median age of patients participating in the study was 60 years. The median duration of imatinib therapy prior to withdrawal was 5.8 years (range, 3-9 years).

Although it is much smaller, the CML-8 trial provides findings similar to those of the French STIM study, Dr. Ross said. "We have seen an almost identical rate of sustained molecular response," he observed.

"We’ve also seen that the strongest predictor [for relapse] is the Sokal score, which suggests that unfavorable disease biology at the very beginning is still, after all these years of treatment, the single most important predictor of relapse risk."

Univariate analysis showed a higher percentage of patients with a low to intermediate Sokal score remaining relapse free compared with those with a high Sokal score (49.3% vs. 14.3% of 35 patients, P = .002).

One year of prior interferon therapy was also found to be predictive of relapse-free survival, with patients who had taken interferon for 1 year faring significantly better than those who had taken it for less than 1 year (60% vs. 20% of 21 patients, P = .0042).

"Again, if you stayed on interferon for more than 12 months it means that you had a good response to interferon, so it’s probably telling you the same thing in a different way," Dr. Ross suggested.

"I think the next step from this [CML-8 study] is to look at what is going to happen with the second-generation drugs," he added. "With the increasing use of nilotinib and dasatinib, the number of patients on imatinib is potentially going to diminish."

Another possible research question, Dr. Ross said, was to determine whether there is any value in pushing patients to achieve a CMR (that is, no detectable BCR-ABL) over achieving a major molecular response (MMR), in which BCR-ABL falls to less than 0.1%.

One trial that will look further at the issue of stopping tyrosine kinase inhibitors (TKIs) in CML is the EURO-SKI (European Stop Kinase Inhibitor) study. This multicenter, open-label, uncontrolled trial is being run by the European LeukemiaNet, and has just started to accrue patients.

"We hope to accrue 500 patients," said the trial’s principal investigator Dr. Susanne Saussele in an interview. Dr. Saussele of the University Medical Centre Mannheim and the University of Heidelberg, both in Germany, noted, however, that the trial does not have the backing of pharmaceutical companies, so getting funding is proving to be a challenge for some countries. To date, the trial has only started in Germany and in Sweden.

The primary aim is to estimate the persistence of molecular remission in CML after stopping treatment with available TKIs. EURO-SKI will measure MMR 4 (BCR-ABL of 0.01% or less) and MMR (BCR-ABL of 0.1% or less). Patients will need to achieve MMR 4 for at least 1 year before they can stop TKI therapy, and will have reached the end point if they lose MMR and the BCR-ABL transcript level rises over the 0.1% threshold.

"We are using MMR, which is one log higher than MMR 4 used in the STIM study," Dr. Saussele said. "This is because the STIM study showed that a lot of patients are between MMR4 and MMR."

The estimated date for completion of the trial is June 2017, with the first data available from the trial expected in roughly 3 years’ time.

The CML-8 study was conducted by the Australasian Leukemia and Lymphoma Group with funding from Novartis. Dr. Ross has received research funding and honoraria from Novartis. Dr. Saussele had no disclosures.

AMSTERDAM – Stopping imatinib in patients who have achieved stable remission of chronic myeloid leukemia for at least 2 years appears to be a safe therapeutic strategy, according to updated results of the Australasian Leukemia and Lymphoma CML-8 trial.

"Approximately 40% of patients who had been in a stable complete molecular response and stopped their treatment are in a complete molecular response with a median follow-up of 3 years," said consultant hematologist Dr. David Ross in an interview at the annual congress of the European Hematology Association.

As of April 2012, 18 of 40 patients remained in stable complete molecular remission (CMR) while off treatment. Although 22 patients had a molecular recurrence at some point after imatinib (Gleevec) withdrawal, they all responded to the reintroduction of imatinib, with most patients rapidly regaining CMR.

These data build on those already released from the STIM (Stop Imatinib) trial (Lancet Oncol. 2010;11:1029-35) and the STOP 2G-TKI study, which have also shown that imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) withdrawal is a feasible therapeutic strategy for some patients with chronic myeloid leukemia (CML).

The CML-8 trial involved 40 adult patients who had been treated with imatinib for at least 3 years and were in CMR for at least 2 years. CMR was defined as no detectable BCR-ABL mRNA as determined by real-time quantitative polymerase chain reaction (RT-PCR) analysis. The latter was checked every month during the first year after imatinib withdrawal, every 2 months in the second year, and then every 3 months for up to 5 years of total follow-up. The last patient entered the trial in 2011, so further data from the trial are likely in the future.

"We’ve not seen any relapses later than 2 years," said Dr. Ross, of SA Pathology and Flinders Medical Centre in Adelaide, Australia.

"If I were designing the study again now, I would only do the monthly testing for 6 months because all of the action is in the first 6 months," Dr. Ross said.

The median age of patients participating in the study was 60 years. The median duration of imatinib therapy prior to withdrawal was 5.8 years (range, 3-9 years).

Although it is much smaller, the CML-8 trial provides findings similar to those of the French STIM study, Dr. Ross said. "We have seen an almost identical rate of sustained molecular response," he observed.

"We’ve also seen that the strongest predictor [for relapse] is the Sokal score, which suggests that unfavorable disease biology at the very beginning is still, after all these years of treatment, the single most important predictor of relapse risk."

Univariate analysis showed a higher percentage of patients with a low to intermediate Sokal score remaining relapse free compared with those with a high Sokal score (49.3% vs. 14.3% of 35 patients, P = .002).

