Sara Freeman

BIRMINGHAM, ENGLAND – Lupus patients are most likely to have the metabolic syndrome early in the course of their disease if they have had the syndrome in the past, data from a large, prospective, observational study have shown.

The odds ratio (OR) for prior metabolic syndrome and having the syndrome in the first 2 years of follow-up was 4.83 in patients recently diagnosed with lupus (less than 15 months).

Hispanic ethnicity (OR, 3.47), elevated anti-dsDNA antibodies (OR, 1.86), age (OR, 1.03), and the use of a high peak prednisolone dose (40 mg) at enrollment (OR, 1.02) were also found to increase the risk for the metabolic syndrome early in the course of the disease.

Patients with systemic lupus erythematosus (SLE) are known to have an increased risk for the metabolic syndrome (Rheum. Dis. Clin. North Am. 2010;36:81-97), and this may contribute to increased cardiovascular risk and subsequent mortality, observed Dr. Ben Parker, a clinical research fellow at the Arthritis UK Epidemiology Unit, University of Manchester, England.

"It is fairly well established that SLE is an independent risk factor for cardiovascular disease," Dr. Parker said at the British Society for Rheumatology annual conference.

The mechanism of cardiovascular risk in SLE is not known, but it is likely to be "very complex and multifactorial," Dr. Parker added. "It is certainly related to ‘classic’ [cardiovascular] risk factors, systemic inflammation, some disease-specific risk factors, and the therapeutic exposures," he said.

Previously, Dr. Parker and his associates have shown that renal lupus, higher daily prednisolone doses, and being of Korean or Hispanic ethnicity are associated with the presence of the metabolic syndrome in SLE (Ann. Rheum. Dis. 2012 Sept. 3 [doi: 10.1136/annrheumdis-2012-202106]).

Their current investigation used data from the SLICC-RAS (Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis) study, a prospective, observational study initiated in 2000 that involves 30 centers in 11 countries in North America, Europe, and Asia. The aim was to identify factors that were associated with the metabolic syndrome during the first 2 years of follow-up.

A total of 1,494 of 1,686 patients with SLE who were diagnosed within the past 15 months in SLICC-RAS had sufficient data to determine their metabolic syndrome status and were included in the analysis. The mean age of patients at enrollment was 35.2 years, and the mean disease duration was 5.5 months.

The prevalence of the metabolic syndrome was 16% (n = 1,494) at enrollment, 12.6% (n = 1,065) at 1 year’s follow-up, and 13.6% (n = 895) at the 2-year follow-up assessment. Metabolic syndrome was defined according to International Diabetes Federation criteria, which require at least three of the following five factors to be present: obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and insulin resistance (Circulation 2009;120:1640-5).

There was fluctuation in metabolic status in the first 2 years of follow-up. Of 720 patients who had attended all three (enrollment, 1-year, and 2-year) assessments, 26.9% had the metabolic syndrome at any time during the first 2 years of follow-up, with 4.3% having the metabolic syndrome at all three assessments, 7.4% at two, and 15.3% at one.

"Around 73.1% of patients did not get the metabolic syndrome at all, and 14% developed it over the first 2 years," Dr. Parker reported. "Prevalent metabolic syndrome strongly predicts ongoing metabolic syndrome," he added.

A high corticosteroid dose at enrollment also increased the risk for the metabolic syndrome, Dr. Parker observed. The peak, daily dose of prednisolone used at enrollment was 40 mg, which decreased to 24.2 mg at the 1-year and 16.2 mg at the 2-year follow-up assessment. The respective average corticosteroid doses used were 20, 12.6, and 9.8 mg.

Dr. Parker concluded that the study data support a more personalized approach to managing patients with early, active SLE "in an attempt to rapidly and effectively control disease while trying to reduce corticosteroid doses," he said. The overall aim is to improve the cardiovascular risk profile for patients over time.

Arthritis Research UK funded the study. Dr. Parker had no conflicts of interest.

BIRMINGHAM, ENGLAND – Lupus patients are most likely to have the metabolic syndrome early in the course of their disease if they have had the syndrome in the past, data from a large, prospective, observational study have shown.

The odds ratio (OR) for prior metabolic syndrome and having the syndrome in the first 2 years of follow-up was 4.83 in patients recently diagnosed with lupus (less than 15 months).

Hispanic ethnicity (OR, 3.47), elevated anti-dsDNA antibodies (OR, 1.86), age (OR, 1.03), and the use of a high peak prednisolone dose (40 mg) at enrollment (OR, 1.02) were also found to increase the risk for the metabolic syndrome early in the course of the disease.

Patients with systemic lupus erythematosus (SLE) are known to have an increased risk for the metabolic syndrome (Rheum. Dis. Clin. North Am. 2010;36:81-97), and this may contribute to increased cardiovascular risk and subsequent mortality, observed Dr. Ben Parker, a clinical research fellow at the Arthritis UK Epidemiology Unit, University of Manchester, England.

"It is fairly well established that SLE is an independent risk factor for cardiovascular disease," Dr. Parker said at the British Society for Rheumatology annual conference.

The mechanism of cardiovascular risk in SLE is not known, but it is likely to be "very complex and multifactorial," Dr. Parker added. "It is certainly related to ‘classic’ [cardiovascular] risk factors, systemic inflammation, some disease-specific risk factors, and the therapeutic exposures," he said.

Previously, Dr. Parker and his associates have shown that renal lupus, higher daily prednisolone doses, and being of Korean or Hispanic ethnicity are associated with the presence of the metabolic syndrome in SLE (Ann. Rheum. Dis. 2012 Sept. 3 [doi: 10.1136/annrheumdis-2012-202106]).

Their current investigation used data from the SLICC-RAS (Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis) study, a prospective, observational study initiated in 2000 that involves 30 centers in 11 countries in North America, Europe, and Asia. The aim was to identify factors that were associated with the metabolic syndrome during the first 2 years of follow-up.

A total of 1,494 of 1,686 patients with SLE who were diagnosed within the past 15 months in SLICC-RAS had sufficient data to determine their metabolic syndrome status and were included in the analysis. The mean age of patients at enrollment was 35.2 years, and the mean disease duration was 5.5 months.

The prevalence of the metabolic syndrome was 16% (n = 1,494) at enrollment, 12.6% (n = 1,065) at 1 year’s follow-up, and 13.6% (n = 895) at the 2-year follow-up assessment. Metabolic syndrome was defined according to International Diabetes Federation criteria, which require at least three of the following five factors to be present: obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and insulin resistance (Circulation 2009;120:1640-5).

There was fluctuation in metabolic status in the first 2 years of follow-up. Of 720 patients who had attended all three (enrollment, 1-year, and 2-year) assessments, 26.9% had the metabolic syndrome at any time during the first 2 years of follow-up, with 4.3% having the metabolic syndrome at all three assessments, 7.4% at two, and 15.3% at one.

"Around 73.1% of patients did not get the metabolic syndrome at all, and 14% developed it over the first 2 years," Dr. Parker reported. "Prevalent metabolic syndrome strongly predicts ongoing metabolic syndrome," he added.

A high corticosteroid dose at enrollment also increased the risk for the metabolic syndrome, Dr. Parker observed. The peak, daily dose of prednisolone used at enrollment was 40 mg, which decreased to 24.2 mg at the 1-year and 16.2 mg at the 2-year follow-up assessment. The respective average corticosteroid doses used were 20, 12.6, and 9.8 mg.

Dr. Parker concluded that the study data support a more personalized approach to managing patients with early, active SLE "in an attempt to rapidly and effectively control disease while trying to reduce corticosteroid doses," he said. The overall aim is to improve the cardiovascular risk profile for patients over time.

Arthritis Research UK funded the study. Dr. Parker had no conflicts of interest.

BIRMINGHAM, ENGLAND – Lupus patients are most likely to have the metabolic syndrome early in the course of their disease if they have had the syndrome in the past, data from a large, prospective, observational study have shown.

The odds ratio (OR) for prior metabolic syndrome and having the syndrome in the first 2 years of follow-up was 4.83 in patients recently diagnosed with lupus (less than 15 months).

Hispanic ethnicity (OR, 3.47), elevated anti-dsDNA antibodies (OR, 1.86), age (OR, 1.03), and the use of a high peak prednisolone dose (40 mg) at enrollment (OR, 1.02) were also found to increase the risk for the metabolic syndrome early in the course of the disease.

Patients with systemic lupus erythematosus (SLE) are known to have an increased risk for the metabolic syndrome (Rheum. Dis. Clin. North Am. 2010;36:81-97), and this may contribute to increased cardiovascular risk and subsequent mortality, observed Dr. Ben Parker, a clinical research fellow at the Arthritis UK Epidemiology Unit, University of Manchester, England.

"It is fairly well established that SLE is an independent risk factor for cardiovascular disease," Dr. Parker said at the British Society for Rheumatology annual conference.

The mechanism of cardiovascular risk in SLE is not known, but it is likely to be "very complex and multifactorial," Dr. Parker added. "It is certainly related to ‘classic’ [cardiovascular] risk factors, systemic inflammation, some disease-specific risk factors, and the therapeutic exposures," he said.

Previously, Dr. Parker and his associates have shown that renal lupus, higher daily prednisolone doses, and being of Korean or Hispanic ethnicity are associated with the presence of the metabolic syndrome in SLE (Ann. Rheum. Dis. 2012 Sept. 3 [doi: 10.1136/annrheumdis-2012-202106]).

Their current investigation used data from the SLICC-RAS (Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis) study, a prospective, observational study initiated in 2000 that involves 30 centers in 11 countries in North America, Europe, and Asia. The aim was to identify factors that were associated with the metabolic syndrome during the first 2 years of follow-up.

A total of 1,494 of 1,686 patients with SLE who were diagnosed within the past 15 months in SLICC-RAS had sufficient data to determine their metabolic syndrome status and were included in the analysis. The mean age of patients at enrollment was 35.2 years, and the mean disease duration was 5.5 months.

The prevalence of the metabolic syndrome was 16% (n = 1,494) at enrollment, 12.6% (n = 1,065) at 1 year’s follow-up, and 13.6% (n = 895) at the 2-year follow-up assessment. Metabolic syndrome was defined according to International Diabetes Federation criteria, which require at least three of the following five factors to be present: obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and insulin resistance (Circulation 2009;120:1640-5).

There was fluctuation in metabolic status in the first 2 years of follow-up. Of 720 patients who had attended all three (enrollment, 1-year, and 2-year) assessments, 26.9% had the metabolic syndrome at any time during the first 2 years of follow-up, with 4.3% having the metabolic syndrome at all three assessments, 7.4% at two, and 15.3% at one.

"Around 73.1% of patients did not get the metabolic syndrome at all, and 14% developed it over the first 2 years," Dr. Parker reported. "Prevalent metabolic syndrome strongly predicts ongoing metabolic syndrome," he added.

A high corticosteroid dose at enrollment also increased the risk for the metabolic syndrome, Dr. Parker observed. The peak, daily dose of prednisolone used at enrollment was 40 mg, which decreased to 24.2 mg at the 1-year and 16.2 mg at the 2-year follow-up assessment. The respective average corticosteroid doses used were 20, 12.6, and 9.8 mg.

Dr. Parker concluded that the study data support a more personalized approach to managing patients with early, active SLE "in an attempt to rapidly and effectively control disease while trying to reduce corticosteroid doses," he said. The overall aim is to improve the cardiovascular risk profile for patients over time.

Arthritis Research UK funded the study. Dr. Parker had no conflicts of interest.

BIRMINGHAM, ENGLAND – Patients with Sjögren’s syndrome had a diverse and high rate of long-term complications over the course of a 25-year review of cases seen at a single center.

Between 1986 and 2011, 152 patients with primary Sjögren’s syndrome were treated at University College London (UCL), England. More than half of the patients developed serological abnormalities (51.3%), followed by additional autoimmune diseases in 49.3% and systemic malignancy in 28.3%.

“We found that the main complications were extraglandular,” Ms. Esha Abrol, a fifth-year medical student at UCL, reported at the British Society for Rheumatology annual conference. Extraglandular manifestations occurred in 71% of patients, and 20% of patients experiencing local or glandular complications, such as parotid swelling.

These data highlight that primary Sjögren’s syndrome is perhaps not as benign as people might think, Ms. Abrol suggested, and that an increase in the risk of non-Hodgkin’s lymphoma (NHL) is not the only problem to watch out for.

The majority of the study population was female (91.4%) and white (86.8%); three-quarters (75.7%) had antinuclear antibodies, 55.9% had anti-Ro/SS-A antibodies, 35.5% anti-La/SS-B antibodies, 54.6% were rheumatoid factor positive, and 36.8% had hypergammaglobulinemia. The mean age at diagnosis was 54.4 years.

At the time of the case review, at a mean of 12.4 years’ follow-up, 55.9% of patients were still alive; 26.6% had been lost to follow-up, which was mainly from old age, and 18.5% had died. The mean age at death was 72 years.

“One of the most common extraglandular manifestations was additional autoimmune diseases,” Ms. Abrol reported. These included autoimmune thyroid disease (for example, Hashimoto’s thyroiditis and Graves’ disease) in 15.8% of patients. Other autoimmune diseases included those affecting the blood vessels (vasculitis occurred in 10.5% of patients), skin (10.5%), gastrointestinal system (10.5%), lungs (7.2%), and kidneys (6.5%).

