ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

Doctor and patient in hospital
Photo courtesy of the CDC

A new study sheds light on whether an increased risk of death in the 30 days to 2 years after contracting sepsis is caused by sepsis itself, or because of pre-existing health conditions the patients had before acquiring the complication.

Using detailed survey data and medical records of more than 30,000 older Americans, the researchers conducted a propensity matched cohort study to investigate the phenomenon of late death after sepsis.

Late death refers to deaths that take place months to years after the acute infection has resolved.

"We know sicker patients are more likely to develop sepsis," lead author Hallie Prescott, MD, of the University of Michigan in Ann Arbor, said. "And that made us wonder: Perhaps those previous health conditions are driving the risk of late death after sepsis?"

So the investigators compared 960 patients aged 65 or older who were admitted to the hospital with sepsis to 3 control groups: 777 adults not currently hospitalized, 788 patients hospitalized with non-sepsis infections, and 504 patients admitted with acute sterile inflammatory conditions.

All patients had participated in the US Health and Retirement Study, a longitudinal survey of 37,000 adults aged over 50 in 23,000 households. The survey is considered broadly representative of the older US population.

The current study included Medicare beneficiaries who had participated in at least one survey between 1998 and 2008.

The main outcome measure was late mortality 31 days to 2 years after sepsis and odds of death at various intervals.

Results

In the sepsis cohort, the mean age was 79, 54% were women, 81% were white, and 12% were nursing home residents.

There were no significant differences among the cohorts in terms of demographics, socioeconomic characteristics, baseline health status, or recent healthcare use.

The sepsis cohort had a 25.4% mortality rate at 30 days, 35.3% at 90 days, 41.3% at 180 days, 48.5% at 1 year, and 56.5% at 2 years.

Over 40% of sepsis patients who survived 30 days after their hospitalization died in the next 2 years. If sepsis patients survived to a year, the adjusted 2-year mortality was 16.0% versus 10.7% for controls not in the hospital.

When investigators compared these mortality rates to matched patients who were not hospitalized, they found that those with sepsis experienced a 22.1% absolute increase in late mortality. This translated into a 2.2-fold relative increase in late mortality.

And when they compared the sepsis patients to patients hospitalized for non-sepsis infections, the investigators determined that sepsis patients experienced a 10.4% absolute increase in late mortality. This translated into a 1.3-fold relative increase in late mortality.

Finally, they compared the sepsis patients to those patients hospitalized for sterile inflammatory conditions and found that the sepsis patients who survived to 31 days experienced a 16.2% absolute increase in late mortality. This translated into 1.6-fold relative increase.

The investigators said this high rate of late mortality could not be explained by the patients’ age, socio-demographics, or their pre-sepsis health status.

"Rather, we found that, compared to the group of adults not in the hospital,” Dr Prescott said, “1 in 5 patients who survived sepsis had a late death that was not explained by their baseline characteristics.”

The investigators said this suggests that late mortality after sepsis could be more amendable to intervention than previously thought.

The investigators published their findings in BMJ.

Doctor and patient in hospital
Photo courtesy of the CDC

A new study sheds light on whether an increased risk of death in the 30 days to 2 years after contracting sepsis is caused by sepsis itself, or because of pre-existing health conditions the patients had before acquiring the complication.

Using detailed survey data and medical records of more than 30,000 older Americans, the researchers conducted a propensity matched cohort study to investigate the phenomenon of late death after sepsis.

Late death refers to deaths that take place months to years after the acute infection has resolved.

"We know sicker patients are more likely to develop sepsis," lead author Hallie Prescott, MD, of the University of Michigan in Ann Arbor, said. "And that made us wonder: Perhaps those previous health conditions are driving the risk of late death after sepsis?"

So the investigators compared 960 patients aged 65 or older who were admitted to the hospital with sepsis to 3 control groups: 777 adults not currently hospitalized, 788 patients hospitalized with non-sepsis infections, and 504 patients admitted with acute sterile inflammatory conditions.

All patients had participated in the US Health and Retirement Study, a longitudinal survey of 37,000 adults aged over 50 in 23,000 households. The survey is considered broadly representative of the older US population.

The current study included Medicare beneficiaries who had participated in at least one survey between 1998 and 2008.

The main outcome measure was late mortality 31 days to 2 years after sepsis and odds of death at various intervals.