One year of prior interferon therapy was also found to be predictive of relapse-free survival, with patients who had taken interferon for 1 year faring significantly better than those who had taken it for less than 1 year (60% vs. 20% of 21 patients, P = .0042).

"Again, if you stayed on interferon for more than 12 months it means that you had a good response to interferon, so it’s probably telling you the same thing in a different way," Dr. Ross suggested.

"I think the next step from this [CML-8 study] is to look at what is going to happen with the second-generation drugs," he added. "With the increasing use of nilotinib and dasatinib, the number of patients on imatinib is potentially going to diminish."

Another possible research question, Dr. Ross said, was to determine whether there is any value in pushing patients to achieve a CMR (that is, no detectable BCR-ABL) over achieving a major molecular response (MMR), in which BCR-ABL falls to less than 0.1%.

One trial that will look further at the issue of stopping tyrosine kinase inhibitors (TKIs) in CML is the EURO-SKI (European Stop Kinase Inhibitor) study. This multicenter, open-label, uncontrolled trial is being run by the European LeukemiaNet, and has just started to accrue patients.

"We hope to accrue 500 patients," said the trial’s principal investigator Dr. Susanne Saussele in an interview. Dr. Saussele of the University Medical Centre Mannheim and the University of Heidelberg, both in Germany, noted, however, that the trial does not have the backing of pharmaceutical companies, so getting funding is proving to be a challenge for some countries. To date, the trial has only started in Germany and in Sweden.

The primary aim is to estimate the persistence of molecular remission in CML after stopping treatment with available TKIs. EURO-SKI will measure MMR 4 (BCR-ABL of 0.01% or less) and MMR (BCR-ABL of 0.1% or less). Patients will need to achieve MMR 4 for at least 1 year before they can stop TKI therapy, and will have reached the end point if they lose MMR and the BCR-ABL transcript level rises over the 0.1% threshold.

"We are using MMR, which is one log higher than MMR 4 used in the STIM study," Dr. Saussele said. "This is because the STIM study showed that a lot of patients are between MMR4 and MMR."

The estimated date for completion of the trial is June 2017, with the first data available from the trial expected in roughly 3 years’ time.

The CML-8 study was conducted by the Australasian Leukemia and Lymphoma Group with funding from Novartis. Dr. Ross has received research funding and honoraria from Novartis. Dr. Saussele had no disclosures.

AMSTERDAM – Stopping imatinib in patients who have achieved stable remission of chronic myeloid leukemia for at least 2 years appears to be a safe therapeutic strategy, according to updated results of the Australasian Leukemia and Lymphoma CML-8 trial.

"Approximately 40% of patients who had been in a stable complete molecular response and stopped their treatment are in a complete molecular response with a median follow-up of 3 years," said consultant hematologist Dr. David Ross in an interview at the annual congress of the European Hematology Association.

As of April 2012, 18 of 40 patients remained in stable complete molecular remission (CMR) while off treatment. Although 22 patients had a molecular recurrence at some point after imatinib (Gleevec) withdrawal, they all responded to the reintroduction of imatinib, with most patients rapidly regaining CMR.

These data build on those already released from the STIM (Stop Imatinib) trial (Lancet Oncol. 2010;11:1029-35) and the STOP 2G-TKI study, which have also shown that imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) withdrawal is a feasible therapeutic strategy for some patients with chronic myeloid leukemia (CML).

The CML-8 trial involved 40 adult patients who had been treated with imatinib for at least 3 years and were in CMR for at least 2 years. CMR was defined as no detectable BCR-ABL mRNA as determined by real-time quantitative polymerase chain reaction (RT-PCR) analysis. The latter was checked every month during the first year after imatinib withdrawal, every 2 months in the second year, and then every 3 months for up to 5 years of total follow-up. The last patient entered the trial in 2011, so further data from the trial are likely in the future.

"We’ve not seen any relapses later than 2 years," said Dr. Ross, of SA Pathology and Flinders Medical Centre in Adelaide, Australia.

"If I were designing the study again now, I would only do the monthly testing for 6 months because all of the action is in the first 6 months," Dr. Ross said.

The median age of patients participating in the study was 60 years. The median duration of imatinib therapy prior to withdrawal was 5.8 years (range, 3-9 years).

Although it is much smaller, the CML-8 trial provides findings similar to those of the French STIM study, Dr. Ross said. "We have seen an almost identical rate of sustained molecular response," he observed.

"We’ve also seen that the strongest predictor [for relapse] is the Sokal score, which suggests that unfavorable disease biology at the very beginning is still, after all these years of treatment, the single most important predictor of relapse risk."

Univariate analysis showed a higher percentage of patients with a low to intermediate Sokal score remaining relapse free compared with those with a high Sokal score (49.3% vs. 14.3% of 35 patients, P = .002).

One year of prior interferon therapy was also found to be predictive of relapse-free survival, with patients who had taken interferon for 1 year faring significantly better than those who had taken it for less than 1 year (60% vs. 20% of 21 patients, P = .0042).

"Again, if you stayed on interferon for more than 12 months it means that you had a good response to interferon, so it’s probably telling you the same thing in a different way," Dr. Ross suggested.

"I think the next step from this [CML-8 study] is to look at what is going to happen with the second-generation drugs," he added. "With the increasing use of nilotinib and dasatinib, the number of patients on imatinib is potentially going to diminish."

Another possible research question, Dr. Ross said, was to determine whether there is any value in pushing patients to achieve a CMR (that is, no detectable BCR-ABL) over achieving a major molecular response (MMR), in which BCR-ABL falls to less than 0.1%.