Ms. Abrol observed that patients who developed autoimmune diseases were more likely to be female than male, have anti-Ro/SS-A or Anti-La/SS-B antibodies, and hypergammaglobulinemia. Nineteen percent of patients had more than one autoimmune disease in addition to Sjögren’s, with one patient having four additional autoimmune diseases.

As expected, the most common type of malignancy seen was NHL, which occurred in approximately one in ten patients (10.5%). A range of other malignancies was seen, including ovarian and cervical (3.3%), bladder (2.6%), skin (2.6%), lung (2.0%), and oropharyngeal (2.0%) cancers, to name a few.

The risk for malignancy was higher in patients older than 50 years, with an odds ratio (OR) of 9.6 (P = .03). Patients who developed cancer were also more likely to be negative for Anti-RNP antibodies (OR, 4.9; P = .06).

The risk for NHL was increased in patients who had vasculitis (OR, 10.5; P less than .001) and in those with glandular manifestations (OR, 3.4; P = .041).

There were other numerous complications, including serologic alterations (51.3%), principally hypergammaglobulinemia, Raynaud’s syndrome (30.9%), and arthritis (19.7%). Peripheral and central nervous system complications were also seen in 15.8% and 9.2% of patients.

These data highlight that primary Sjögren’s syndrome carries a higher disease burden than previously suggested, Ms. Abrol concluded, noting that they can be used to inform patients on what may happen to them long-term.

Ms. Abrol had no conflicts of interest.

BIRMINGHAM, ENGLAND – Patients with Sjögren’s syndrome had a diverse and high rate of long-term complications over the course of a 25-year review of cases seen at a single center.

Between 1986 and 2011, 152 patients with primary Sjögren’s syndrome were treated at University College London (UCL), England. More than half of the patients developed serological abnormalities (51.3%), followed by additional autoimmune diseases in 49.3% and systemic malignancy in 28.3%.

“We found that the main complications were extraglandular,” Ms. Esha Abrol, a fifth-year medical student at UCL, reported at the British Society for Rheumatology annual conference. Extraglandular manifestations occurred in 71% of patients, and 20% of patients experiencing local or glandular complications, such as parotid swelling.

These data highlight that primary Sjögren’s syndrome is perhaps not as benign as people might think, Ms. Abrol suggested, and that an increase in the risk of non-Hodgkin’s lymphoma (NHL) is not the only problem to watch out for.

The majority of the study population was female (91.4%) and white (86.8%); three-quarters (75.7%) had antinuclear antibodies, 55.9% had anti-Ro/SS-A antibodies, 35.5% anti-La/SS-B antibodies, 54.6% were rheumatoid factor positive, and 36.8% had hypergammaglobulinemia. The mean age at diagnosis was 54.4 years.

At the time of the case review, at a mean of 12.4 years’ follow-up, 55.9% of patients were still alive; 26.6% had been lost to follow-up, which was mainly from old age, and 18.5% had died. The mean age at death was 72 years.

“One of the most common extraglandular manifestations was additional autoimmune diseases,” Ms. Abrol reported. These included autoimmune thyroid disease (for example, Hashimoto’s thyroiditis and Graves’ disease) in 15.8% of patients. Other autoimmune diseases included those affecting the blood vessels (vasculitis occurred in 10.5% of patients), skin (10.5%), gastrointestinal system (10.5%), lungs (7.2%), and kidneys (6.5%).

Ms. Abrol observed that patients who developed autoimmune diseases were more likely to be female than male, have anti-Ro/SS-A or Anti-La/SS-B antibodies, and hypergammaglobulinemia. Nineteen percent of patients had more than one autoimmune disease in addition to Sjögren’s, with one patient having four additional autoimmune diseases.

As expected, the most common type of malignancy seen was NHL, which occurred in approximately one in ten patients (10.5%). A range of other malignancies was seen, including ovarian and cervical (3.3%), bladder (2.6%), skin (2.6%), lung (2.0%), and oropharyngeal (2.0%) cancers, to name a few.

The risk for malignancy was higher in patients older than 50 years, with an odds ratio (OR) of 9.6 (P = .03). Patients who developed cancer were also more likely to be negative for Anti-RNP antibodies (OR, 4.9; P = .06).

The risk for NHL was increased in patients who had vasculitis (OR, 10.5; P less than .001) and in those with glandular manifestations (OR, 3.4; P = .041).

There were other numerous complications, including serologic alterations (51.3%), principally hypergammaglobulinemia, Raynaud’s syndrome (30.9%), and arthritis (19.7%). Peripheral and central nervous system complications were also seen in 15.8% and 9.2% of patients.

These data highlight that primary Sjögren’s syndrome carries a higher disease burden than previously suggested, Ms. Abrol concluded, noting that they can be used to inform patients on what may happen to them long-term.

Ms. Abrol had no conflicts of interest.

BIRMINGHAM, ENGLAND – Patients with Sjögren’s syndrome had a diverse and high rate of long-term complications over the course of a 25-year review of cases seen at a single center.

Between 1986 and 2011, 152 patients with primary Sjögren’s syndrome were treated at University College London (UCL), England. More than half of the patients developed serological abnormalities (51.3%), followed by additional autoimmune diseases in 49.3% and systemic malignancy in 28.3%.

“We found that the main complications were extraglandular,” Ms. Esha Abrol, a fifth-year medical student at UCL, reported at the British Society for Rheumatology annual conference. Extraglandular manifestations occurred in 71% of patients, and 20% of patients experiencing local or glandular complications, such as parotid swelling.

These data highlight that primary Sjögren’s syndrome is perhaps not as benign as people might think, Ms. Abrol suggested, and that an increase in the risk of non-Hodgkin’s lymphoma (NHL) is not the only problem to watch out for.

The majority of the study population was female (91.4%) and white (86.8%); three-quarters (75.7%) had antinuclear antibodies, 55.9% had anti-Ro/SS-A antibodies, 35.5% anti-La/SS-B antibodies, 54.6% were rheumatoid factor positive, and 36.8% had hypergammaglobulinemia. The mean age at diagnosis was 54.4 years.

At the time of the case review, at a mean of 12.4 years’ follow-up, 55.9% of patients were still alive; 26.6% had been lost to follow-up, which was mainly from old age, and 18.5% had died. The mean age at death was 72 years.

“One of the most common extraglandular manifestations was additional autoimmune diseases,” Ms. Abrol reported. These included autoimmune thyroid disease (for example, Hashimoto’s thyroiditis and Graves’ disease) in 15.8% of patients. Other autoimmune diseases included those affecting the blood vessels (vasculitis occurred in 10.5% of patients), skin (10.5%), gastrointestinal system (10.5%), lungs (7.2%), and kidneys (6.5%).

Ms. Abrol observed that patients who developed autoimmune diseases were more likely to be female than male, have anti-Ro/SS-A or Anti-La/SS-B antibodies, and hypergammaglobulinemia. Nineteen percent of patients had more than one autoimmune disease in addition to Sjögren’s, with one patient having four additional autoimmune diseases.

As expected, the most common type of malignancy seen was NHL, which occurred in approximately one in ten patients (10.5%). A range of other malignancies was seen, including ovarian and cervical (3.3%), bladder (2.6%), skin (2.6%), lung (2.0%), and oropharyngeal (2.0%) cancers, to name a few.

The risk for malignancy was higher in patients older than 50 years, with an odds ratio (OR) of 9.6 (P = .03). Patients who developed cancer were also more likely to be negative for Anti-RNP antibodies (OR, 4.9; P = .06).

The risk for NHL was increased in patients who had vasculitis (OR, 10.5; P less than .001) and in those with glandular manifestations (OR, 3.4; P = .041).

There were other numerous complications, including serologic alterations (51.3%), principally hypergammaglobulinemia, Raynaud’s syndrome (30.9%), and arthritis (19.7%). Peripheral and central nervous system complications were also seen in 15.8% and 9.2% of patients.

These data highlight that primary Sjögren’s syndrome carries a higher disease burden than previously suggested, Ms. Abrol concluded, noting that they can be used to inform patients on what may happen to them long-term.

Ms. Abrol had no conflicts of interest.

BIRMINGHAM, ENGLAND – The risk of heart attack appears to be lower in patients treated with anti–tumor necrosis factor therapy than with conventional disease-modifying antirheumatic drugs.

Patients treated with the biologic agents had a 30% lower risk for having a myocardial infarction, based on data from the British Society for Rheumatology Biologics Register (BSRBR) for rheumatoid arthritis. However, no differences were detected in 30-day or 1-year mortality rates (adjusted hazard ratios of 0.9 and 0.97, respectively).

"There seems to be a signal that subjects ever exposed to anti-TNF therapy were potentially at reduced risk for developing an MI," Dr. Audrey Low said in an interview at the British Society for Rheumatology annual conference.

Dr. Low, a clinical research fellow in the Arthritis Research UK Epidemiology Unit, University of Manchester, England, explained that traditional risk factors do not fully account for the well-known increased risk for cardiovascular disease in patients with rheumatoid arthritis. Underlying inflammation might play a role, and it was hypothesized that anti-TNF therapy might help to reduce this inflammation, with subsequent cardiovascular benefits.

The BSRBR-RA is one of the largest biologics registers in the world and has been running for more than 10 years. The register currently includes data on more than 20,000 participants treated with either anti-TNF agents or nonbiologic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate.

The present study used data collated between 2001 and 2008 on 11,536 patients treated with anti-TNF drugs licensed at the time in the United Kingdom (etanercept, infliximab, and adalimumab), and 3,225 patients who received nonbiologic DMARDs. Patients with prior MI or angina were excluded, and patients were followed up through April 2010 or until death, incident MI, or date of last clinician assessment, whichever came first.

Patients treated with anti-TNF therapy were younger than those given nonbiologic DMARDs, with a mean age of 56 years versus 60 years at recruitment into the BSRBR-RA. They also tended to have higher disease activity and longer disease duration (11 years vs. 6 years). There were similar percentages of patients with hypertension (29% vs. 32%), diabetes (6% for both), and a history of ever having smoked (59% vs. 62%).

There were 224 incident MIs in the anti-TNF–treated group at a median follow-up of 6 years per person, and 52 heart attacks in the nonbiologic DMARD–treated group at a median follow-up of 4 years per person. "Even though the study has been running for over 10 years, the amount of follow-up per person is between 4 and 6 years," Dr. Low observed.

The unadjusted hazard ratio for MI risk was 0.9, and it increased to 1.2 when adjusted for age and gender. "The hazard ratio goes up as you’d expect," Dr. Low observed. "People in the anti-TNF cohort are younger, and there are more females [77% vs. 74% for nonbiologic DMARDs]."

After adjustment for risk factors, analysis gave a hazard ratio of 0.7 in favor of anti-TNFs reducing the risk for MI. The risk factors included disease-specific factors (age, gender, disease duration, disease activity, steroid exposure, number of previous nonbiologic DMARDs received, and year of entry into the study), as well as traditional cardiovascular risk factors (hypertension, diabetes, smoking, chronic obstructive pulmonary disease, antiplatelet therapy, and use of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors). "Statins were also included in the adjustment," Dr. Low confirmed.

The possible reduction in the risk for heart attack is another potential benefit of anti-TNFs that can be discussed with patients, she suggested, although patients would of course not be put on these drugs in order to reduce their cardiovascular risk.

Why anti-TNFs have this effect is still not clear. Dr. Low said. "It’s going to be very difficult to tease out whether it’s the inflammation that has been reduced by the anti-TNF therapy or whether anti-TNF therapy affects other factors, such as hypertension and lipids, but I don’t think we can say that for certain from this analysis.

Further research will look at the effect of anti-TNFs on the severity of MI to see if there is any difference from nonbiologic DMARDs.

The BSRBR is funded by a grant from the British Society for Rheumatology (BSR), which receives funding from multiple drug companies. This income finances a wholly separate contract between the BSR and the University of Manchester to host the BSRBR. Dr. Low had no conflicts of interest.

BIRMINGHAM, ENGLAND – The risk of heart attack appears to be lower in patients treated with anti–tumor necrosis factor therapy than with conventional disease-modifying antirheumatic drugs.

Patients treated with the biologic agents had a 30% lower risk for having a myocardial infarction, based on data from the British Society for Rheumatology Biologics Register (BSRBR) for rheumatoid arthritis. However, no differences were detected in 30-day or 1-year mortality rates (adjusted hazard ratios of 0.9 and 0.97, respectively).

"There seems to be a signal that subjects ever exposed to anti-TNF therapy were potentially at reduced risk for developing an MI," Dr. Audrey Low said in an interview at the British Society for Rheumatology annual conference.

Dr. Low, a clinical research fellow in the Arthritis Research UK Epidemiology Unit, University of Manchester, England, explained that traditional risk factors do not fully account for the well-known increased risk for cardiovascular disease in patients with rheumatoid arthritis. Underlying inflammation might play a role, and it was hypothesized that anti-TNF therapy might help to reduce this inflammation, with subsequent cardiovascular benefits.

The BSRBR-RA is one of the largest biologics registers in the world and has been running for more than 10 years. The register currently includes data on more than 20,000 participants treated with either anti-TNF agents or nonbiologic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate.

The present study used data collated between 2001 and 2008 on 11,536 patients treated with anti-TNF drugs licensed at the time in the United Kingdom (etanercept, infliximab, and adalimumab), and 3,225 patients who received nonbiologic DMARDs. Patients with prior MI or angina were excluded, and patients were followed up through April 2010 or until death, incident MI, or date of last clinician assessment, whichever came first.