Results

In the sepsis cohort, the mean age was 79, 54% were women, 81% were white, and 12% were nursing home residents.

There were no significant differences among the cohorts in terms of demographics, socioeconomic characteristics, baseline health status, or recent healthcare use.

The sepsis cohort had a 25.4% mortality rate at 30 days, 35.3% at 90 days, 41.3% at 180 days, 48.5% at 1 year, and 56.5% at 2 years.

Over 40% of sepsis patients who survived 30 days after their hospitalization died in the next 2 years. If sepsis patients survived to a year, the adjusted 2-year mortality was 16.0% versus 10.7% for controls not in the hospital.

When investigators compared these mortality rates to matched patients who were not hospitalized, they found that those with sepsis experienced a 22.1% absolute increase in late mortality. This translated into a 2.2-fold relative increase in late mortality.

And when they compared the sepsis patients to patients hospitalized for non-sepsis infections, the investigators determined that sepsis patients experienced a 10.4% absolute increase in late mortality. This translated into a 1.3-fold relative increase in late mortality.

Finally, they compared the sepsis patients to those patients hospitalized for sterile inflammatory conditions and found that the sepsis patients who survived to 31 days experienced a 16.2% absolute increase in late mortality. This translated into 1.6-fold relative increase.

The investigators said this high rate of late mortality could not be explained by the patients’ age, socio-demographics, or their pre-sepsis health status.

"Rather, we found that, compared to the group of adults not in the hospital,” Dr Prescott said, “1 in 5 patients who survived sepsis had a late death that was not explained by their baseline characteristics.”

The investigators said this suggests that late mortality after sepsis could be more amendable to intervention than previously thought.

The investigators published their findings in BMJ.

Doctor and patient in hospital
Photo courtesy of the CDC

A new study sheds light on whether an increased risk of death in the 30 days to 2 years after contracting sepsis is caused by sepsis itself, or because of pre-existing health conditions the patients had before acquiring the complication.

Using detailed survey data and medical records of more than 30,000 older Americans, the researchers conducted a propensity matched cohort study to investigate the phenomenon of late death after sepsis.

Late death refers to deaths that take place months to years after the acute infection has resolved.

"We know sicker patients are more likely to develop sepsis," lead author Hallie Prescott, MD, of the University of Michigan in Ann Arbor, said. "And that made us wonder: Perhaps those previous health conditions are driving the risk of late death after sepsis?"

So the investigators compared 960 patients aged 65 or older who were admitted to the hospital with sepsis to 3 control groups: 777 adults not currently hospitalized, 788 patients hospitalized with non-sepsis infections, and 504 patients admitted with acute sterile inflammatory conditions.

All patients had participated in the US Health and Retirement Study, a longitudinal survey of 37,000 adults aged over 50 in 23,000 households. The survey is considered broadly representative of the older US population.

The current study included Medicare beneficiaries who had participated in at least one survey between 1998 and 2008.

The main outcome measure was late mortality 31 days to 2 years after sepsis and odds of death at various intervals.

Results

In the sepsis cohort, the mean age was 79, 54% were women, 81% were white, and 12% were nursing home residents.

There were no significant differences among the cohorts in terms of demographics, socioeconomic characteristics, baseline health status, or recent healthcare use.

The sepsis cohort had a 25.4% mortality rate at 30 days, 35.3% at 90 days, 41.3% at 180 days, 48.5% at 1 year, and 56.5% at 2 years.

Over 40% of sepsis patients who survived 30 days after their hospitalization died in the next 2 years. If sepsis patients survived to a year, the adjusted 2-year mortality was 16.0% versus 10.7% for controls not in the hospital.

When investigators compared these mortality rates to matched patients who were not hospitalized, they found that those with sepsis experienced a 22.1% absolute increase in late mortality. This translated into a 2.2-fold relative increase in late mortality.

And when they compared the sepsis patients to patients hospitalized for non-sepsis infections, the investigators determined that sepsis patients experienced a 10.4% absolute increase in late mortality. This translated into a 1.3-fold relative increase in late mortality.

Finally, they compared the sepsis patients to those patients hospitalized for sterile inflammatory conditions and found that the sepsis patients who survived to 31 days experienced a 16.2% absolute increase in late mortality. This translated into 1.6-fold relative increase.