One trial that will look further at the issue of stopping tyrosine kinase inhibitors (TKIs) in CML is the EURO-SKI (European Stop Kinase Inhibitor) study. This multicenter, open-label, uncontrolled trial is being run by the European LeukemiaNet, and has just started to accrue patients.

"We hope to accrue 500 patients," said the trial’s principal investigator Dr. Susanne Saussele in an interview. Dr. Saussele of the University Medical Centre Mannheim and the University of Heidelberg, both in Germany, noted, however, that the trial does not have the backing of pharmaceutical companies, so getting funding is proving to be a challenge for some countries. To date, the trial has only started in Germany and in Sweden.

The primary aim is to estimate the persistence of molecular remission in CML after stopping treatment with available TKIs. EURO-SKI will measure MMR 4 (BCR-ABL of 0.01% or less) and MMR (BCR-ABL of 0.1% or less). Patients will need to achieve MMR 4 for at least 1 year before they can stop TKI therapy, and will have reached the end point if they lose MMR and the BCR-ABL transcript level rises over the 0.1% threshold.

"We are using MMR, which is one log higher than MMR 4 used in the STIM study," Dr. Saussele said. "This is because the STIM study showed that a lot of patients are between MMR4 and MMR."

The estimated date for completion of the trial is June 2017, with the first data available from the trial expected in roughly 3 years’ time.

The CML-8 study was conducted by the Australasian Leukemia and Lymphoma Group with funding from Novartis. Dr. Ross has received research funding and honoraria from Novartis. Dr. Saussele had no disclosures.

AMSTERDAM – Standard drugs commonly used to treat patients with hematologic and other malignancies are in worryingly short supply, not only in the United States, but also around the globe – a situation that has prompted three leading U.S. and European societies to issue an urgent call to action.

The American Society for Hematology (ASH), the European Hematology Association (EHA), and the European Cancer Patient Coalition (ECPC) issued joint statements June 16 to highlight the problem, which affects the care of patients with leukemia, lymphoma, myeloma, and other life-threatening blood disorders.

The international collaborative announced it would collect data on drug shortages and report the information to the respective authorities, as has been done in the United States. In addition, it "pledged to support legislation in the United States, Europe, and around the world that provides clear, effective interventions to alleviate drug shortages."

"Medicine should be available for any patient who needs it and there should be no barriers to access medicine."

Europe Takes Action

"In the United States, legislation is well under way that may curb drug shortages," Dr. Ulrich Jäger of the Medical University of Vienna, noted in the EHA press statement.

"In Europe, we do not even have a proper understanding of the problem," the EHA president added. "We must work together with our partners to raise awareness and protect the heath of patients with blood disorders worldwide."

In addition to issuing joint press statements, the societies used the joint ESH-ASH symposium at the annual congress of the European Hematology Association to highlight the issue. From the patient’s perspective, it is one of the most basic human rights to be given appropriate access to health care, said Viorica Cursaru, the president of Myeloma Euronet Romania, a member of the ECPC.

Ms. Cursaru noted that the EU health commissioner had stated that the ultimate objective of the EU is to have patients treated well in their own countries and that the time had come to implement Europewide strategies for health.

For this to happen, she argued, there needs to be not only a harmonized legal framework, but also appropriate infrastructure that is lacking in many, particularly eastern European, countries, the professional staff to implement changes, and the political will at both an EU and at a national level.

Big Pharma’s Perspective

Giving the European Federation of Pharmaceutical Industries and Associations (EFPIA), perspective, Brendan Barnes said that medicine shortages come down to more than just the price and availability; the issue is also about affordability and economic viability. EFPIA is a trade association representing the interests of the research-based pharmaceutical industry,

"We are private sector entities and we need to have a basis to do the business," Mr. Barnes maintained. While the industry wants to do all it can to ensure the adequate provision of drugs to everyone in need, via patient access schemes and reimbursement, accessibility, and affordability ultimately also comes down to local governments and their policies.

"We look to governments to support innovation through fair prices. We look to them for adequately resourced health systems, but health is a right we can only deliver if governments invest in health systems," Mr. Barnes said.

Changing the law is one thing, he said, but there also needs to be a health system in place to ensure that health interventions can successfully be delivered.

European Situation More Complex

"There are two issues at stake here as far as I can see, first is availability and second affordability," said hematologist Dr. Anton Hagenbeek of the Academic Medical Center at the University of Amsterdam in the Netherlands.

ASH is well ahead of the EU in keeping track of the drugs shortages problem, Dr. Hagenbeek observed. Indeed, ASH has collected data on hematologic drug shortages via its dedicated drug shortages portal for the past 18 months and regularly reports its findings to the Food & Drug Administration.

Drugs currently on the ASH/FDA shortage list include many generic, injectable drugs, including methotrexate, leucovorin, bleomycin, anthracyclines, and cisplatin, to name a few. According to the ASH press statement, more that 200 drugs were reported to be in short supply in the United States at one point last year, several dozen of which were critical to the care of patients with hematologic disorders.

The situation in Europe is undoubtedly more complex than in the United States, Dr. Hagenbeek observed. "We are not 1 country; we are 27 countries with our own rules and regulations."

Although it seems as if the EU has fewer drug shortages, compared with the United States, the number of incidents is increasing annually, he noted, citing a sudden shortage last year of cytosine arabinoside in the Netherlands.

The lack of an inventory to keep track of shortages needs addressing, Dr. Hagenbeek said. "Medicine should be available for any patient who needs it and there should be no barriers to access medicine," he said.