Patients treated with anti-TNF therapy were younger than those given nonbiologic DMARDs, with a mean age of 56 years versus 60 years at recruitment into the BSRBR-RA. They also tended to have higher disease activity and longer disease duration (11 years vs. 6 years). There were similar percentages of patients with hypertension (29% vs. 32%), diabetes (6% for both), and a history of ever having smoked (59% vs. 62%).

There were 224 incident MIs in the anti-TNF–treated group at a median follow-up of 6 years per person, and 52 heart attacks in the nonbiologic DMARD–treated group at a median follow-up of 4 years per person. "Even though the study has been running for over 10 years, the amount of follow-up per person is between 4 and 6 years," Dr. Low observed.

The unadjusted hazard ratio for MI risk was 0.9, and it increased to 1.2 when adjusted for age and gender. "The hazard ratio goes up as you’d expect," Dr. Low observed. "People in the anti-TNF cohort are younger, and there are more females [77% vs. 74% for nonbiologic DMARDs]."

After adjustment for risk factors, analysis gave a hazard ratio of 0.7 in favor of anti-TNFs reducing the risk for MI. The risk factors included disease-specific factors (age, gender, disease duration, disease activity, steroid exposure, number of previous nonbiologic DMARDs received, and year of entry into the study), as well as traditional cardiovascular risk factors (hypertension, diabetes, smoking, chronic obstructive pulmonary disease, antiplatelet therapy, and use of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors). "Statins were also included in the adjustment," Dr. Low confirmed.

The possible reduction in the risk for heart attack is another potential benefit of anti-TNFs that can be discussed with patients, she suggested, although patients would of course not be put on these drugs in order to reduce their cardiovascular risk.

Why anti-TNFs have this effect is still not clear. Dr. Low said. "It’s going to be very difficult to tease out whether it’s the inflammation that has been reduced by the anti-TNF therapy or whether anti-TNF therapy affects other factors, such as hypertension and lipids, but I don’t think we can say that for certain from this analysis.

Further research will look at the effect of anti-TNFs on the severity of MI to see if there is any difference from nonbiologic DMARDs.

The BSRBR is funded by a grant from the British Society for Rheumatology (BSR), which receives funding from multiple drug companies. This income finances a wholly separate contract between the BSR and the University of Manchester to host the BSRBR. Dr. Low had no conflicts of interest.

BIRMINGHAM, ENGLAND – The risk of heart attack appears to be lower in patients treated with anti–tumor necrosis factor therapy than with conventional disease-modifying antirheumatic drugs.

Patients treated with the biologic agents had a 30% lower risk for having a myocardial infarction, based on data from the British Society for Rheumatology Biologics Register (BSRBR) for rheumatoid arthritis. However, no differences were detected in 30-day or 1-year mortality rates (adjusted hazard ratios of 0.9 and 0.97, respectively).

"There seems to be a signal that subjects ever exposed to anti-TNF therapy were potentially at reduced risk for developing an MI," Dr. Audrey Low said in an interview at the British Society for Rheumatology annual conference.

Dr. Low, a clinical research fellow in the Arthritis Research UK Epidemiology Unit, University of Manchester, England, explained that traditional risk factors do not fully account for the well-known increased risk for cardiovascular disease in patients with rheumatoid arthritis. Underlying inflammation might play a role, and it was hypothesized that anti-TNF therapy might help to reduce this inflammation, with subsequent cardiovascular benefits.

The BSRBR-RA is one of the largest biologics registers in the world and has been running for more than 10 years. The register currently includes data on more than 20,000 participants treated with either anti-TNF agents or nonbiologic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate.

The present study used data collated between 2001 and 2008 on 11,536 patients treated with anti-TNF drugs licensed at the time in the United Kingdom (etanercept, infliximab, and adalimumab), and 3,225 patients who received nonbiologic DMARDs. Patients with prior MI or angina were excluded, and patients were followed up through April 2010 or until death, incident MI, or date of last clinician assessment, whichever came first.

Patients treated with anti-TNF therapy were younger than those given nonbiologic DMARDs, with a mean age of 56 years versus 60 years at recruitment into the BSRBR-RA. They also tended to have higher disease activity and longer disease duration (11 years vs. 6 years). There were similar percentages of patients with hypertension (29% vs. 32%), diabetes (6% for both), and a history of ever having smoked (59% vs. 62%).

There were 224 incident MIs in the anti-TNF–treated group at a median follow-up of 6 years per person, and 52 heart attacks in the nonbiologic DMARD–treated group at a median follow-up of 4 years per person. "Even though the study has been running for over 10 years, the amount of follow-up per person is between 4 and 6 years," Dr. Low observed.

The unadjusted hazard ratio for MI risk was 0.9, and it increased to 1.2 when adjusted for age and gender. "The hazard ratio goes up as you’d expect," Dr. Low observed. "People in the anti-TNF cohort are younger, and there are more females [77% vs. 74% for nonbiologic DMARDs]."

After adjustment for risk factors, analysis gave a hazard ratio of 0.7 in favor of anti-TNFs reducing the risk for MI. The risk factors included disease-specific factors (age, gender, disease duration, disease activity, steroid exposure, number of previous nonbiologic DMARDs received, and year of entry into the study), as well as traditional cardiovascular risk factors (hypertension, diabetes, smoking, chronic obstructive pulmonary disease, antiplatelet therapy, and use of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors). "Statins were also included in the adjustment," Dr. Low confirmed.

The possible reduction in the risk for heart attack is another potential benefit of anti-TNFs that can be discussed with patients, she suggested, although patients would of course not be put on these drugs in order to reduce their cardiovascular risk.

Why anti-TNFs have this effect is still not clear. Dr. Low said. "It’s going to be very difficult to tease out whether it’s the inflammation that has been reduced by the anti-TNF therapy or whether anti-TNF therapy affects other factors, such as hypertension and lipids, but I don’t think we can say that for certain from this analysis.

Further research will look at the effect of anti-TNFs on the severity of MI to see if there is any difference from nonbiologic DMARDs.

The BSRBR is funded by a grant from the British Society for Rheumatology (BSR), which receives funding from multiple drug companies. This income finances a wholly separate contract between the BSR and the University of Manchester to host the BSRBR. Dr. Low had no conflicts of interest.

BIRMINGHAM, ENGLAND – In the first 6 months after the diagnosis of polymyalgia rheumatica, the risk of cancer was almost doubled, with a hazard ratio of 1.96, in a primary care–based matched cohort study of more than 12,000 individuals.

After 6 months, the cancer risk subsided, with a hazard ratio of 1.03 at 6-12 months after diagnosis, 1.04 at 1-2 years, 1.05 at 2-5 years, 1.1 at 5-10 years, and 1.00 after 10 years, reported Sara Muller, Ph.D., of the Research Institute for Primary Care & Health Sciences, Keele University, England.

The drop-off in cancer diagnosis may reflect "a differential diagnosis issue. Maybe there are early cancer symptoms that are being diagnosed as PMR [polymyalgia rheumatica]," she added at the British Society for Rheumatology annual conference.

Monitor PMR patients closely for the first 6 months after diagnosis, Dr. Muller advised. Future research needs to try to tease out how to identify PMR patients who might actually have cancer from those whose condition is limited to joint problems.

PMR is the most common inflammatory rheumatologic condition in older adults. The study was performed to see if there was any link between PMR and cancer, as has been seen for rheumatoid arthritis and lymphoma.

Case reports indicate PMR has been misdiagnosed as renal, testicular, gastric, or hematologic (lymphoma) cancer. The results of a Swedish study (Rheumatology 2010;49:1158-63) suggest that cancer risk is slightly increased in patients diagnosed with PMR or giant cell arteritis. These were all secondary care studies, however, so Dr. Muller and her associates decided to look at a primary care population, where most cases of PMR are diagnosed and treated.

Using the U.K. General Practice Research Database (GPRD), now known as the Clinical Practice Research Datalink, the research team identified 2,877 cases of PMR in individuals aged 50 years or older who were diagnosed between 1987 and 1999. Each case was then matched to five individuals without PMR as controls (n = 9,942). The development of cancer was assessed from 1987 to 2011. Patients with a prior history of cancer or vascular disease were excluded from the study. The cohort was 73% female, and the mean age of the study population was 72 years.

The median observation time was 7.8 years, with some patients followed for more than 20 years. During this time, 667 (23.2%) cases of cancer were diagnosed in patients with PMR and 1,938 (19.5%) in those without, giving respective cancer diagnosis rates of 27.7 and 24.4 per 1,000 person-years.

"In those people with PMR, there were more genitourinary cancers, which were mainly prostate cancers, than in those without PMR," observed Dr. Muller. She added that there were also more cancers affecting the lymphatic system and hematopoietic tissue, and unspecified cancers categorized as "other" by the GPRD coding system.

Conversely, PMR patients were less likely than those without PMR to have cancers of the bone, connective tissue, skin and breast, digestive system and peritoneum, and the respiratory tract and intrathoracic organs.

However, these were only trends and not statistically significant. "We could not really look at the statistical significance of these differences in types of cancer because, despite this being possibly one of the largest datasets where you would find this kind of information, we still didn’t really have enough numbers to make any formal statistical analysis," Dr. Muller said.

The Royal College of General Practitioners Scientific Foundation Board supported the research. Dr. Muller had no conflicts of interest.

BIRMINGHAM, ENGLAND – In the first 6 months after the diagnosis of polymyalgia rheumatica, the risk of cancer was almost doubled, with a hazard ratio of 1.96, in a primary care–based matched cohort study of more than 12,000 individuals.

After 6 months, the cancer risk subsided, with a hazard ratio of 1.03 at 6-12 months after diagnosis, 1.04 at 1-2 years, 1.05 at 2-5 years, 1.1 at 5-10 years, and 1.00 after 10 years, reported Sara Muller, Ph.D., of the Research Institute for Primary Care & Health Sciences, Keele University, England.

The drop-off in cancer diagnosis may reflect "a differential diagnosis issue. Maybe there are early cancer symptoms that are being diagnosed as PMR [polymyalgia rheumatica]," she added at the British Society for Rheumatology annual conference.

Monitor PMR patients closely for the first 6 months after diagnosis, Dr. Muller advised. Future research needs to try to tease out how to identify PMR patients who might actually have cancer from those whose condition is limited to joint problems.

PMR is the most common inflammatory rheumatologic condition in older adults. The study was performed to see if there was any link between PMR and cancer, as has been seen for rheumatoid arthritis and lymphoma.

Case reports indicate PMR has been misdiagnosed as renal, testicular, gastric, or hematologic (lymphoma) cancer. The results of a Swedish study (Rheumatology 2010;49:1158-63) suggest that cancer risk is slightly increased in patients diagnosed with PMR or giant cell arteritis. These were all secondary care studies, however, so Dr. Muller and her associates decided to look at a primary care population, where most cases of PMR are diagnosed and treated.

Using the U.K. General Practice Research Database (GPRD), now known as the Clinical Practice Research Datalink, the research team identified 2,877 cases of PMR in individuals aged 50 years or older who were diagnosed between 1987 and 1999. Each case was then matched to five individuals without PMR as controls (n = 9,942). The development of cancer was assessed from 1987 to 2011. Patients with a prior history of cancer or vascular disease were excluded from the study. The cohort was 73% female, and the mean age of the study population was 72 years.

The median observation time was 7.8 years, with some patients followed for more than 20 years. During this time, 667 (23.2%) cases of cancer were diagnosed in patients with PMR and 1,938 (19.5%) in those without, giving respective cancer diagnosis rates of 27.7 and 24.4 per 1,000 person-years.

"In those people with PMR, there were more genitourinary cancers, which were mainly prostate cancers, than in those without PMR," observed Dr. Muller. She added that there were also more cancers affecting the lymphatic system and hematopoietic tissue, and unspecified cancers categorized as "other" by the GPRD coding system.

Conversely, PMR patients were less likely than those without PMR to have cancers of the bone, connective tissue, skin and breast, digestive system and peritoneum, and the respiratory tract and intrathoracic organs.

However, these were only trends and not statistically significant. "We could not really look at the statistical significance of these differences in types of cancer because, despite this being possibly one of the largest datasets where you would find this kind of information, we still didn’t really have enough numbers to make any formal statistical analysis," Dr. Muller said.

The Royal College of General Practitioners Scientific Foundation Board supported the research. Dr. Muller had no conflicts of interest.

BIRMINGHAM, ENGLAND – In the first 6 months after the diagnosis of polymyalgia rheumatica, the risk of cancer was almost doubled, with a hazard ratio of 1.96, in a primary care–based matched cohort study of more than 12,000 individuals.

After 6 months, the cancer risk subsided, with a hazard ratio of 1.03 at 6-12 months after diagnosis, 1.04 at 1-2 years, 1.05 at 2-5 years, 1.1 at 5-10 years, and 1.00 after 10 years, reported Sara Muller, Ph.D., of the Research Institute for Primary Care & Health Sciences, Keele University, England.

The drop-off in cancer diagnosis may reflect "a differential diagnosis issue. Maybe there are early cancer symptoms that are being diagnosed as PMR [polymyalgia rheumatica]," she added at the British Society for Rheumatology annual conference.

Monitor PMR patients closely for the first 6 months after diagnosis, Dr. Muller advised. Future research needs to try to tease out how to identify PMR patients who might actually have cancer from those whose condition is limited to joint problems.

PMR is the most common inflammatory rheumatologic condition in older adults. The study was performed to see if there was any link between PMR and cancer, as has been seen for rheumatoid arthritis and lymphoma.