The investigators said this high rate of late mortality could not be explained by the patients’ age, socio-demographics, or their pre-sepsis health status.

"Rather, we found that, compared to the group of adults not in the hospital,” Dr Prescott said, “1 in 5 patients who survived sepsis had a late death that was not explained by their baseline characteristics.”

The investigators said this suggests that late mortality after sepsis could be more amendable to intervention than previously thought.

The investigators published their findings in BMJ.

CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.

The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.

University of Nebraska Medical Center

“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.

Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).

Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).

“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”

However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.

Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.

Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.

When asked to comment on this, Dr. Daniel E. Furst noted that “there could be an awfully large selection bias in this study. If you ask yourself, ‘Why do people go to subcutaneous in an observational trial?’ it is possible that they didn’t have enough response to the oral. They didn’t go to a higher dose, but, rather stopped methotrexate altogether. The result is that injection looks better. I think this study has a significant flaw, as is often unavoidable in observational studies. This study, per se, does not prove that s.c. methotrexate has an advantage over oral methotrexate in terms of delay of starting a biologic.”

The increased bioavailability of subcutaneous administration versus oral – which is about 17% – does not make it necessarily better for all patients, Dr. Furst contended, although it can certainly be a good option for those affected by gastrointestinal side effects with oral administration. “Given that a 17% increase in bioavailability with subcutaneous administration, this equals about 3-4 mg extra methotrexate. 20 mg/week s.c. methotrexate equals about 23 or 24 mg/week of oral methotrexate. My point is that if a patients tolerates it, giving a little higher dose of oral methotrexate may be the same as giving a slightly higher dose subcutaneously. It is probably true, incidentally, that subcutaneous methotrexate, when given as a generic is less expensive than the oral. A 25-mg/mL vial costs somewhere in the range of one-half to one-third of oral.”

Waiting for 6 months of treatment with oral methotrexate is ideal when a patient is having some response but may not be appropriate for all, according to Dr. Furst, the Carl Pearson Professor of Medicine in the division of rheumatology at the University of California, Los Angeles. He cited research showing 35% of patients who did not yet have an ACR 20–level response at 12 weeks of treatment with oral methotrexate alone at 7.5-20 mg/week can reach that level of response by 26 weeks (Rheumatology. 2010;49[6]:1201-3). “What I took away from that is, on a practical basis, if patients have absolutely no response, however you define it, by 12 weeks, then stop. If they’re having some response, then wait and see if they get more response before stopping,” he said.

The claims analysis that Dr. O’Dell discussed at the NCRA annual meeting gets straight to that point of whether rheumatologists are giving methotrexate a long enough time to work. What compounds the problem, according to Dr. O’Dell, is that too few people are giving oral methotrexate a long enough chance to work or trying subcutaneous dosing. The analysis of claims data from 35,640 RA patients during 2009-2014 that he originally presented at the 2015 American College of Rheumatology annual meeting showed that 44% of patients who started on oral methotrexate alone stayed on it throughout the study period and didn’t need anything else.

Prescribers, however, stopped oral methotrexate at a mean dose of 15.3 mg and moved 87% straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients. Of the patients who were given subcutaneous methotrexate when their oral formulation wasn’t enough that’s all most of them needed, as 72% remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years. The same results applied to patients who started treatment in 2009 or 2012.

What the evidence from the claims data study does not say is why physicians are prescribing this way. Some might suggest that the influence of pharmaceutical companies might have something to do with it, although the notion is controversial. A recent systematic review and meta-analysis of randomized, controlled trials that involved a direct comparison of methotrexate monotherapy against methotrexate plus a biologic or biologic monotherapy to treat RA concluded that there is a dosing bias in the trials where methotrexate monotherapy is underdosed because none of the 13 trials that met criteria to be in the review used a methotrexate dose of 25 mg/week (Ann Rheum Dis. 2016 Apr 18. doi: 10.1136/annrheumdis-2016-209383). The investigators, led by Dr. Josefina Durán of Pontificia Universidad Católica de Chile, Santiago, said that they used 25 mg/week as the maximum recommended dose because it is recommended by EULAR and expert opinion.

The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”

“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”

“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”

Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.

[email protected]

CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.

The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.

University of Nebraska Medical Center

“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.

Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).

Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).

“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”

However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.

Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.

Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.