"Imagine AML induction without cytosine arabinoside, ALL induction without methotrexate and vincristine, and BEAM without the B, E, and A," Dr. Hagenbeek noted. This is a situation that is "simply unacceptable" for both hematologists as well as patients.

Following the U.S. Example

Speaking from the EHA’s perspective, Dr. Hagenbeek commented that European hematologists should follow the lead set by the United States by creating drug shortage databases in their respective countries and also by reporting drug shortages directly to the society.

Raising awareness is the start, Dr. Hagenbeek suggested. Notification of health authorities, and ultimately, hopefully changing European legislation will be the important next steps.

"EHA is in an excellent position to build on what we have already achieved as ASH in influencing legislation as a first step in dealing with the drug shortage issue," ASH president Armand Keating of the University of Toronto and the Princess Margaret Hospital in Toronto said in an interview.

"I think there are a number of potential solutions," Dr. Keating added, suggesting that an incentive-based rather than punitive-based system might be more successful in addressing drug shortages in the United States in particular.

"One of the things hematologists can do is inform patients about the issue," Dr. Keating suggested, as well as reporting drug shortages to their national health authorities and professional societies such as ASH and EHA.

Dr. Keating, Dr. Jäger, Ms. Cursaru, Mr. Barnes, and Dr. Hagenbeek had no relevant conflicts of interest other than representing their respective societies or professions.

AMSTERDAM – Standard drugs commonly used to treat patients with hematologic and other malignancies are in worryingly short supply, not only in the United States, but also around the globe – a situation that has prompted three leading U.S. and European societies to issue an urgent call to action.

The American Society for Hematology (ASH), the European Hematology Association (EHA), and the European Cancer Patient Coalition (ECPC) issued joint statements June 16 to highlight the problem, which affects the care of patients with leukemia, lymphoma, myeloma, and other life-threatening blood disorders.

The international collaborative announced it would collect data on drug shortages and report the information to the respective authorities, as has been done in the United States. In addition, it "pledged to support legislation in the United States, Europe, and around the world that provides clear, effective interventions to alleviate drug shortages."

"Medicine should be available for any patient who needs it and there should be no barriers to access medicine."

Europe Takes Action

"In the United States, legislation is well under way that may curb drug shortages," Dr. Ulrich Jäger of the Medical University of Vienna, noted in the EHA press statement.

"In Europe, we do not even have a proper understanding of the problem," the EHA president added. "We must work together with our partners to raise awareness and protect the heath of patients with blood disorders worldwide."

In addition to issuing joint press statements, the societies used the joint ESH-ASH symposium at the annual congress of the European Hematology Association to highlight the issue. From the patient’s perspective, it is one of the most basic human rights to be given appropriate access to health care, said Viorica Cursaru, the president of Myeloma Euronet Romania, a member of the ECPC.

Ms. Cursaru noted that the EU health commissioner had stated that the ultimate objective of the EU is to have patients treated well in their own countries and that the time had come to implement Europewide strategies for health.

For this to happen, she argued, there needs to be not only a harmonized legal framework, but also appropriate infrastructure that is lacking in many, particularly eastern European, countries, the professional staff to implement changes, and the political will at both an EU and at a national level.

Big Pharma’s Perspective

Giving the European Federation of Pharmaceutical Industries and Associations (EFPIA), perspective, Brendan Barnes said that medicine shortages come down to more than just the price and availability; the issue is also about affordability and economic viability. EFPIA is a trade association representing the interests of the research-based pharmaceutical industry,

"We are private sector entities and we need to have a basis to do the business," Mr. Barnes maintained. While the industry wants to do all it can to ensure the adequate provision of drugs to everyone in need, via patient access schemes and reimbursement, accessibility, and affordability ultimately also comes down to local governments and their policies.

"We look to governments to support innovation through fair prices. We look to them for adequately resourced health systems, but health is a right we can only deliver if governments invest in health systems," Mr. Barnes said.

Changing the law is one thing, he said, but there also needs to be a health system in place to ensure that health interventions can successfully be delivered.

European Situation More Complex

"There are two issues at stake here as far as I can see, first is availability and second affordability," said hematologist Dr. Anton Hagenbeek of the Academic Medical Center at the University of Amsterdam in the Netherlands.

ASH is well ahead of the EU in keeping track of the drugs shortages problem, Dr. Hagenbeek observed. Indeed, ASH has collected data on hematologic drug shortages via its dedicated drug shortages portal for the past 18 months and regularly reports its findings to the Food & Drug Administration.

Drugs currently on the ASH/FDA shortage list include many generic, injectable drugs, including methotrexate, leucovorin, bleomycin, anthracyclines, and cisplatin, to name a few. According to the ASH press statement, more that 200 drugs were reported to be in short supply in the United States at one point last year, several dozen of which were critical to the care of patients with hematologic disorders.

The situation in Europe is undoubtedly more complex than in the United States, Dr. Hagenbeek observed. "We are not 1 country; we are 27 countries with our own rules and regulations."

Although it seems as if the EU has fewer drug shortages, compared with the United States, the number of incidents is increasing annually, he noted, citing a sudden shortage last year of cytosine arabinoside in the Netherlands.

The lack of an inventory to keep track of shortages needs addressing, Dr. Hagenbeek said. "Medicine should be available for any patient who needs it and there should be no barriers to access medicine," he said.

"Imagine AML induction without cytosine arabinoside, ALL induction without methotrexate and vincristine, and BEAM without the B, E, and A," Dr. Hagenbeek noted. This is a situation that is "simply unacceptable" for both hematologists as well as patients.