Case reports indicate PMR has been misdiagnosed as renal, testicular, gastric, or hematologic (lymphoma) cancer. The results of a Swedish study (Rheumatology 2010;49:1158-63) suggest that cancer risk is slightly increased in patients diagnosed with PMR or giant cell arteritis. These were all secondary care studies, however, so Dr. Muller and her associates decided to look at a primary care population, where most cases of PMR are diagnosed and treated.

Using the U.K. General Practice Research Database (GPRD), now known as the Clinical Practice Research Datalink, the research team identified 2,877 cases of PMR in individuals aged 50 years or older who were diagnosed between 1987 and 1999. Each case was then matched to five individuals without PMR as controls (n = 9,942). The development of cancer was assessed from 1987 to 2011. Patients with a prior history of cancer or vascular disease were excluded from the study. The cohort was 73% female, and the mean age of the study population was 72 years.

The median observation time was 7.8 years, with some patients followed for more than 20 years. During this time, 667 (23.2%) cases of cancer were diagnosed in patients with PMR and 1,938 (19.5%) in those without, giving respective cancer diagnosis rates of 27.7 and 24.4 per 1,000 person-years.

"In those people with PMR, there were more genitourinary cancers, which were mainly prostate cancers, than in those without PMR," observed Dr. Muller. She added that there were also more cancers affecting the lymphatic system and hematopoietic tissue, and unspecified cancers categorized as "other" by the GPRD coding system.

Conversely, PMR patients were less likely than those without PMR to have cancers of the bone, connective tissue, skin and breast, digestive system and peritoneum, and the respiratory tract and intrathoracic organs.

However, these were only trends and not statistically significant. "We could not really look at the statistical significance of these differences in types of cancer because, despite this being possibly one of the largest datasets where you would find this kind of information, we still didn’t really have enough numbers to make any formal statistical analysis," Dr. Muller said.

The Royal College of General Practitioners Scientific Foundation Board supported the research. Dr. Muller had no conflicts of interest.

BIRMINGHAM, ENGLAND – Contrary to expectations, metal-on-metal hip resurfacing for osteoarthritis was associated with higher patient survival at 10 years than was total hip arthroplasty in a large, population-based study.

Cumulative mortality rates were 2.8% for hip resurfacing versus 7.3% for cemented total hip replacement (THR; hazard ratio, 0.51). Ten-year mortality rates comparing hip resurfacing to uncemented THR were 2.6% and 3.2%, respectively (HR, 0.64).

Furthermore, the number needed to treat with hip resurfacing to prevent 1 excess death was 29 when compared to cemented THR, and it was 88 when compared to uncemented THR.

"Patients who received a metal-on-metal resurfacing [MoMR] procedure seem to have a long-term survival advantage compared to patients receiving cemented or an uncemented THR," said Dr. Adrian Kendal of the National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit at the University of Oxford, England.

"Our findings were robust after adjustment for known confounders," Dr. Kendal said at the British Society for Rheumatology annual conference. Propensity matching was used in the trial, which took age, gender, comorbidity, rurality, and social deprivation into account.

For the study, data from the English Hospital Episode Statistics database were obtained and linked to Office for National Statistics mortality records for all adults (over age 18) undergoing elective primary hip replacement for osteoarthritis in National Health Service hospitals in England and Wales between April 1999 and March 2012.

After propensity score matching, there were 91,633 procedures performed, of which 12,580 were MoMR, 37,740 were cemented THR, and 41,312 were uncemented THR.

In response to a comment that perhaps people opting for MoMR were more likely to be younger, more active, and hence more likely to exercise, Dr. Kendal conceded that other factors might exist that could have affected survival.

Speculating about why there might be such a difference in survival, he said: "I personally don’t think it’s just the use of cement, because that doesn’t explain the group that received an uncemented total hip replacement."

He added that the way the femur is prepared during THR might be important, regardless of whether or not cement is used. The known risk of thrombotic consequences also could affect survival. In addition, health care inequality might be important, as resurfacing procedures are less common than THR, perhaps because of the lack of specialized centers or dedicated teams.

Commenting on the findings after their presentation, consultant rheumatologist Dr. Alex MacGregor, of the University of East Anglia, Norwich, England, noted that similar data were published on this topic last year (BMJ 2012;344:e3319), but the results had proved somewhat controversial as the authors had a conflict of interest in favor of hip resurfacing.

Dr. MacGregor, who is a member of the National Joint Registry Steering Committee, has been involved in a subsequent reanalysis of the paper’s findings and said that the results will be made public later in the year.

"One of my concerns [with this study] is the use of the 10-year mortality endpoint. If these resurfacing procedures are saving lives, then you would expect to see a survival benefit sooner, say at 90 days," Dr. MacGregor said.

Dr. Kendal responded that they tried to account for this, but the answer will need to come from a properly organized, randomized controlled trial.

"We don’t have a conflict of interest here. If anything, we were perhaps looking for the opposite effect; we were expecting to see an increased mortality rate in the resurfacing group," Dr. Kendal said. "That was not the case as it turned out, so I am reasonably confident that our data support the findings of that BMJ article."

Dr. Kendal and Dr. MacGregor reported no conflicts of interest.

rhnews@frontlinemedcom.com

BIRMINGHAM, ENGLAND – Contrary to expectations, metal-on-metal hip resurfacing for osteoarthritis was associated with higher patient survival at 10 years than was total hip arthroplasty in a large, population-based study.

Cumulative mortality rates were 2.8% for hip resurfacing versus 7.3% for cemented total hip replacement (THR; hazard ratio, 0.51). Ten-year mortality rates comparing hip resurfacing to uncemented THR were 2.6% and 3.2%, respectively (HR, 0.64).

Furthermore, the number needed to treat with hip resurfacing to prevent 1 excess death was 29 when compared to cemented THR, and it was 88 when compared to uncemented THR.

"Patients who received a metal-on-metal resurfacing [MoMR] procedure seem to have a long-term survival advantage compared to patients receiving cemented or an uncemented THR," said Dr. Adrian Kendal of the National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit at the University of Oxford, England.

"Our findings were robust after adjustment for known confounders," Dr. Kendal said at the British Society for Rheumatology annual conference. Propensity matching was used in the trial, which took age, gender, comorbidity, rurality, and social deprivation into account.

For the study, data from the English Hospital Episode Statistics database were obtained and linked to Office for National Statistics mortality records for all adults (over age 18) undergoing elective primary hip replacement for osteoarthritis in National Health Service hospitals in England and Wales between April 1999 and March 2012.

After propensity score matching, there were 91,633 procedures performed, of which 12,580 were MoMR, 37,740 were cemented THR, and 41,312 were uncemented THR.

In response to a comment that perhaps people opting for MoMR were more likely to be younger, more active, and hence more likely to exercise, Dr. Kendal conceded that other factors might exist that could have affected survival.

Speculating about why there might be such a difference in survival, he said: "I personally don’t think it’s just the use of cement, because that doesn’t explain the group that received an uncemented total hip replacement."

He added that the way the femur is prepared during THR might be important, regardless of whether or not cement is used. The known risk of thrombotic consequences also could affect survival. In addition, health care inequality might be important, as resurfacing procedures are less common than THR, perhaps because of the lack of specialized centers or dedicated teams.

Commenting on the findings after their presentation, consultant rheumatologist Dr. Alex MacGregor, of the University of East Anglia, Norwich, England, noted that similar data were published on this topic last year (BMJ 2012;344:e3319), but the results had proved somewhat controversial as the authors had a conflict of interest in favor of hip resurfacing.

Dr. MacGregor, who is a member of the National Joint Registry Steering Committee, has been involved in a subsequent reanalysis of the paper’s findings and said that the results will be made public later in the year.

"One of my concerns [with this study] is the use of the 10-year mortality endpoint. If these resurfacing procedures are saving lives, then you would expect to see a survival benefit sooner, say at 90 days," Dr. MacGregor said.

Dr. Kendal responded that they tried to account for this, but the answer will need to come from a properly organized, randomized controlled trial.

"We don’t have a conflict of interest here. If anything, we were perhaps looking for the opposite effect; we were expecting to see an increased mortality rate in the resurfacing group," Dr. Kendal said. "That was not the case as it turned out, so I am reasonably confident that our data support the findings of that BMJ article."

Dr. Kendal and Dr. MacGregor reported no conflicts of interest.

rhnews@frontlinemedcom.com

BIRMINGHAM, ENGLAND – Contrary to expectations, metal-on-metal hip resurfacing for osteoarthritis was associated with higher patient survival at 10 years than was total hip arthroplasty in a large, population-based study.

Cumulative mortality rates were 2.8% for hip resurfacing versus 7.3% for cemented total hip replacement (THR; hazard ratio, 0.51). Ten-year mortality rates comparing hip resurfacing to uncemented THR were 2.6% and 3.2%, respectively (HR, 0.64).

Furthermore, the number needed to treat with hip resurfacing to prevent 1 excess death was 29 when compared to cemented THR, and it was 88 when compared to uncemented THR.

"Patients who received a metal-on-metal resurfacing [MoMR] procedure seem to have a long-term survival advantage compared to patients receiving cemented or an uncemented THR," said Dr. Adrian Kendal of the National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit at the University of Oxford, England.

"Our findings were robust after adjustment for known confounders," Dr. Kendal said at the British Society for Rheumatology annual conference. Propensity matching was used in the trial, which took age, gender, comorbidity, rurality, and social deprivation into account.

For the study, data from the English Hospital Episode Statistics database were obtained and linked to Office for National Statistics mortality records for all adults (over age 18) undergoing elective primary hip replacement for osteoarthritis in National Health Service hospitals in England and Wales between April 1999 and March 2012.

After propensity score matching, there were 91,633 procedures performed, of which 12,580 were MoMR, 37,740 were cemented THR, and 41,312 were uncemented THR.

In response to a comment that perhaps people opting for MoMR were more likely to be younger, more active, and hence more likely to exercise, Dr. Kendal conceded that other factors might exist that could have affected survival.

Speculating about why there might be such a difference in survival, he said: "I personally don’t think it’s just the use of cement, because that doesn’t explain the group that received an uncemented total hip replacement."

He added that the way the femur is prepared during THR might be important, regardless of whether or not cement is used. The known risk of thrombotic consequences also could affect survival. In addition, health care inequality might be important, as resurfacing procedures are less common than THR, perhaps because of the lack of specialized centers or dedicated teams.

Commenting on the findings after their presentation, consultant rheumatologist Dr. Alex MacGregor, of the University of East Anglia, Norwich, England, noted that similar data were published on this topic last year (BMJ 2012;344:e3319), but the results had proved somewhat controversial as the authors had a conflict of interest in favor of hip resurfacing.

Dr. MacGregor, who is a member of the National Joint Registry Steering Committee, has been involved in a subsequent reanalysis of the paper’s findings and said that the results will be made public later in the year.

"One of my concerns [with this study] is the use of the 10-year mortality endpoint. If these resurfacing procedures are saving lives, then you would expect to see a survival benefit sooner, say at 90 days," Dr. MacGregor said.

Dr. Kendal responded that they tried to account for this, but the answer will need to come from a properly organized, randomized controlled trial.

"We don’t have a conflict of interest here. If anything, we were perhaps looking for the opposite effect; we were expecting to see an increased mortality rate in the resurfacing group," Dr. Kendal said. "That was not the case as it turned out, so I am reasonably confident that our data support the findings of that BMJ article."

Dr. Kendal and Dr. MacGregor reported no conflicts of interest.

rhnews@frontlinemedcom.com

BIRMINGHAM, ENGLAND – Long-term bisphosphonate use reduced the risk for joint implant failure and subsequent hip or knee revision survey in 40% of patients in a large, retrospective, observational study.

The rate for revision surgery at a median of 2.6 years’ follow-up was 1.88% in the 1,911 participants who had taken bisphosphonates for at least 6 months, compared with 4.36% in the 10,755 nonbisphosphonate users (hazard ratio, 0.62).

"The observed effect size is stronger in patients with higher therapy duration and adherence," Dr. Daniel Prieto-Alhambra reported at the annual meeting of the British Society for Rheumatology.

"This association does not differ by age, gender, joint replaced, or fracture history," added Dr. Prieto-Alhambra, senior clinical research fellow from the Nuffield department of orthopaedics, rheumatology, and musculoskeletal sciences at the University of Oxford, England.

Osteolysis and aseptic loosening are the most common causes of revision surgery, the researcher noted, adding that bisphosphonates have antiosteoclast activity that may have potential benefits on implant survival.

"Patients need to be on treatment for at least 6 months for the drug to be effective," Dr. Prieto-Alhambra emphasized. He later said after his presentation that data from a sub-analysis suggest that patients benefit further if they started therapy in the weeks following surgery.*

Data used in the study were obtained from Danish nationwide health registries on more than 80,000 patients aged 40 years or older who had total hip arthroplasty (THA) or total knee arthroplasty (TKA) in Denmark between 1998 and 2007. Patients were excluded if they had experienced a prior hip fracture; had inflammatory arthritis or used disease-modifying antirheumatic drugs; or had Paget’s disease, bone cancer, or metastasis. Baseline characteristics of those who did and those who did not use bisphosphonates were comparable except for calcium and vitamin D supplementation, which was higher in the bisphosphonate-treated group (9.9% vs. 4.8%).

The longer the duration of treatment, the less chance there was for implant failure: 5 implants failed in 352 (1.4%) patients treated with bisphosphonates for more than 2 years (HR, 0.53); 16 (1.6%) in 1,006 patients treated for 1-2 years (HR, 0.52); and 15 (2.7%) in 553 patients treated for 6-12 months (HR, 1.31).