When asked to comment on this, Dr. Daniel E. Furst noted that “there could be an awfully large selection bias in this study. If you ask yourself, ‘Why do people go to subcutaneous in an observational trial?’ it is possible that they didn’t have enough response to the oral. They didn’t go to a higher dose, but, rather stopped methotrexate altogether. The result is that injection looks better. I think this study has a significant flaw, as is often unavoidable in observational studies. This study, per se, does not prove that s.c. methotrexate has an advantage over oral methotrexate in terms of delay of starting a biologic.”

The increased bioavailability of subcutaneous administration versus oral – which is about 17% – does not make it necessarily better for all patients, Dr. Furst contended, although it can certainly be a good option for those affected by gastrointestinal side effects with oral administration. “Given that a 17% increase in bioavailability with subcutaneous administration, this equals about 3-4 mg extra methotrexate. 20 mg/week s.c. methotrexate equals about 23 or 24 mg/week of oral methotrexate. My point is that if a patients tolerates it, giving a little higher dose of oral methotrexate may be the same as giving a slightly higher dose subcutaneously. It is probably true, incidentally, that subcutaneous methotrexate, when given as a generic is less expensive than the oral. A 25-mg/mL vial costs somewhere in the range of one-half to one-third of oral.”

Waiting for 6 months of treatment with oral methotrexate is ideal when a patient is having some response but may not be appropriate for all, according to Dr. Furst, the Carl Pearson Professor of Medicine in the division of rheumatology at the University of California, Los Angeles. He cited research showing 35% of patients who did not yet have an ACR 20–level response at 12 weeks of treatment with oral methotrexate alone at 7.5-20 mg/week can reach that level of response by 26 weeks (Rheumatology. 2010;49[6]:1201-3). “What I took away from that is, on a practical basis, if patients have absolutely no response, however you define it, by 12 weeks, then stop. If they’re having some response, then wait and see if they get more response before stopping,” he said.

The claims analysis that Dr. O’Dell discussed at the NCRA annual meeting gets straight to that point of whether rheumatologists are giving methotrexate a long enough time to work. What compounds the problem, according to Dr. O’Dell, is that too few people are giving oral methotrexate a long enough chance to work or trying subcutaneous dosing. The analysis of claims data from 35,640 RA patients during 2009-2014 that he originally presented at the 2015 American College of Rheumatology annual meeting showed that 44% of patients who started on oral methotrexate alone stayed on it throughout the study period and didn’t need anything else.

Prescribers, however, stopped oral methotrexate at a mean dose of 15.3 mg and moved 87% straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients. Of the patients who were given subcutaneous methotrexate when their oral formulation wasn’t enough that’s all most of them needed, as 72% remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years. The same results applied to patients who started treatment in 2009 or 2012.

What the evidence from the claims data study does not say is why physicians are prescribing this way. Some might suggest that the influence of pharmaceutical companies might have something to do with it, although the notion is controversial. A recent systematic review and meta-analysis of randomized, controlled trials that involved a direct comparison of methotrexate monotherapy against methotrexate plus a biologic or biologic monotherapy to treat RA concluded that there is a dosing bias in the trials where methotrexate monotherapy is underdosed because none of the 13 trials that met criteria to be in the review used a methotrexate dose of 25 mg/week (Ann Rheum Dis. 2016 Apr 18. doi: 10.1136/annrheumdis-2016-209383). The investigators, led by Dr. Josefina Durán of Pontificia Universidad Católica de Chile, Santiago, said that they used 25 mg/week as the maximum recommended dose because it is recommended by EULAR and expert opinion.

The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”

“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”

“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”

Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.

[email protected]

CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.

The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.

University of Nebraska Medical Center

“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.

Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).

Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).

“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”

However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.

Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.

Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.

When asked to comment on this, Dr. Daniel E. Furst noted that “there could be an awfully large selection bias in this study. If you ask yourself, ‘Why do people go to subcutaneous in an observational trial?’ it is possible that they didn’t have enough response to the oral. They didn’t go to a higher dose, but, rather stopped methotrexate altogether. The result is that injection looks better. I think this study has a significant flaw, as is often unavoidable in observational studies. This study, per se, does not prove that s.c. methotrexate has an advantage over oral methotrexate in terms of delay of starting a biologic.”