Following the U.S. Example

Speaking from the EHA’s perspective, Dr. Hagenbeek commented that European hematologists should follow the lead set by the United States by creating drug shortage databases in their respective countries and also by reporting drug shortages directly to the society.

Raising awareness is the start, Dr. Hagenbeek suggested. Notification of health authorities, and ultimately, hopefully changing European legislation will be the important next steps.

"EHA is in an excellent position to build on what we have already achieved as ASH in influencing legislation as a first step in dealing with the drug shortage issue," ASH president Armand Keating of the University of Toronto and the Princess Margaret Hospital in Toronto said in an interview.

"I think there are a number of potential solutions," Dr. Keating added, suggesting that an incentive-based rather than punitive-based system might be more successful in addressing drug shortages in the United States in particular.

"One of the things hematologists can do is inform patients about the issue," Dr. Keating suggested, as well as reporting drug shortages to their national health authorities and professional societies such as ASH and EHA.

Dr. Keating, Dr. Jäger, Ms. Cursaru, Mr. Barnes, and Dr. Hagenbeek had no relevant conflicts of interest other than representing their respective societies or professions.

AMSTERDAM – Standard drugs commonly used to treat patients with hematologic and other malignancies are in worryingly short supply, not only in the United States, but also around the globe – a situation that has prompted three leading U.S. and European societies to issue an urgent call to action.

The American Society for Hematology (ASH), the European Hematology Association (EHA), and the European Cancer Patient Coalition (ECPC) issued joint statements June 16 to highlight the problem, which affects the care of patients with leukemia, lymphoma, myeloma, and other life-threatening blood disorders.

The international collaborative announced it would collect data on drug shortages and report the information to the respective authorities, as has been done in the United States. In addition, it "pledged to support legislation in the United States, Europe, and around the world that provides clear, effective interventions to alleviate drug shortages."

"Medicine should be available for any patient who needs it and there should be no barriers to access medicine."

Europe Takes Action

"In the United States, legislation is well under way that may curb drug shortages," Dr. Ulrich Jäger of the Medical University of Vienna, noted in the EHA press statement.

"In Europe, we do not even have a proper understanding of the problem," the EHA president added. "We must work together with our partners to raise awareness and protect the heath of patients with blood disorders worldwide."

In addition to issuing joint press statements, the societies used the joint ESH-ASH symposium at the annual congress of the European Hematology Association to highlight the issue. From the patient’s perspective, it is one of the most basic human rights to be given appropriate access to health care, said Viorica Cursaru, the president of Myeloma Euronet Romania, a member of the ECPC.

Ms. Cursaru noted that the EU health commissioner had stated that the ultimate objective of the EU is to have patients treated well in their own countries and that the time had come to implement Europewide strategies for health.

For this to happen, she argued, there needs to be not only a harmonized legal framework, but also appropriate infrastructure that is lacking in many, particularly eastern European, countries, the professional staff to implement changes, and the political will at both an EU and at a national level.

Big Pharma’s Perspective

Giving the European Federation of Pharmaceutical Industries and Associations (EFPIA), perspective, Brendan Barnes said that medicine shortages come down to more than just the price and availability; the issue is also about affordability and economic viability. EFPIA is a trade association representing the interests of the research-based pharmaceutical industry,

"We are private sector entities and we need to have a basis to do the business," Mr. Barnes maintained. While the industry wants to do all it can to ensure the adequate provision of drugs to everyone in need, via patient access schemes and reimbursement, accessibility, and affordability ultimately also comes down to local governments and their policies.

"We look to governments to support innovation through fair prices. We look to them for adequately resourced health systems, but health is a right we can only deliver if governments invest in health systems," Mr. Barnes said.

Changing the law is one thing, he said, but there also needs to be a health system in place to ensure that health interventions can successfully be delivered.

European Situation More Complex

"There are two issues at stake here as far as I can see, first is availability and second affordability," said hematologist Dr. Anton Hagenbeek of the Academic Medical Center at the University of Amsterdam in the Netherlands.

ASH is well ahead of the EU in keeping track of the drugs shortages problem, Dr. Hagenbeek observed. Indeed, ASH has collected data on hematologic drug shortages via its dedicated drug shortages portal for the past 18 months and regularly reports its findings to the Food & Drug Administration.

Drugs currently on the ASH/FDA shortage list include many generic, injectable drugs, including methotrexate, leucovorin, bleomycin, anthracyclines, and cisplatin, to name a few. According to the ASH press statement, more that 200 drugs were reported to be in short supply in the United States at one point last year, several dozen of which were critical to the care of patients with hematologic disorders.

The situation in Europe is undoubtedly more complex than in the United States, Dr. Hagenbeek observed. "We are not 1 country; we are 27 countries with our own rules and regulations."

Although it seems as if the EU has fewer drug shortages, compared with the United States, the number of incidents is increasing annually, he noted, citing a sudden shortage last year of cytosine arabinoside in the Netherlands.

The lack of an inventory to keep track of shortages needs addressing, Dr. Hagenbeek said. "Medicine should be available for any patient who needs it and there should be no barriers to access medicine," he said.

"Imagine AML induction without cytosine arabinoside, ALL induction without methotrexate and vincristine, and BEAM without the B, E, and A," Dr. Hagenbeek noted. This is a situation that is "simply unacceptable" for both hematologists as well as patients.

Following the U.S. Example

Speaking from the EHA’s perspective, Dr. Hagenbeek commented that European hematologists should follow the lead set by the United States by creating drug shortage databases in their respective countries and also by reporting drug shortages directly to the society.