Adherence was assessed using a medication possession ratio (MPR), with lower MPR values indicating poorer adherence. Failure rates were 3%, 2.9%, and 1.5% for MPRs of less than 0.5 (HR, 0.93), 0.5-0.79 (HR, 0.48), and 0.8 or greater (HR, 0.56), respectively.

The study’s findings support those of a recent U.K. population-based, retrospective cohort study (BMJ 2011 [doi:10.1136/bmj.d7222]) that involved more than 41,000 primary THA/TKA patients.

The U.K. data showed that fewer surgical revisions occurred at 5 years in bisphosphonate users (0.93% vs. 1.96% in nonusers), and that there was a 46% decrease in the risk of revision surgery (HR for implant survival of 0.54; P = .047). It was also estimated, however, that at least 107 patients would need to be treated with bisphosphonates to avoid one revision surgery.

Osteoarthritis accounts for more than 90% of THAs and TKAs performed in the United Kingdom, with 1 in 75 patients experiencing implant failure and revision surgery within 3 years of the index surgery. Such surgery is associated with a worse clinical outcome than the primary procedure, and it is also associated with greater health care costs (PLoS Med. 2008;5:e179). Bisphosphonates could potentially offer a simple and hopefully cost-effective solution to reducing the likelihood of such surgery.

"Confirmation in a randomized controlled trial is needed to test the efficacy of bisphosphonates to improve implant survival, Dr. Prieto-Alhambra said.

A 40% reduction in the risk of aseptic loosening of the prosthesis is potentially very good news for patients, observed Dr. Ken Poole, a clinical lecturer at the University of Cambridge, England. Randomized trial data would be welcomed and warranted, he added.

Dr. Poole, who was chairing the session at which these data were presented, highlighted that this was another "good news" story for bisphosphonates, adding to recent evidence that they increased survival after hip fracture and have also been associated with reductions in the incidence of certain cancers.

"Many of my patients are well versed in the potential harms of bisphosphonate treatments for osteoporosis, often because of enthusiastic media coverage of the ‘bad news’ aspect," he said in an interview.

"The upshot is that ‘at-risk’ patients are increasingly reluctant to commence therapy; indeed, it is easy to find out about rare and frightening side effects like osteonecrosis of the jaw and atraumatic fractures of the femur from a few clicks on the Internet," Dr. Poole commented.

Although serious adverse events should be borne in mind when considering treatment choice, Dr. Poole noted that bisphosphonates were effective for osteoporosis in the right patients, and that Dr. Prieto-Alhambra’s study was one of several identifying additional health benefits in patients undergoing total hip or knee replacement.

A poor public perception of bisphosphonates could influence adherence, and there is recent evidence that only 30% of women actually take their prescriptions to the pharmacist (Osteoporos. Int. 2013 [doi:10.1007/s00198-013-2326-5]). Concern over calcium supplementation causing heart attacks and stroke might also be a factor, as this, together with vitamin D, goes along with bisphosphonate use. Indeed, a study of 233 women taking bisphosphonates for osteoporosis also presented at the British Society for Rheumatology meeting found that a lack of concomitant calcium and vitamin D supplementation was predictive of poor adherence (Rheumatology 2013;52[Suppl. 1]:i116-7; abstract 163). Other predictive factors were older age and the use of sleeping tablets.

Dr. Prieto-Alhambra and Dr. Poole had no conflicts of interests.

* Revised, 5/1/13

BIRMINGHAM, ENGLAND – Long-term bisphosphonate use reduced the risk for joint implant failure and subsequent hip or knee revision survey in 40% of patients in a large, retrospective, observational study.

The rate for revision surgery at a median of 2.6 years’ follow-up was 1.88% in the 1,911 participants who had taken bisphosphonates for at least 6 months, compared with 4.36% in the 10,755 nonbisphosphonate users (hazard ratio, 0.62).

"The observed effect size is stronger in patients with higher therapy duration and adherence," Dr. Daniel Prieto-Alhambra reported at the annual meeting of the British Society for Rheumatology.

"This association does not differ by age, gender, joint replaced, or fracture history," added Dr. Prieto-Alhambra, senior clinical research fellow from the Nuffield department of orthopaedics, rheumatology, and musculoskeletal sciences at the University of Oxford, England.

Osteolysis and aseptic loosening are the most common causes of revision surgery, the researcher noted, adding that bisphosphonates have antiosteoclast activity that may have potential benefits on implant survival.

"Patients need to be on treatment for at least 6 months for the drug to be effective," Dr. Prieto-Alhambra emphasized. He later said after his presentation that data from a sub-analysis suggest that patients benefit further if they started therapy in the weeks following surgery.*

Data used in the study were obtained from Danish nationwide health registries on more than 80,000 patients aged 40 years or older who had total hip arthroplasty (THA) or total knee arthroplasty (TKA) in Denmark between 1998 and 2007. Patients were excluded if they had experienced a prior hip fracture; had inflammatory arthritis or used disease-modifying antirheumatic drugs; or had Paget’s disease, bone cancer, or metastasis. Baseline characteristics of those who did and those who did not use bisphosphonates were comparable except for calcium and vitamin D supplementation, which was higher in the bisphosphonate-treated group (9.9% vs. 4.8%).

The longer the duration of treatment, the less chance there was for implant failure: 5 implants failed in 352 (1.4%) patients treated with bisphosphonates for more than 2 years (HR, 0.53); 16 (1.6%) in 1,006 patients treated for 1-2 years (HR, 0.52); and 15 (2.7%) in 553 patients treated for 6-12 months (HR, 1.31).

Adherence was assessed using a medication possession ratio (MPR), with lower MPR values indicating poorer adherence. Failure rates were 3%, 2.9%, and 1.5% for MPRs of less than 0.5 (HR, 0.93), 0.5-0.79 (HR, 0.48), and 0.8 or greater (HR, 0.56), respectively.

The study’s findings support those of a recent U.K. population-based, retrospective cohort study (BMJ 2011 [doi:10.1136/bmj.d7222]) that involved more than 41,000 primary THA/TKA patients.

The U.K. data showed that fewer surgical revisions occurred at 5 years in bisphosphonate users (0.93% vs. 1.96% in nonusers), and that there was a 46% decrease in the risk of revision surgery (HR for implant survival of 0.54; P = .047). It was also estimated, however, that at least 107 patients would need to be treated with bisphosphonates to avoid one revision surgery.

Osteoarthritis accounts for more than 90% of THAs and TKAs performed in the United Kingdom, with 1 in 75 patients experiencing implant failure and revision surgery within 3 years of the index surgery. Such surgery is associated with a worse clinical outcome than the primary procedure, and it is also associated with greater health care costs (PLoS Med. 2008;5:e179). Bisphosphonates could potentially offer a simple and hopefully cost-effective solution to reducing the likelihood of such surgery.

"Confirmation in a randomized controlled trial is needed to test the efficacy of bisphosphonates to improve implant survival, Dr. Prieto-Alhambra said.

A 40% reduction in the risk of aseptic loosening of the prosthesis is potentially very good news for patients, observed Dr. Ken Poole, a clinical lecturer at the University of Cambridge, England. Randomized trial data would be welcomed and warranted, he added.

Dr. Poole, who was chairing the session at which these data were presented, highlighted that this was another "good news" story for bisphosphonates, adding to recent evidence that they increased survival after hip fracture and have also been associated with reductions in the incidence of certain cancers.

"Many of my patients are well versed in the potential harms of bisphosphonate treatments for osteoporosis, often because of enthusiastic media coverage of the ‘bad news’ aspect," he said in an interview.

"The upshot is that ‘at-risk’ patients are increasingly reluctant to commence therapy; indeed, it is easy to find out about rare and frightening side effects like osteonecrosis of the jaw and atraumatic fractures of the femur from a few clicks on the Internet," Dr. Poole commented.

Although serious adverse events should be borne in mind when considering treatment choice, Dr. Poole noted that bisphosphonates were effective for osteoporosis in the right patients, and that Dr. Prieto-Alhambra’s study was one of several identifying additional health benefits in patients undergoing total hip or knee replacement.

A poor public perception of bisphosphonates could influence adherence, and there is recent evidence that only 30% of women actually take their prescriptions to the pharmacist (Osteoporos. Int. 2013 [doi:10.1007/s00198-013-2326-5]). Concern over calcium supplementation causing heart attacks and stroke might also be a factor, as this, together with vitamin D, goes along with bisphosphonate use. Indeed, a study of 233 women taking bisphosphonates for osteoporosis also presented at the British Society for Rheumatology meeting found that a lack of concomitant calcium and vitamin D supplementation was predictive of poor adherence (Rheumatology 2013;52[Suppl. 1]:i116-7; abstract 163). Other predictive factors were older age and the use of sleeping tablets.

Dr. Prieto-Alhambra and Dr. Poole had no conflicts of interests.

* Revised, 5/1/13

BIRMINGHAM, ENGLAND – Long-term bisphosphonate use reduced the risk for joint implant failure and subsequent hip or knee revision survey in 40% of patients in a large, retrospective, observational study.

The rate for revision surgery at a median of 2.6 years’ follow-up was 1.88% in the 1,911 participants who had taken bisphosphonates for at least 6 months, compared with 4.36% in the 10,755 nonbisphosphonate users (hazard ratio, 0.62).

"The observed effect size is stronger in patients with higher therapy duration and adherence," Dr. Daniel Prieto-Alhambra reported at the annual meeting of the British Society for Rheumatology.

"This association does not differ by age, gender, joint replaced, or fracture history," added Dr. Prieto-Alhambra, senior clinical research fellow from the Nuffield department of orthopaedics, rheumatology, and musculoskeletal sciences at the University of Oxford, England.

Osteolysis and aseptic loosening are the most common causes of revision surgery, the researcher noted, adding that bisphosphonates have antiosteoclast activity that may have potential benefits on implant survival.

"Patients need to be on treatment for at least 6 months for the drug to be effective," Dr. Prieto-Alhambra emphasized. He later said after his presentation that data from a sub-analysis suggest that patients benefit further if they started therapy in the weeks following surgery.*

Data used in the study were obtained from Danish nationwide health registries on more than 80,000 patients aged 40 years or older who had total hip arthroplasty (THA) or total knee arthroplasty (TKA) in Denmark between 1998 and 2007. Patients were excluded if they had experienced a prior hip fracture; had inflammatory arthritis or used disease-modifying antirheumatic drugs; or had Paget’s disease, bone cancer, or metastasis. Baseline characteristics of those who did and those who did not use bisphosphonates were comparable except for calcium and vitamin D supplementation, which was higher in the bisphosphonate-treated group (9.9% vs. 4.8%).

The longer the duration of treatment, the less chance there was for implant failure: 5 implants failed in 352 (1.4%) patients treated with bisphosphonates for more than 2 years (HR, 0.53); 16 (1.6%) in 1,006 patients treated for 1-2 years (HR, 0.52); and 15 (2.7%) in 553 patients treated for 6-12 months (HR, 1.31).

Adherence was assessed using a medication possession ratio (MPR), with lower MPR values indicating poorer adherence. Failure rates were 3%, 2.9%, and 1.5% for MPRs of less than 0.5 (HR, 0.93), 0.5-0.79 (HR, 0.48), and 0.8 or greater (HR, 0.56), respectively.

The study’s findings support those of a recent U.K. population-based, retrospective cohort study (BMJ 2011 [doi:10.1136/bmj.d7222]) that involved more than 41,000 primary THA/TKA patients.

The U.K. data showed that fewer surgical revisions occurred at 5 years in bisphosphonate users (0.93% vs. 1.96% in nonusers), and that there was a 46% decrease in the risk of revision surgery (HR for implant survival of 0.54; P = .047). It was also estimated, however, that at least 107 patients would need to be treated with bisphosphonates to avoid one revision surgery.

Osteoarthritis accounts for more than 90% of THAs and TKAs performed in the United Kingdom, with 1 in 75 patients experiencing implant failure and revision surgery within 3 years of the index surgery. Such surgery is associated with a worse clinical outcome than the primary procedure, and it is also associated with greater health care costs (PLoS Med. 2008;5:e179). Bisphosphonates could potentially offer a simple and hopefully cost-effective solution to reducing the likelihood of such surgery.

"Confirmation in a randomized controlled trial is needed to test the efficacy of bisphosphonates to improve implant survival, Dr. Prieto-Alhambra said.

A 40% reduction in the risk of aseptic loosening of the prosthesis is potentially very good news for patients, observed Dr. Ken Poole, a clinical lecturer at the University of Cambridge, England. Randomized trial data would be welcomed and warranted, he added.

Dr. Poole, who was chairing the session at which these data were presented, highlighted that this was another "good news" story for bisphosphonates, adding to recent evidence that they increased survival after hip fracture and have also been associated with reductions in the incidence of certain cancers.

"Many of my patients are well versed in the potential harms of bisphosphonate treatments for osteoporosis, often because of enthusiastic media coverage of the ‘bad news’ aspect," he said in an interview.

"The upshot is that ‘at-risk’ patients are increasingly reluctant to commence therapy; indeed, it is easy to find out about rare and frightening side effects like osteonecrosis of the jaw and atraumatic fractures of the femur from a few clicks on the Internet," Dr. Poole commented.

Although serious adverse events should be borne in mind when considering treatment choice, Dr. Poole noted that bisphosphonates were effective for osteoporosis in the right patients, and that Dr. Prieto-Alhambra’s study was one of several identifying additional health benefits in patients undergoing total hip or knee replacement.