The increased bioavailability of subcutaneous administration versus oral – which is about 17% – does not make it necessarily better for all patients, Dr. Furst contended, although it can certainly be a good option for those affected by gastrointestinal side effects with oral administration. “Given that a 17% increase in bioavailability with subcutaneous administration, this equals about 3-4 mg extra methotrexate. 20 mg/week s.c. methotrexate equals about 23 or 24 mg/week of oral methotrexate. My point is that if a patients tolerates it, giving a little higher dose of oral methotrexate may be the same as giving a slightly higher dose subcutaneously. It is probably true, incidentally, that subcutaneous methotrexate, when given as a generic is less expensive than the oral. A 25-mg/mL vial costs somewhere in the range of one-half to one-third of oral.”

Waiting for 6 months of treatment with oral methotrexate is ideal when a patient is having some response but may not be appropriate for all, according to Dr. Furst, the Carl Pearson Professor of Medicine in the division of rheumatology at the University of California, Los Angeles. He cited research showing 35% of patients who did not yet have an ACR 20–level response at 12 weeks of treatment with oral methotrexate alone at 7.5-20 mg/week can reach that level of response by 26 weeks (Rheumatology. 2010;49[6]:1201-3). “What I took away from that is, on a practical basis, if patients have absolutely no response, however you define it, by 12 weeks, then stop. If they’re having some response, then wait and see if they get more response before stopping,” he said.

The claims analysis that Dr. O’Dell discussed at the NCRA annual meeting gets straight to that point of whether rheumatologists are giving methotrexate a long enough time to work. What compounds the problem, according to Dr. O’Dell, is that too few people are giving oral methotrexate a long enough chance to work or trying subcutaneous dosing. The analysis of claims data from 35,640 RA patients during 2009-2014 that he originally presented at the 2015 American College of Rheumatology annual meeting showed that 44% of patients who started on oral methotrexate alone stayed on it throughout the study period and didn’t need anything else.

Prescribers, however, stopped oral methotrexate at a mean dose of 15.3 mg and moved 87% straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients. Of the patients who were given subcutaneous methotrexate when their oral formulation wasn’t enough that’s all most of them needed, as 72% remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years. The same results applied to patients who started treatment in 2009 or 2012.

What the evidence from the claims data study does not say is why physicians are prescribing this way. Some might suggest that the influence of pharmaceutical companies might have something to do with it, although the notion is controversial. A recent systematic review and meta-analysis of randomized, controlled trials that involved a direct comparison of methotrexate monotherapy against methotrexate plus a biologic or biologic monotherapy to treat RA concluded that there is a dosing bias in the trials where methotrexate monotherapy is underdosed because none of the 13 trials that met criteria to be in the review used a methotrexate dose of 25 mg/week (Ann Rheum Dis. 2016 Apr 18. doi: 10.1136/annrheumdis-2016-209383). The investigators, led by Dr. Josefina Durán of Pontificia Universidad Católica de Chile, Santiago, said that they used 25 mg/week as the maximum recommended dose because it is recommended by EULAR and expert opinion.

The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”

“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”

“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”

Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.

[email protected]

SAN DIEGO – Gastric peroral endoscopic myotomy, a novel procedure for gastroparesis, restored gastric emptying in 30 refractory patients at Johns Hopkins University, Baltimore, and elsewhere in the largest series to date for the technique.

Drug therapy had failed, and Botox injections and transpyloric stenting weren’t helping much. On gastric emptying scans (GES), patients had around 40% of solid meals in their stomachs at 4 hours. Their gastroparesis was related mostly to diabetes and postoperative complications, but about a quarter of the cases were idiopathic.

Twenty-six patients (87%) responded to gastric peroral endoscopic myotomy (G-POEM) during a median follow-up of 5.5 months. Nausea, vomiting, and abdominal pain resolved or improved in most. On repeat GES in 17 patients, emptying time normalized in about half and improved in a third. Overall, patients had 17% of solid meals in their stomachs at 4 hours. G-POEM took an average of 72 minutes, and patients were in the hospital for about 3 days. One patient in the series developed pneumoperitoneum, and another had a prepyloric ulcer.

“The problem with transpyloric stents is that they migrate,” said investigator Dr. Mouen A. Khashab, director of therapeutic endoscopy at Johns Hopkins University. “G-POEM offers a permanent solution with few side effects. You have to be good at doing POEM in the esophagus first, as a prerequisite.”