Raising awareness is the start, Dr. Hagenbeek suggested. Notification of health authorities, and ultimately, hopefully changing European legislation will be the important next steps.

"EHA is in an excellent position to build on what we have already achieved as ASH in influencing legislation as a first step in dealing with the drug shortage issue," ASH president Armand Keating of the University of Toronto and the Princess Margaret Hospital in Toronto said in an interview.

"I think there are a number of potential solutions," Dr. Keating added, suggesting that an incentive-based rather than punitive-based system might be more successful in addressing drug shortages in the United States in particular.

"One of the things hematologists can do is inform patients about the issue," Dr. Keating suggested, as well as reporting drug shortages to their national health authorities and professional societies such as ASH and EHA.

Dr. Keating, Dr. Jäger, Ms. Cursaru, Mr. Barnes, and Dr. Hagenbeek had no relevant conflicts of interest other than representing their respective societies or professions.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.

Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).

"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.

"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.

Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.

"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.

Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.

GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.

The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).

Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.

The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.

Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.

Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.

"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.

Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.

Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.

"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."

Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.

The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.

CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.

Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).

"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.

"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.

Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.

"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.

Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.

GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.

The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).

Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.

The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.

Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.

Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.

"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.

Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.

Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.

"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."

Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.

The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.

CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.

Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).

"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.

"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.

Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.

"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.

Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.

GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.

The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).

Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.

The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.

Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.

Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.

"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.

Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.

Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.

"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."

Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.

The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.

GLASGOW, SCOTLAND – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study.

Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154).

Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).

Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).

"We think that patients who develop scleroderma and cancer can be divided into two different groups," trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology.

"The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease."

The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.

Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.

This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).

"Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer," Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).

The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues.

Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.

The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%).

"We found no differences in gender, age, and disease subsets between patients with and without cancer," Dr. Moinzadeh said.

"When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies."

Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.

While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several "red flags" that could perhaps signal if patients were likely to have "paraneoplastic scleroderma."

These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.

"This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine," said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.

Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.

GLASGOW, SCOTLAND – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study.

Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154).

Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).

Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).

"We think that patients who develop scleroderma and cancer can be divided into two different groups," trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology.

"The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease."

The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.

Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.

This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).

"Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer," Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).

The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues.

Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.

The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%).

"We found no differences in gender, age, and disease subsets between patients with and without cancer," Dr. Moinzadeh said.

"When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies."

Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.

While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several "red flags" that could perhaps signal if patients were likely to have "paraneoplastic scleroderma."

These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.

"This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine," said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.

Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.

GLASGOW, SCOTLAND – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study.

Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154).

Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).

Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).

"We think that patients who develop scleroderma and cancer can be divided into two different groups," trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology.

"The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease."

The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.

Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.

This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).

"Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer," Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).

The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues.

Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.

The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%).

"We found no differences in gender, age, and disease subsets between patients with and without cancer," Dr. Moinzadeh said.

"When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies."

Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.

While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several "red flags" that could perhaps signal if patients were likely to have "paraneoplastic scleroderma."

These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.

"This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine," said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.

Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.

GLASGOW, SCOTLAND – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.

Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.

Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.

"TNF has huge effects on metabolism," said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.

"Metabolomics assess many metabolites together in biological samples, such as urine or blood," explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?

Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA).

The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15).

Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment.

All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.

Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).

Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.

The baseline clinical characteristics of "good responders" and "not good responders" were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use.

RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment.

"There was a significant [P = .04] correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28," Dr. Kapoor said.

Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.

"Urine is actually a cleaner biofluid than other biofluids, such as serum," Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR.

The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh.

These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.

Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here.

GLASGOW, SCOTLAND – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.

Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.

Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.

"TNF has huge effects on metabolism," said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.

"Metabolomics assess many metabolites together in biological samples, such as urine or blood," explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?

Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA).

The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15).

Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment.

All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.

Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).

Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.

The baseline clinical characteristics of "good responders" and "not good responders" were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use.

RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment.

"There was a significant [P = .04] correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28," Dr. Kapoor said.

Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.

"Urine is actually a cleaner biofluid than other biofluids, such as serum," Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR.

The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh.

These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.

Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here.

GLASGOW, SCOTLAND – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.

Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.

Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.

"TNF has huge effects on metabolism," said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.

"Metabolomics assess many metabolites together in biological samples, such as urine or blood," explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?

Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA).

The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15).

Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment.

All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.

Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).

Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.

The baseline clinical characteristics of "good responders" and "not good responders" were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use.

RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment.

"There was a significant [P = .04] correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28," Dr. Kapoor said.

Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.

"Urine is actually a cleaner biofluid than other biofluids, such as serum," Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR.

The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh.

These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.

Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here.

GLASGOW, SCOTLAND – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked.

The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.

Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.

©Sveta Kashkina/iStockphoto.com

A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.

This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology.

Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive.

Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.

The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.

RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months.

Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA

"Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses," Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77.

Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.

Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.

Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that "these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes."

Dr. Khan noted that they also raise an ethical dilemma for clinicians. "The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.

"This observation creates a complex ethical dilemma which needs to be addressed."

Dr. Khan and Dr. Scott had no financial disclosures.

GLASGOW, SCOTLAND – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked.

The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.

Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.

©Sveta Kashkina/iStockphoto.com

A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.

This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology.

Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive.

Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.

The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.

RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months.

Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA

"Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses," Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77.

Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.

Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.

Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that "these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes."

Dr. Khan noted that they also raise an ethical dilemma for clinicians. "The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.

"This observation creates a complex ethical dilemma which needs to be addressed."