A poor public perception of bisphosphonates could influence adherence, and there is recent evidence that only 30% of women actually take their prescriptions to the pharmacist (Osteoporos. Int. 2013 [doi:10.1007/s00198-013-2326-5]). Concern over calcium supplementation causing heart attacks and stroke might also be a factor, as this, together with vitamin D, goes along with bisphosphonate use. Indeed, a study of 233 women taking bisphosphonates for osteoporosis also presented at the British Society for Rheumatology meeting found that a lack of concomitant calcium and vitamin D supplementation was predictive of poor adherence (Rheumatology 2013;52[Suppl. 1]:i116-7; abstract 163). Other predictive factors were older age and the use of sleeping tablets.

Dr. Prieto-Alhambra and Dr. Poole had no conflicts of interests.

* Revised, 5/1/13

BIRMINGHAM, ENGLAND – Combinations of conventional antirheumatic drugs are as clinically effective as more expensive biologic agents in managing patients with active, established rheumatoid arthritis, randomized trial data suggest.

Health Assessment Questionnaire (HAQ) scores at 12 months were lower in patients given conventional disease-modifying antirheumatic drugs (cDMARDs) as compared to a tumor necrosis factor inhibitor (TNFi) after failure of methotrexate and at least one other DMARD (1.35 vs. 1.60, P = .046).

Nevertheless, the two approaches were "clinically equivalent," said trial investigator Dr. David L. Scott at the annual meeting of the British Society for Rheumatology.

"In patients with methotrexate-resistant rheumatoid arthritis [RA], giving the cDMARD intensive therapy and starting off with a TNFi achieves similar outcomes, causes comparable harms, but the cDMARDs cost less," said Dr. Scott, who is professor of clinical rheumatology at King’s College London.

These data, from the TACIT (Tumor Necrosis Factor Inhibitors or Conventional Drugs in Rheumatoid Arthritis) trial, suggest that combination DMARD therapy could be an alternative approach for patients with established RA, reserving anti-TNF agents for those who fail intensive DMARD treatment.

Dr. Scott noted that the findings might warrant a change in practice in the United Kingdom, where anti-TNFs are currently recommended as the next choice in patients who do not respond to treatment with two individual DMARDs, one of which must be methotrexate. Such an approach is based on evidence from placebo-controlled, rather than head-to-head, trials, however, and such a "one size fits all" approach perhaps needs reevaluation.

The TACIT trial was conducted in 24 centers in the United Kingdom and involved 205 patients who had RA for a median duration of 4 years. The aim of the trial was to directly compare two different treatment strategies: a TNFi (infliximab, etanercept, or adalimumab) given to patients after failing methotrexate and a subsequent DMARD versus methotrexate followed by combination cDMARDs and then a TNFi.

Combinations of cDMARDs used in the trial included triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine; other methotrexate combinations (methotrexate-cyclosporin, methotrexate-leflunomide, and methotrexate-gold); and one sulfasalazine combination (sulfasalazine-leflunomide).

At 12 months’ follow-up, there was no significant difference between the treatment strategies in terms of quality of life measured using the EuroQol instrument, radiographic progression assessed using Larsen scores, or disease activity assessed via monthly Disease Activity Score-28 (DAS28).

The mean change in DAS28 score was initially greater in TNFi-treated patients (–2.07 vs. –1.45, P = .007) at 6 months, Dr. Scott said, but this difference was lost with longer follow-up. "This simply shows that, as we’ve always known, TNFi’s act rapidly and DMARDs are slow acting," he observed.

Economic analysis showed a clear advantage for the use of cDMARDs over anti-TNF agents, with an annual estimated saving of health and social care costs of £5,552 (U.S.$8,400) per patient. Taking lost productivity and social security payments into account did not change the findings.

Safety is a concern of using multiple cDMARDs, particularly older combinations, but the TACIT data showed that there were a comparable number of adverse reactions. The total number of events was 635 for cDMARDs and 465 in the TNFi group. Of these, there were more digestive adverse events in the cDMARD arm than in the TNFi group (148 vs. 60), but more infections in the anti-TNF-treated patients than in the cDMARD group (54 vs. 30).

Serious adverse events were noted in 10 and 18 of cDMARD- and TNFi-treated patients, respectively, with 10 and 6 patients in each group withdrawing as a result of experiencing a side effect. There was one death, due to pneumonia and multiple organ failure, in the anti-TNF arm.

"We should think about the treatment strategy in terms of intensive DMARDs first of all and then moving onto biologics," Dr. Scott said. Remission needs to be a target of treatment, he added, although this is rarely achieved by either strategy. Remission rates at 12 months seen in TACIT are comparable to rates reported from several registries, including CORRONA (Consortium of Rheumatology Researchers of North America) in the United States, DANBIO in Denmark, RABBIT in Germany, and BSRBR-RA (British Society for Rheumatology Biologics Register-Rheumatoid Arthritis) in the United Kingdom.

Dr. Scott concluded by noting that there are three unresolved questions. First, it is not clear what the best combination of cDMARDs is; second, the optimum way to use biologics is currently unknown; and third, it is not clear how to convert patients with intermediate disease activity into patients who may achieve clinical remission.

The TACIT trial was supported by a Health Technology Assessment grant from the U.K. National Institute for Health Research. Dr. Scott and his coinvestigators reported having no conflicts of interest.

BIRMINGHAM, ENGLAND – Combinations of conventional antirheumatic drugs are as clinically effective as more expensive biologic agents in managing patients with active, established rheumatoid arthritis, randomized trial data suggest.

Health Assessment Questionnaire (HAQ) scores at 12 months were lower in patients given conventional disease-modifying antirheumatic drugs (cDMARDs) as compared to a tumor necrosis factor inhibitor (TNFi) after failure of methotrexate and at least one other DMARD (1.35 vs. 1.60, P = .046).

Nevertheless, the two approaches were "clinically equivalent," said trial investigator Dr. David L. Scott at the annual meeting of the British Society for Rheumatology.

"In patients with methotrexate-resistant rheumatoid arthritis [RA], giving the cDMARD intensive therapy and starting off with a TNFi achieves similar outcomes, causes comparable harms, but the cDMARDs cost less," said Dr. Scott, who is professor of clinical rheumatology at King’s College London.

These data, from the TACIT (Tumor Necrosis Factor Inhibitors or Conventional Drugs in Rheumatoid Arthritis) trial, suggest that combination DMARD therapy could be an alternative approach for patients with established RA, reserving anti-TNF agents for those who fail intensive DMARD treatment.

Dr. Scott noted that the findings might warrant a change in practice in the United Kingdom, where anti-TNFs are currently recommended as the next choice in patients who do not respond to treatment with two individual DMARDs, one of which must be methotrexate. Such an approach is based on evidence from placebo-controlled, rather than head-to-head, trials, however, and such a "one size fits all" approach perhaps needs reevaluation.

The TACIT trial was conducted in 24 centers in the United Kingdom and involved 205 patients who had RA for a median duration of 4 years. The aim of the trial was to directly compare two different treatment strategies: a TNFi (infliximab, etanercept, or adalimumab) given to patients after failing methotrexate and a subsequent DMARD versus methotrexate followed by combination cDMARDs and then a TNFi.

Combinations of cDMARDs used in the trial included triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine; other methotrexate combinations (methotrexate-cyclosporin, methotrexate-leflunomide, and methotrexate-gold); and one sulfasalazine combination (sulfasalazine-leflunomide).

At 12 months’ follow-up, there was no significant difference between the treatment strategies in terms of quality of life measured using the EuroQol instrument, radiographic progression assessed using Larsen scores, or disease activity assessed via monthly Disease Activity Score-28 (DAS28).

The mean change in DAS28 score was initially greater in TNFi-treated patients (–2.07 vs. –1.45, P = .007) at 6 months, Dr. Scott said, but this difference was lost with longer follow-up. "This simply shows that, as we’ve always known, TNFi’s act rapidly and DMARDs are slow acting," he observed.

Economic analysis showed a clear advantage for the use of cDMARDs over anti-TNF agents, with an annual estimated saving of health and social care costs of £5,552 (U.S.$8,400) per patient. Taking lost productivity and social security payments into account did not change the findings.

Safety is a concern of using multiple cDMARDs, particularly older combinations, but the TACIT data showed that there were a comparable number of adverse reactions. The total number of events was 635 for cDMARDs and 465 in the TNFi group. Of these, there were more digestive adverse events in the cDMARD arm than in the TNFi group (148 vs. 60), but more infections in the anti-TNF-treated patients than in the cDMARD group (54 vs. 30).

Serious adverse events were noted in 10 and 18 of cDMARD- and TNFi-treated patients, respectively, with 10 and 6 patients in each group withdrawing as a result of experiencing a side effect. There was one death, due to pneumonia and multiple organ failure, in the anti-TNF arm.

"We should think about the treatment strategy in terms of intensive DMARDs first of all and then moving onto biologics," Dr. Scott said. Remission needs to be a target of treatment, he added, although this is rarely achieved by either strategy. Remission rates at 12 months seen in TACIT are comparable to rates reported from several registries, including CORRONA (Consortium of Rheumatology Researchers of North America) in the United States, DANBIO in Denmark, RABBIT in Germany, and BSRBR-RA (British Society for Rheumatology Biologics Register-Rheumatoid Arthritis) in the United Kingdom.

Dr. Scott concluded by noting that there are three unresolved questions. First, it is not clear what the best combination of cDMARDs is; second, the optimum way to use biologics is currently unknown; and third, it is not clear how to convert patients with intermediate disease activity into patients who may achieve clinical remission.

The TACIT trial was supported by a Health Technology Assessment grant from the U.K. National Institute for Health Research. Dr. Scott and his coinvestigators reported having no conflicts of interest.

BIRMINGHAM, ENGLAND – Combinations of conventional antirheumatic drugs are as clinically effective as more expensive biologic agents in managing patients with active, established rheumatoid arthritis, randomized trial data suggest.

Health Assessment Questionnaire (HAQ) scores at 12 months were lower in patients given conventional disease-modifying antirheumatic drugs (cDMARDs) as compared to a tumor necrosis factor inhibitor (TNFi) after failure of methotrexate and at least one other DMARD (1.35 vs. 1.60, P = .046).

Nevertheless, the two approaches were "clinically equivalent," said trial investigator Dr. David L. Scott at the annual meeting of the British Society for Rheumatology.

"In patients with methotrexate-resistant rheumatoid arthritis [RA], giving the cDMARD intensive therapy and starting off with a TNFi achieves similar outcomes, causes comparable harms, but the cDMARDs cost less," said Dr. Scott, who is professor of clinical rheumatology at King’s College London.

These data, from the TACIT (Tumor Necrosis Factor Inhibitors or Conventional Drugs in Rheumatoid Arthritis) trial, suggest that combination DMARD therapy could be an alternative approach for patients with established RA, reserving anti-TNF agents for those who fail intensive DMARD treatment.

Dr. Scott noted that the findings might warrant a change in practice in the United Kingdom, where anti-TNFs are currently recommended as the next choice in patients who do not respond to treatment with two individual DMARDs, one of which must be methotrexate. Such an approach is based on evidence from placebo-controlled, rather than head-to-head, trials, however, and such a "one size fits all" approach perhaps needs reevaluation.

The TACIT trial was conducted in 24 centers in the United Kingdom and involved 205 patients who had RA for a median duration of 4 years. The aim of the trial was to directly compare two different treatment strategies: a TNFi (infliximab, etanercept, or adalimumab) given to patients after failing methotrexate and a subsequent DMARD versus methotrexate followed by combination cDMARDs and then a TNFi.

Combinations of cDMARDs used in the trial included triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine; other methotrexate combinations (methotrexate-cyclosporin, methotrexate-leflunomide, and methotrexate-gold); and one sulfasalazine combination (sulfasalazine-leflunomide).

At 12 months’ follow-up, there was no significant difference between the treatment strategies in terms of quality of life measured using the EuroQol instrument, radiographic progression assessed using Larsen scores, or disease activity assessed via monthly Disease Activity Score-28 (DAS28).

The mean change in DAS28 score was initially greater in TNFi-treated patients (–2.07 vs. –1.45, P = .007) at 6 months, Dr. Scott said, but this difference was lost with longer follow-up. "This simply shows that, as we’ve always known, TNFi’s act rapidly and DMARDs are slow acting," he observed.

Economic analysis showed a clear advantage for the use of cDMARDs over anti-TNF agents, with an annual estimated saving of health and social care costs of £5,552 (U.S.$8,400) per patient. Taking lost productivity and social security payments into account did not change the findings.

Safety is a concern of using multiple cDMARDs, particularly older combinations, but the TACIT data showed that there were a comparable number of adverse reactions. The total number of events was 635 for cDMARDs and 465 in the TNFi group. Of these, there were more digestive adverse events in the cDMARD arm than in the TNFi group (148 vs. 60), but more infections in the anti-TNF-treated patients than in the cDMARD group (54 vs. 30).

Serious adverse events were noted in 10 and 18 of cDMARD- and TNFi-treated patients, respectively, with 10 and 6 patients in each group withdrawing as a result of experiencing a side effect. There was one death, due to pneumonia and multiple organ failure, in the anti-TNF arm.