In an interview at the annual Digestive Disease Week, Dr. Khashab explained the procedure in detail, as well as how he incorporates it into his practice and the patient population most likely to benefit.

[email protected]

SAN DIEGO – Gastric peroral endoscopic myotomy, a novel procedure for gastroparesis, restored gastric emptying in 30 refractory patients at Johns Hopkins University, Baltimore, and elsewhere in the largest series to date for the technique.

Drug therapy had failed, and Botox injections and transpyloric stenting weren’t helping much. On gastric emptying scans (GES), patients had around 40% of solid meals in their stomachs at 4 hours. Their gastroparesis was related mostly to diabetes and postoperative complications, but about a quarter of the cases were idiopathic.

Twenty-six patients (87%) responded to gastric peroral endoscopic myotomy (G-POEM) during a median follow-up of 5.5 months. Nausea, vomiting, and abdominal pain resolved or improved in most. On repeat GES in 17 patients, emptying time normalized in about half and improved in a third. Overall, patients had 17% of solid meals in their stomachs at 4 hours. G-POEM took an average of 72 minutes, and patients were in the hospital for about 3 days. One patient in the series developed pneumoperitoneum, and another had a prepyloric ulcer.

“The problem with transpyloric stents is that they migrate,” said investigator Dr. Mouen A. Khashab, director of therapeutic endoscopy at Johns Hopkins University. “G-POEM offers a permanent solution with few side effects. You have to be good at doing POEM in the esophagus first, as a prerequisite.”

In an interview at the annual Digestive Disease Week, Dr. Khashab explained the procedure in detail, as well as how he incorporates it into his practice and the patient population most likely to benefit.

[email protected]

SAN DIEGO – Gastric peroral endoscopic myotomy, a novel procedure for gastroparesis, restored gastric emptying in 30 refractory patients at Johns Hopkins University, Baltimore, and elsewhere in the largest series to date for the technique.

Drug therapy had failed, and Botox injections and transpyloric stenting weren’t helping much. On gastric emptying scans (GES), patients had around 40% of solid meals in their stomachs at 4 hours. Their gastroparesis was related mostly to diabetes and postoperative complications, but about a quarter of the cases were idiopathic.

Twenty-six patients (87%) responded to gastric peroral endoscopic myotomy (G-POEM) during a median follow-up of 5.5 months. Nausea, vomiting, and abdominal pain resolved or improved in most. On repeat GES in 17 patients, emptying time normalized in about half and improved in a third. Overall, patients had 17% of solid meals in their stomachs at 4 hours. G-POEM took an average of 72 minutes, and patients were in the hospital for about 3 days. One patient in the series developed pneumoperitoneum, and another had a prepyloric ulcer.

“The problem with transpyloric stents is that they migrate,” said investigator Dr. Mouen A. Khashab, director of therapeutic endoscopy at Johns Hopkins University. “G-POEM offers a permanent solution with few side effects. You have to be good at doing POEM in the esophagus first, as a prerequisite.”

In an interview at the annual Digestive Disease Week, Dr. Khashab explained the procedure in detail, as well as how he incorporates it into his practice and the patient population most likely to benefit.

[email protected]

Building owners, managers, and administrators of hospitals and other health care facilities around the country are being urged to shore up their water system management facilities to prevent further outbreaks of Legionnaires’ disease, which is the focus of the Center for Disease Control and Prevention’s latest Vital Signs report.

“Almost all Legionnaires’ disease outbreaks are preventable with improvements in water system management,” explained CDC Director Tom Frieden, adding that “At the end of the day, building owners and managers need to take steps to reduce the risk of Legionnaires’ disease [and] work together to reduce this risk and limit the number of people exposed, infected, and hospitalized or, potentially, fatally infected.”

Courtesy Janice Haney Carr/CDC

For the report, the CDC investigated 27 outbreaks of Legionnaires’ disease in the United States from 2000 through 2014, which involved a total of 415 cases and 65 fatalities. In each outbreak analysis, the location, source of exposure, and problems with environmental controls of Legionella – the bacterium that causes the disease – were evaluated.