Dr. Khan and Dr. Scott had no financial disclosures.

GLASGOW, SCOTLAND – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked.

The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.

Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.

©Sveta Kashkina/iStockphoto.com

A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.

This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology.

Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive.

Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.

The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.

RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months.

Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA

"Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses," Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77.

Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.

Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.

Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that "these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes."

Dr. Khan noted that they also raise an ethical dilemma for clinicians. "The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.

"This observation creates a complex ethical dilemma which needs to be addressed."

Dr. Khan and Dr. Scott had no financial disclosures.

GLASGOW, SCOTLAND – Five-year mortality following the diagnosis of systemic rheumatoid vasculitis hovers around 60%, according to an analysis of 34 cases identified in a British-based patient registry.

Although the annual incidence of SRV has reportedly been decreasing since the 1990s, these data suggest it remains a problem despite the introduction of modern immunosuppressive therapies and the use of earlier and more aggressive treatment for rheumatoid arthritis, Dr. Eleana Ntatsaki, a rheumatology specialist trainee at Norfolk and Norwich (England) University Hospital, said at the annual meeting of the British Society for Rheumatology.

The Norfolk Vasculitis Register (NORVASC) is a prospective patient registry established in 1988 to log cases of vasculitis that occur in the county of Norfolk, England. This is a region particularly well suited to epidemiological study, as it is an isolated geographical area with a stable and well-defined population. This is also one of the reasons the Norfolk Arthritis Register (NOAR) is situated in this part of the country.

Between Jan. 1, 2001, and Dec. 31, 2010, a total of 34 cases were reviewed in detail, with 18 patients (10 men) confirmed as having SRV according to previously published criteria (Am. J. Med. 1984;76:377-84), chart review, and independent physician assessment.

The median age of confirmed cases at diagnosis was 72 years and the average disease duration before SRV diagnosis was nearly 16 years. All patients were rheumatoid factor positive, 13 had documented erosive disease, and three had rheumatoid nodules.

All patients had been treated with steroids, a median of two prior DMARDs had been used (methotrexate in 65% of patients), and two patients had received biologic agents. SRV had been treated with intravenous cyclophosphamide (median six cycles) in all but one patient.

The average annual incidence of SRV was calculated to be 3.9 per million (95% confidence interval [CI], 2.3-6.2). This was substantially lower than the 9.1 per million (95% CI, 6.8-12.0) seen in a reference population of 47 patients who developed the complication between 1998 and 2000.

The average annual incidence rates in 2001-2010 were 4.5 (95% CI, 2.2-8.3) for men and 3.4 (95% CI, 1.4-6.6) for women. In 1998-2000, the rates were 8.9 (95% CI, 5.7-13.1) for men and 8.7 (95% CI, 5.6-12.8) for women.

No statistically significant differences were found in the number of patients experiencing systemic, cutaneous, neurologic, pulmonary, renal, ophthalmic, or gastrointestinal manifestations between the two time periods.

Mortality rates at 1 year were also similar between the cohorts, at 12% for 2001-2010 and 14% for 1998-2000. Five-year mortality rates were 60% and 51%, respectively.

"Modern immunosuppression therapy seems to be associated with a decrease in the incidence" of systemic rheumatoid vasculitis, said Dr. Ntatsaki, "but has had no significant influence on clinical features, or outcome."

Whether the decrease in incidence can truly be attributed to methotrexate or improvements in RA treatment in general is questionable, suggested Dr. Deborah Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England).

This decline in the incidence of rheumatoid vasculitis is not necessarily because rheumatoid arthritis treatments have improved, she said. "Perhaps it is just the natural history of rheumatoid arthritis that vasculitis is becoming rare. Clearly when people do get it they do just as badly as they ever did, and perhaps all this about methotrexate is completely coincidental."

Dr. Ntatsaki reported having no financial disclosures.

GLASGOW, SCOTLAND – Five-year mortality following the diagnosis of systemic rheumatoid vasculitis hovers around 60%, according to an analysis of 34 cases identified in a British-based patient registry.

Although the annual incidence of SRV has reportedly been decreasing since the 1990s, these data suggest it remains a problem despite the introduction of modern immunosuppressive therapies and the use of earlier and more aggressive treatment for rheumatoid arthritis, Dr. Eleana Ntatsaki, a rheumatology specialist trainee at Norfolk and Norwich (England) University Hospital, said at the annual meeting of the British Society for Rheumatology.

The Norfolk Vasculitis Register (NORVASC) is a prospective patient registry established in 1988 to log cases of vasculitis that occur in the county of Norfolk, England. This is a region particularly well suited to epidemiological study, as it is an isolated geographical area with a stable and well-defined population. This is also one of the reasons the Norfolk Arthritis Register (NOAR) is situated in this part of the country.

Between Jan. 1, 2001, and Dec. 31, 2010, a total of 34 cases were reviewed in detail, with 18 patients (10 men) confirmed as having SRV according to previously published criteria (Am. J. Med. 1984;76:377-84), chart review, and independent physician assessment.

The median age of confirmed cases at diagnosis was 72 years and the average disease duration before SRV diagnosis was nearly 16 years. All patients were rheumatoid factor positive, 13 had documented erosive disease, and three had rheumatoid nodules.

All patients had been treated with steroids, a median of two prior DMARDs had been used (methotrexate in 65% of patients), and two patients had received biologic agents. SRV had been treated with intravenous cyclophosphamide (median six cycles) in all but one patient.