"We should think about the treatment strategy in terms of intensive DMARDs first of all and then moving onto biologics," Dr. Scott said. Remission needs to be a target of treatment, he added, although this is rarely achieved by either strategy. Remission rates at 12 months seen in TACIT are comparable to rates reported from several registries, including CORRONA (Consortium of Rheumatology Researchers of North America) in the United States, DANBIO in Denmark, RABBIT in Germany, and BSRBR-RA (British Society for Rheumatology Biologics Register-Rheumatoid Arthritis) in the United Kingdom.

Dr. Scott concluded by noting that there are three unresolved questions. First, it is not clear what the best combination of cDMARDs is; second, the optimum way to use biologics is currently unknown; and third, it is not clear how to convert patients with intermediate disease activity into patients who may achieve clinical remission.

The TACIT trial was supported by a Health Technology Assessment grant from the U.K. National Institute for Health Research. Dr. Scott and his coinvestigators reported having no conflicts of interest.

A DNA repair protein appears to have limited use for determining response to cisplatin-based adjuvant chemotherapy for non–small cell lung cancer, according to the results of an international study.

"We were unable to validate the predictive effect of immunostaining for ERCC1 protein," Dr. Jean-Charles Soria of the Institut Gustave-Roussy, Villejuif, France, and his associates reported in the New England Journal of Medicine (2013;368:1101-10).

The absence of excision repair cross-complementation group 1 (ERCC1) protein expression and better response to platinum-based chemotherapy were first linked 7 years ago in a biology substudy of the IALT (International Adjuvant Lung Cancer Trial) (N. Engl. J. Med. 2006;355:983-91).

Dr. Soria and his team were unable to replicate these findings, however, in the LACE (Lung Adjuvant Cisplatin Evaluation) Biology biomarker project. In fact, they found contrary evidence, suggesting that the presence rather than the absence of ERCC1 might confer a slight overall survival advantage with cisplatin-based chemotherapy.

The hazard ratio (HR) for death in patients with ERCC1-negative tumors was 1.16 (P = .62), and for ERCC1-positive tumors it was 0.78 (P = .09), but there was no overall predictive value of the marker (P = .23).

The LACE Biology biomarker project used the 8F1 mouse monoclonal antibody to detect ERCC1 expression in tumor samples taken from two independent, randomized, phase III trials of postoperative adjuvant cisplatin-based chemotherapy. The aim was to confirm ERCC1 as a predictive biomarker as seen in the IALT substudy.

A total of 494 whole-tissue sections were obtained from the Cancer and Leukemia Group B (CALGB) 9633 trial and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trials. A lack of confirmatory findings prompted a reanalysis of the entire original set of tissue samples taken from 589 patients who had participated in the 2006 IALT.

"Repeated staining showed important discrepancies between the ERC1 immunohistochemical results obtained in 2006 and those obtained in 2011," Dr. Soria and his team reported. They found that tumors previously classified as ERCC1-negative were ERCC1-positive on reexamination. The discrepancies might be explained by changes in the 8F1 antibody between 2006 and 2011, although the researchers were unable to test this hypothesis.

Other antibodies have been proposed to detect ERCC1 expression, but testing a further 15 of these antibodies showed that none was specific for any of the four known isoforms of ERCC1.

Results obtained using reverse transcriptase–polymerase chain reaction highlighted the fact that ERCC1 isoform transcripts and proteins are heterogeneously expressed in cell lines and tumor samples.

"We were unable to validate ERCC1 protein expression as a predictive marker in a new, independent series of homogeneously treated patients with NSCLC," the researchers commented.

This could be because there are currently inadequate tools to detect expression levels of the protein or because the biologic complexity of the protein’s expression has been underestimated.

A third explanation is that the ERCC1 biomarker is not an efficient predictor of the response to cisplatin-based chemotherapy.

"Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform," the researchers concluded.

"As a result, its usefulness in guiding therapeutic decision making is limited."

The research was supported by various grants associated with the clinical trials involved: an unrestricted educational grant from Eli Lilly and grants from l’Institut National du Cancer Programme National d’Excellence Spécialisé and Programme Hospitalier de Recherche Clinique (for the IALT); a grant from La Ligue Nationale contre le Cancer and an unrestricted grant from Sanofi-Aventis (for the LACE Biology project); and a grant from the European Union Seventh Framework Program. Support also came from a translational research fellowship from Roche.

tor@frontlinemedcom.com

A DNA repair protein appears to have limited use for determining response to cisplatin-based adjuvant chemotherapy for non–small cell lung cancer, according to the results of an international study.

"We were unable to validate the predictive effect of immunostaining for ERCC1 protein," Dr. Jean-Charles Soria of the Institut Gustave-Roussy, Villejuif, France, and his associates reported in the New England Journal of Medicine (2013;368:1101-10).

The absence of excision repair cross-complementation group 1 (ERCC1) protein expression and better response to platinum-based chemotherapy were first linked 7 years ago in a biology substudy of the IALT (International Adjuvant Lung Cancer Trial) (N. Engl. J. Med. 2006;355:983-91).

Dr. Soria and his team were unable to replicate these findings, however, in the LACE (Lung Adjuvant Cisplatin Evaluation) Biology biomarker project. In fact, they found contrary evidence, suggesting that the presence rather than the absence of ERCC1 might confer a slight overall survival advantage with cisplatin-based chemotherapy.

The hazard ratio (HR) for death in patients with ERCC1-negative tumors was 1.16 (P = .62), and for ERCC1-positive tumors it was 0.78 (P = .09), but there was no overall predictive value of the marker (P = .23).

The LACE Biology biomarker project used the 8F1 mouse monoclonal antibody to detect ERCC1 expression in tumor samples taken from two independent, randomized, phase III trials of postoperative adjuvant cisplatin-based chemotherapy. The aim was to confirm ERCC1 as a predictive biomarker as seen in the IALT substudy.

A total of 494 whole-tissue sections were obtained from the Cancer and Leukemia Group B (CALGB) 9633 trial and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trials. A lack of confirmatory findings prompted a reanalysis of the entire original set of tissue samples taken from 589 patients who had participated in the 2006 IALT.

"Repeated staining showed important discrepancies between the ERC1 immunohistochemical results obtained in 2006 and those obtained in 2011," Dr. Soria and his team reported. They found that tumors previously classified as ERCC1-negative were ERCC1-positive on reexamination. The discrepancies might be explained by changes in the 8F1 antibody between 2006 and 2011, although the researchers were unable to test this hypothesis.

Other antibodies have been proposed to detect ERCC1 expression, but testing a further 15 of these antibodies showed that none was specific for any of the four known isoforms of ERCC1.

Results obtained using reverse transcriptase–polymerase chain reaction highlighted the fact that ERCC1 isoform transcripts and proteins are heterogeneously expressed in cell lines and tumor samples.

"We were unable to validate ERCC1 protein expression as a predictive marker in a new, independent series of homogeneously treated patients with NSCLC," the researchers commented.

This could be because there are currently inadequate tools to detect expression levels of the protein or because the biologic complexity of the protein’s expression has been underestimated.

A third explanation is that the ERCC1 biomarker is not an efficient predictor of the response to cisplatin-based chemotherapy.

"Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform," the researchers concluded.

"As a result, its usefulness in guiding therapeutic decision making is limited."

The research was supported by various grants associated with the clinical trials involved: an unrestricted educational grant from Eli Lilly and grants from l’Institut National du Cancer Programme National d’Excellence Spécialisé and Programme Hospitalier de Recherche Clinique (for the IALT); a grant from La Ligue Nationale contre le Cancer and an unrestricted grant from Sanofi-Aventis (for the LACE Biology project); and a grant from the European Union Seventh Framework Program. Support also came from a translational research fellowship from Roche.

tor@frontlinemedcom.com

A DNA repair protein appears to have limited use for determining response to cisplatin-based adjuvant chemotherapy for non–small cell lung cancer, according to the results of an international study.

"We were unable to validate the predictive effect of immunostaining for ERCC1 protein," Dr. Jean-Charles Soria of the Institut Gustave-Roussy, Villejuif, France, and his associates reported in the New England Journal of Medicine (2013;368:1101-10).

The absence of excision repair cross-complementation group 1 (ERCC1) protein expression and better response to platinum-based chemotherapy were first linked 7 years ago in a biology substudy of the IALT (International Adjuvant Lung Cancer Trial) (N. Engl. J. Med. 2006;355:983-91).

Dr. Soria and his team were unable to replicate these findings, however, in the LACE (Lung Adjuvant Cisplatin Evaluation) Biology biomarker project. In fact, they found contrary evidence, suggesting that the presence rather than the absence of ERCC1 might confer a slight overall survival advantage with cisplatin-based chemotherapy.

The hazard ratio (HR) for death in patients with ERCC1-negative tumors was 1.16 (P = .62), and for ERCC1-positive tumors it was 0.78 (P = .09), but there was no overall predictive value of the marker (P = .23).

The LACE Biology biomarker project used the 8F1 mouse monoclonal antibody to detect ERCC1 expression in tumor samples taken from two independent, randomized, phase III trials of postoperative adjuvant cisplatin-based chemotherapy. The aim was to confirm ERCC1 as a predictive biomarker as seen in the IALT substudy.

A total of 494 whole-tissue sections were obtained from the Cancer and Leukemia Group B (CALGB) 9633 trial and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trials. A lack of confirmatory findings prompted a reanalysis of the entire original set of tissue samples taken from 589 patients who had participated in the 2006 IALT.

"Repeated staining showed important discrepancies between the ERC1 immunohistochemical results obtained in 2006 and those obtained in 2011," Dr. Soria and his team reported. They found that tumors previously classified as ERCC1-negative were ERCC1-positive on reexamination. The discrepancies might be explained by changes in the 8F1 antibody between 2006 and 2011, although the researchers were unable to test this hypothesis.

Other antibodies have been proposed to detect ERCC1 expression, but testing a further 15 of these antibodies showed that none was specific for any of the four known isoforms of ERCC1.

Results obtained using reverse transcriptase–polymerase chain reaction highlighted the fact that ERCC1 isoform transcripts and proteins are heterogeneously expressed in cell lines and tumor samples.

"We were unable to validate ERCC1 protein expression as a predictive marker in a new, independent series of homogeneously treated patients with NSCLC," the researchers commented.

This could be because there are currently inadequate tools to detect expression levels of the protein or because the biologic complexity of the protein’s expression has been underestimated.

A third explanation is that the ERCC1 biomarker is not an efficient predictor of the response to cisplatin-based chemotherapy.

"Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform," the researchers concluded.

"As a result, its usefulness in guiding therapeutic decision making is limited."

The research was supported by various grants associated with the clinical trials involved: an unrestricted educational grant from Eli Lilly and grants from l’Institut National du Cancer Programme National d’Excellence Spécialisé and Programme Hospitalier de Recherche Clinique (for the IALT); a grant from La Ligue Nationale contre le Cancer and an unrestricted grant from Sanofi-Aventis (for the LACE Biology project); and a grant from the European Union Seventh Framework Program. Support also came from a translational research fellowship from Roche.

tor@frontlinemedcom.com

Low-dose macrolide antibiotics given for 12 months significantly reduced pulmonary exacerbations in non–cystic fibrosis bronchiectasis, according to findings from two randomized, controlled trials.

However, antibiotic resistance concerns could temper the use of such an approach in clinical practice, the studies’ investigators cautioned.

In BLESS (Bronchiectasis and Low-Dose Erythromycin Study), the annualized mean rate of pulmonary exacerbations per patient per year was 1.29 in patients treated with erythromycin, compared with 1.97 in those given placebo (P = .003) (JAMA 2013;309:1260-7).

In the BAT (Bronchiectasis and Long-Term Azithromycin Treatment) study, the median number of exacerbations after 1 year was 0 in azithromycin-treated patients, compared with 2 in patients given placebo (P less than .001) (JAMA 2013;309:1251-9).

Both studies’ findings are consistent with those of the EMBRACE trial published last year (Lancet 2012;380:660-77), which showed a 500 mg-dose of azithromycin given for 6 months reduced the incidence of pulmonary exacerbations, compared with placebo, in patients who had at least one exacerbation in the past year.

"The BLESS and BAT trials provide robust evidence for a beneficial effect of long-term macrolide maintenance therapy in patients with bronchiectasis," observed Dr. J. Stuart Elborn and Michael Tunney, Ph.D., in an editorial accompanying the articles (JAMA 2013;309:1295-6).

"Given the paucity of evidence for treatments in bronchiectasis, the results of these studies and the recently published EMBRACE trial are welcome, because they provide a good evidence base for an effective therapy for bronchiectasis," added the commentators, both of Queen’s University Belfast, U.K.

Bronchiectasis is characterized by widening of the airways – specifically, the small and medium-size bronchi – mucosal thickening, and bronchial inflammation. Sufferers are usually dogged by a chronic cough and sputum production, impaired lung function, and infection-related exacerbations.

BLESS was a single-center trial conducted in Australia involving 117 outpatients with a history of two or more infective exacerbations in the past year. Patients were treated with twice-daily erythromycin (400 mg) or placebo. The mean ages of antibiotic- and placebo-treated patients were 61.1 years and 63.5 years, respectively.

Treatment with erythromycin resulted in a 43% relative reduction in the mean annualized exacerbation rate. Exacerbations also were significantly decreased in a pre-specified subgroup of patients with Pseudomonas aeruginosa airway infection.

Furthermore, "erythromycin reduced 24-hour sputum production and attenuated lung function," wrote Dr. David Serisier and his colleagues at Mater Adult Hospital in South Brisbane, Australia.