Hotels and resorts accounted for 44% of all outbreaks over the 15-year period, followed by long-term care facilities (19%) and hospitals (15%). However, outbreaks at the latter two location types accounted for 85% of all deaths, while outbreaks at hotels and resorts accounted for only 6%. Potable water was the most common direct cause of Legionella infections, followed by water from cooling towers, hot tubs, industrial equipment, and decorative fountains.

Additionally, 23 of the investigations yielded enough information to determine the exact cause of the outbreak, all of which were caused by at least one of 4 issues. The first was process failures, such as not having a proper water system management program in place to handle Legionella; this was found in two-thirds of the outbreaks. The second major cause was human error, such as not replacing filters or tubing as recommended by manufacturers, which was a cause in half of the outbreaks. The third was equipment breakdown, which was found in one-third of the outbreaks. Finally, reasons external to the buildings themselves – such as water main breaks or disruptions caused by nearby construction – factored into one-third of the outbreaks.

“Large, recent outbreaks of Legionnaires’ disease in New York City and Flint, Michigan, have brought attention to the disease and highlight the need for us to understand why these outbreaks happen and how best to prevent them, [which is] why this Vital Signs is targeted to a specific audience that we in public health don’t talk [to] often enough: building owners and managers,” Dr. Frieden said. “It’s not a traditional public health audience, [but] they are the key to environmental controls in buildings that we live in, get our health care in, and work in everyday.”

To that end, Dr. Frieden announced the release of a new CDC toolkit entitled “Developing a Water Management Program to Reduce Legionella Growth & Spread in Buildings: A Practical Guide to Implementing Industry Standards,” which building owners, managers, and administrators can turn to for guidance on how to implement effective water system management protocols in their buildings.

Legionnaires’ disease is a serious lung infection caused by inhalation of the bacteria Legionella, which can be found in water and inhaled as airborne mist. Elderly individuals, as well as those with suppressed immune systems because of underlying illnesses, are at a heightened risk for Legionnaires’ disease, which would explain the higher death rates observed at hospitals and long-term care facilities. Dr. Frieden stated that outbreaks and cases of Legionnaires’ disease are on the rise nationally, with about 5,000 infections and 20 outbreaks occurring annually; roughly 10% of infections result in death.

The uptick in recent cases is likely because of “the aging of the population, the increase in chronic illness, [an] increase in immunosuppression through use of medication to treat a variety of conditions [and] an aging plumbing infrastructure and that makes maintenance all the more challenging,” according to Dr. Frieden. “It is also possible that increased use of diagnostic tests and more reliable reporting are contributing to some of the rising rates.”

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Building owners, managers, and administrators of hospitals and other health care facilities around the country are being urged to shore up their water system management facilities to prevent further outbreaks of Legionnaires’ disease, which is the focus of the Center for Disease Control and Prevention’s latest Vital Signs report.

“Almost all Legionnaires’ disease outbreaks are preventable with improvements in water system management,” explained CDC Director Tom Frieden, adding that “At the end of the day, building owners and managers need to take steps to reduce the risk of Legionnaires’ disease [and] work together to reduce this risk and limit the number of people exposed, infected, and hospitalized or, potentially, fatally infected.”

Courtesy Janice Haney Carr/CDC

For the report, the CDC investigated 27 outbreaks of Legionnaires’ disease in the United States from 2000 through 2014, which involved a total of 415 cases and 65 fatalities. In each outbreak analysis, the location, source of exposure, and problems with environmental controls of Legionella – the bacterium that causes the disease – were evaluated.

Hotels and resorts accounted for 44% of all outbreaks over the 15-year period, followed by long-term care facilities (19%) and hospitals (15%). However, outbreaks at the latter two location types accounted for 85% of all deaths, while outbreaks at hotels and resorts accounted for only 6%. Potable water was the most common direct cause of Legionella infections, followed by water from cooling towers, hot tubs, industrial equipment, and decorative fountains.

Additionally, 23 of the investigations yielded enough information to determine the exact cause of the outbreak, all of which were caused by at least one of 4 issues. The first was process failures, such as not having a proper water system management program in place to handle Legionella; this was found in two-thirds of the outbreaks. The second major cause was human error, such as not replacing filters or tubing as recommended by manufacturers, which was a cause in half of the outbreaks. The third was equipment breakdown, which was found in one-third of the outbreaks. Finally, reasons external to the buildings themselves – such as water main breaks or disruptions caused by nearby construction – factored into one-third of the outbreaks.