The average annual incidence of SRV was calculated to be 3.9 per million (95% confidence interval [CI], 2.3-6.2). This was substantially lower than the 9.1 per million (95% CI, 6.8-12.0) seen in a reference population of 47 patients who developed the complication between 1998 and 2000.

The average annual incidence rates in 2001-2010 were 4.5 (95% CI, 2.2-8.3) for men and 3.4 (95% CI, 1.4-6.6) for women. In 1998-2000, the rates were 8.9 (95% CI, 5.7-13.1) for men and 8.7 (95% CI, 5.6-12.8) for women.

No statistically significant differences were found in the number of patients experiencing systemic, cutaneous, neurologic, pulmonary, renal, ophthalmic, or gastrointestinal manifestations between the two time periods.

Mortality rates at 1 year were also similar between the cohorts, at 12% for 2001-2010 and 14% for 1998-2000. Five-year mortality rates were 60% and 51%, respectively.

"Modern immunosuppression therapy seems to be associated with a decrease in the incidence" of systemic rheumatoid vasculitis, said Dr. Ntatsaki, "but has had no significant influence on clinical features, or outcome."

Whether the decrease in incidence can truly be attributed to methotrexate or improvements in RA treatment in general is questionable, suggested Dr. Deborah Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England).

This decline in the incidence of rheumatoid vasculitis is not necessarily because rheumatoid arthritis treatments have improved, she said. "Perhaps it is just the natural history of rheumatoid arthritis that vasculitis is becoming rare. Clearly when people do get it they do just as badly as they ever did, and perhaps all this about methotrexate is completely coincidental."

Dr. Ntatsaki reported having no financial disclosures.

GLASGOW, SCOTLAND – Five-year mortality following the diagnosis of systemic rheumatoid vasculitis hovers around 60%, according to an analysis of 34 cases identified in a British-based patient registry.

Although the annual incidence of SRV has reportedly been decreasing since the 1990s, these data suggest it remains a problem despite the introduction of modern immunosuppressive therapies and the use of earlier and more aggressive treatment for rheumatoid arthritis, Dr. Eleana Ntatsaki, a rheumatology specialist trainee at Norfolk and Norwich (England) University Hospital, said at the annual meeting of the British Society for Rheumatology.

The Norfolk Vasculitis Register (NORVASC) is a prospective patient registry established in 1988 to log cases of vasculitis that occur in the county of Norfolk, England. This is a region particularly well suited to epidemiological study, as it is an isolated geographical area with a stable and well-defined population. This is also one of the reasons the Norfolk Arthritis Register (NOAR) is situated in this part of the country.

Between Jan. 1, 2001, and Dec. 31, 2010, a total of 34 cases were reviewed in detail, with 18 patients (10 men) confirmed as having SRV according to previously published criteria (Am. J. Med. 1984;76:377-84), chart review, and independent physician assessment.

The median age of confirmed cases at diagnosis was 72 years and the average disease duration before SRV diagnosis was nearly 16 years. All patients were rheumatoid factor positive, 13 had documented erosive disease, and three had rheumatoid nodules.

All patients had been treated with steroids, a median of two prior DMARDs had been used (methotrexate in 65% of patients), and two patients had received biologic agents. SRV had been treated with intravenous cyclophosphamide (median six cycles) in all but one patient.

The average annual incidence of SRV was calculated to be 3.9 per million (95% confidence interval [CI], 2.3-6.2). This was substantially lower than the 9.1 per million (95% CI, 6.8-12.0) seen in a reference population of 47 patients who developed the complication between 1998 and 2000.

The average annual incidence rates in 2001-2010 were 4.5 (95% CI, 2.2-8.3) for men and 3.4 (95% CI, 1.4-6.6) for women. In 1998-2000, the rates were 8.9 (95% CI, 5.7-13.1) for men and 8.7 (95% CI, 5.6-12.8) for women.

No statistically significant differences were found in the number of patients experiencing systemic, cutaneous, neurologic, pulmonary, renal, ophthalmic, or gastrointestinal manifestations between the two time periods.

Mortality rates at 1 year were also similar between the cohorts, at 12% for 2001-2010 and 14% for 1998-2000. Five-year mortality rates were 60% and 51%, respectively.

"Modern immunosuppression therapy seems to be associated with a decrease in the incidence" of systemic rheumatoid vasculitis, said Dr. Ntatsaki, "but has had no significant influence on clinical features, or outcome."

Whether the decrease in incidence can truly be attributed to methotrexate or improvements in RA treatment in general is questionable, suggested Dr. Deborah Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England).

This decline in the incidence of rheumatoid vasculitis is not necessarily because rheumatoid arthritis treatments have improved, she said. "Perhaps it is just the natural history of rheumatoid arthritis that vasculitis is becoming rare. Clearly when people do get it they do just as badly as they ever did, and perhaps all this about methotrexate is completely coincidental."

Dr. Ntatsaki reported having no financial disclosures.

GLASGOW, SCOTLAND – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.

Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.

Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.

"There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases," said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.

Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).

The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).

Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus.

Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR.

Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9).

A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.

The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001) and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).

Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).

In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.

"We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort," Dr. Ng commented.

Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council.

GLASGOW, SCOTLAND – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.

Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.

Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.

"There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases," said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.

Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).

The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).

Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus.

Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR.

Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9).

A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.

The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001) and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).

Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).

In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.

"We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort," Dr. Ng commented.

Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council.

GLASGOW, SCOTLAND – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.

Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.

Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.

"There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases," said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.

Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).

The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).

Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus.

Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR.

Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9).

A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.

The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001) and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).

Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).

In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.

"We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort," Dr. Ng commented.

Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council.