The BAT study was conducted in 14 Dutch hospitals and involved 83 outpatients with a history of three or more lower respiratory tract infections in the past year. Patients were randomized to a daily dose of 250 mg azithromycin or placebo. The mean ages of antibiotic- and placebo-treated patients were 59.9 years and 64.6 years, respectively.

The risk of patients experiencing at least one exacerbation during the trial was significantly lower if they had been treated with the antibiotic rather than being given placebo (46.5% vs. 80%, hazard ratio = 0.29).

"The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0," Dr. Josje Altenburg, Medical Centre Alkmaar, the Netherlands, and associates reported. Azithromycin therapy also was associated with improved lung function, compared with placebo.

One concern with long-term treatment using these antibiotics is the possible development of macrolide resistance. Dr. Altenburg and colleagues reported a macrolide resistance rate of 88% with azithromycin, vs. 26% with placebo. In BLESS, Dr. Serisier and his coauthors observed an increased proportion of macrolide-resistant oropharyngeal streptococci, with a median increase of 27.7%, compared with 0.04% with placebo (P less than .001).

"The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice," Dr. Serisier and associates acknowledged. They added that the potential for resistance must "curb enthusiasm" for widespread erythromycin use.

"The benefits of long-term macrolide treatment for individual patients with bronchiectasis need to be balanced with increasing concerns regarding the development of resistance to both macrolides and other antibiotics among airway microbiota," Dr. Elborn and Dr. Tunney similarly observed in their accompanying editorial.

"Further long-term studies are required to better determine the relationship between maintenance macrolide treatment, the airway microbiome and resistome, and clinical efficacy in patients with bronchiectasis," they cautioned.

The Mater Adult Respiratory Research Trust Fund funded the BLESS trial. Dr. Serisier reported receiving honoraria, speaker fees, or travel support from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Pharmaxia, and Phebra. The BAT trial was supported by a research grant from the Foreest Medical School, Alkmaar, the Netherlands, and an unrestricted research grant from GlaxoSmithKline. Teva Netherlands provided the azathioprine tablets. Dr. Altenburg, Dr. Elborn, and Dr. Tunney had no disclosures.

Low-dose macrolide antibiotics given for 12 months significantly reduced pulmonary exacerbations in non–cystic fibrosis bronchiectasis, according to findings from two randomized, controlled trials.

However, antibiotic resistance concerns could temper the use of such an approach in clinical practice, the studies’ investigators cautioned.

In BLESS (Bronchiectasis and Low-Dose Erythromycin Study), the annualized mean rate of pulmonary exacerbations per patient per year was 1.29 in patients treated with erythromycin, compared with 1.97 in those given placebo (P = .003) (JAMA 2013;309:1260-7).

In the BAT (Bronchiectasis and Long-Term Azithromycin Treatment) study, the median number of exacerbations after 1 year was 0 in azithromycin-treated patients, compared with 2 in patients given placebo (P less than .001) (JAMA 2013;309:1251-9).

Both studies’ findings are consistent with those of the EMBRACE trial published last year (Lancet 2012;380:660-77), which showed a 500 mg-dose of azithromycin given for 6 months reduced the incidence of pulmonary exacerbations, compared with placebo, in patients who had at least one exacerbation in the past year.

"The BLESS and BAT trials provide robust evidence for a beneficial effect of long-term macrolide maintenance therapy in patients with bronchiectasis," observed Dr. J. Stuart Elborn and Michael Tunney, Ph.D., in an editorial accompanying the articles (JAMA 2013;309:1295-6).

"Given the paucity of evidence for treatments in bronchiectasis, the results of these studies and the recently published EMBRACE trial are welcome, because they provide a good evidence base for an effective therapy for bronchiectasis," added the commentators, both of Queen’s University Belfast, U.K.

Bronchiectasis is characterized by widening of the airways – specifically, the small and medium-size bronchi – mucosal thickening, and bronchial inflammation. Sufferers are usually dogged by a chronic cough and sputum production, impaired lung function, and infection-related exacerbations.

BLESS was a single-center trial conducted in Australia involving 117 outpatients with a history of two or more infective exacerbations in the past year. Patients were treated with twice-daily erythromycin (400 mg) or placebo. The mean ages of antibiotic- and placebo-treated patients were 61.1 years and 63.5 years, respectively.

Treatment with erythromycin resulted in a 43% relative reduction in the mean annualized exacerbation rate. Exacerbations also were significantly decreased in a pre-specified subgroup of patients with Pseudomonas aeruginosa airway infection.

Furthermore, "erythromycin reduced 24-hour sputum production and attenuated lung function," wrote Dr. David Serisier and his colleagues at Mater Adult Hospital in South Brisbane, Australia.

The BAT study was conducted in 14 Dutch hospitals and involved 83 outpatients with a history of three or more lower respiratory tract infections in the past year. Patients were randomized to a daily dose of 250 mg azithromycin or placebo. The mean ages of antibiotic- and placebo-treated patients were 59.9 years and 64.6 years, respectively.

The risk of patients experiencing at least one exacerbation during the trial was significantly lower if they had been treated with the antibiotic rather than being given placebo (46.5% vs. 80%, hazard ratio = 0.29).

"The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0," Dr. Josje Altenburg, Medical Centre Alkmaar, the Netherlands, and associates reported. Azithromycin therapy also was associated with improved lung function, compared with placebo.

One concern with long-term treatment using these antibiotics is the possible development of macrolide resistance. Dr. Altenburg and colleagues reported a macrolide resistance rate of 88% with azithromycin, vs. 26% with placebo. In BLESS, Dr. Serisier and his coauthors observed an increased proportion of macrolide-resistant oropharyngeal streptococci, with a median increase of 27.7%, compared with 0.04% with placebo (P less than .001).

"The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice," Dr. Serisier and associates acknowledged. They added that the potential for resistance must "curb enthusiasm" for widespread erythromycin use.

"The benefits of long-term macrolide treatment for individual patients with bronchiectasis need to be balanced with increasing concerns regarding the development of resistance to both macrolides and other antibiotics among airway microbiota," Dr. Elborn and Dr. Tunney similarly observed in their accompanying editorial.

"Further long-term studies are required to better determine the relationship between maintenance macrolide treatment, the airway microbiome and resistome, and clinical efficacy in patients with bronchiectasis," they cautioned.

The Mater Adult Respiratory Research Trust Fund funded the BLESS trial. Dr. Serisier reported receiving honoraria, speaker fees, or travel support from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Pharmaxia, and Phebra. The BAT trial was supported by a research grant from the Foreest Medical School, Alkmaar, the Netherlands, and an unrestricted research grant from GlaxoSmithKline. Teva Netherlands provided the azathioprine tablets. Dr. Altenburg, Dr. Elborn, and Dr. Tunney had no disclosures.

Low-dose macrolide antibiotics given for 12 months significantly reduced pulmonary exacerbations in non–cystic fibrosis bronchiectasis, according to findings from two randomized, controlled trials.

However, antibiotic resistance concerns could temper the use of such an approach in clinical practice, the studies’ investigators cautioned.

In BLESS (Bronchiectasis and Low-Dose Erythromycin Study), the annualized mean rate of pulmonary exacerbations per patient per year was 1.29 in patients treated with erythromycin, compared with 1.97 in those given placebo (P = .003) (JAMA 2013;309:1260-7).

In the BAT (Bronchiectasis and Long-Term Azithromycin Treatment) study, the median number of exacerbations after 1 year was 0 in azithromycin-treated patients, compared with 2 in patients given placebo (P less than .001) (JAMA 2013;309:1251-9).

Both studies’ findings are consistent with those of the EMBRACE trial published last year (Lancet 2012;380:660-77), which showed a 500 mg-dose of azithromycin given for 6 months reduced the incidence of pulmonary exacerbations, compared with placebo, in patients who had at least one exacerbation in the past year.

"The BLESS and BAT trials provide robust evidence for a beneficial effect of long-term macrolide maintenance therapy in patients with bronchiectasis," observed Dr. J. Stuart Elborn and Michael Tunney, Ph.D., in an editorial accompanying the articles (JAMA 2013;309:1295-6).

"Given the paucity of evidence for treatments in bronchiectasis, the results of these studies and the recently published EMBRACE trial are welcome, because they provide a good evidence base for an effective therapy for bronchiectasis," added the commentators, both of Queen’s University Belfast, U.K.

Bronchiectasis is characterized by widening of the airways – specifically, the small and medium-size bronchi – mucosal thickening, and bronchial inflammation. Sufferers are usually dogged by a chronic cough and sputum production, impaired lung function, and infection-related exacerbations.

BLESS was a single-center trial conducted in Australia involving 117 outpatients with a history of two or more infective exacerbations in the past year. Patients were treated with twice-daily erythromycin (400 mg) or placebo. The mean ages of antibiotic- and placebo-treated patients were 61.1 years and 63.5 years, respectively.

Treatment with erythromycin resulted in a 43% relative reduction in the mean annualized exacerbation rate. Exacerbations also were significantly decreased in a pre-specified subgroup of patients with Pseudomonas aeruginosa airway infection.

Furthermore, "erythromycin reduced 24-hour sputum production and attenuated lung function," wrote Dr. David Serisier and his colleagues at Mater Adult Hospital in South Brisbane, Australia.

The BAT study was conducted in 14 Dutch hospitals and involved 83 outpatients with a history of three or more lower respiratory tract infections in the past year. Patients were randomized to a daily dose of 250 mg azithromycin or placebo. The mean ages of antibiotic- and placebo-treated patients were 59.9 years and 64.6 years, respectively.

The risk of patients experiencing at least one exacerbation during the trial was significantly lower if they had been treated with the antibiotic rather than being given placebo (46.5% vs. 80%, hazard ratio = 0.29).

"The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0," Dr. Josje Altenburg, Medical Centre Alkmaar, the Netherlands, and associates reported. Azithromycin therapy also was associated with improved lung function, compared with placebo.

One concern with long-term treatment using these antibiotics is the possible development of macrolide resistance. Dr. Altenburg and colleagues reported a macrolide resistance rate of 88% with azithromycin, vs. 26% with placebo. In BLESS, Dr. Serisier and his coauthors observed an increased proportion of macrolide-resistant oropharyngeal streptococci, with a median increase of 27.7%, compared with 0.04% with placebo (P less than .001).

"The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice," Dr. Serisier and associates acknowledged. They added that the potential for resistance must "curb enthusiasm" for widespread erythromycin use.

"The benefits of long-term macrolide treatment for individual patients with bronchiectasis need to be balanced with increasing concerns regarding the development of resistance to both macrolides and other antibiotics among airway microbiota," Dr. Elborn and Dr. Tunney similarly observed in their accompanying editorial.

"Further long-term studies are required to better determine the relationship between maintenance macrolide treatment, the airway microbiome and resistome, and clinical efficacy in patients with bronchiectasis," they cautioned.

The Mater Adult Respiratory Research Trust Fund funded the BLESS trial. Dr. Serisier reported receiving honoraria, speaker fees, or travel support from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Pharmaxia, and Phebra. The BAT trial was supported by a research grant from the Foreest Medical School, Alkmaar, the Netherlands, and an unrestricted research grant from GlaxoSmithKline. Teva Netherlands provided the azathioprine tablets. Dr. Altenburg, Dr. Elborn, and Dr. Tunney had no disclosures.

An alteration in the gene that regulates the G-protein signaling pathway has been linked to a reduced risk for bladder cancer in a case-control study.

The single nucleotide polymorphism (SNP) rs10759 found on the RGS4 gene conferred a 0.77-fold reduced risk for nonmuscle-invasive bladder cancer (NMIBC).

Other alterations in the regulator of the G-protein signaling (RGS) pathway were linked to NMIBC recurrence and progression and to patient survival in muscle-invasive bladder cancer (MIBC).

"Our current findings have significant clinical implications in personalized medicine," Dr. Eugene Lee and his colleagues report in an early online edition of Cancer (March 25; doi:10.1002/cncr.27871).

"By identifying individuals at increased risk for bladder cancer, we have the ability to initiate comprehensive screening," wrote the authors from the University of Texas MD Anderson Cancer Center in Houston. In addition, the findings could lead to better treatment, with the potential to target patients who may require earlier systemic chemotherapy or treatment with novel targeted agents.

"Furthermore," Dr. Lee noted in a press statement, "we can identify patients who already have a diagnosis of bladder cancer that are at increased risk of worsening of disease or dying."

The ultimate goal, he adds, "is to find as many genetic alterations that confer risk and create a panel of markers that would aid in diagnosis, treatment, and follow-up."

The RGS pathway produces a heterogeneous group of proteins that are involved in cell signaling. Genetic alterations in the pathway have already been linked to several tumors, including breast, prostate, lung cancers, and squamous cell cancer of the head and neck.

The study population consisted of 1,606 individuals, 803 of whom had newly-diagnosed, histologically confirmed, untreated bladder cancer. Each of these individuals was matched, based on age, gender, and ethnicity, to a healthy individual without a history of cancer.

Cases and controls were demographically similar, with a mean age of about 64 years; 79% of participants in each group were men and all were white. Not surprisingly, a higher percentage of patients than of controls were current (23% vs. 8%) or former (50% vs. 47%) smokers.

A total of 85 SNPs in 17 RGS genes were assessed for their potential association with bladder cancer risk, recurrence and progression in nonmuscle-invasive disease, and survival in muscle-invasive.

Bladder cancer risk was associated with six SNPs, including rs10759, which had the only, and the strongest, association for a positive outcome. Individuals with two or more of the five unfavorable SNPs were twice as likely as those without the SNPs to have bladder cancer. The presence of all five unfavorable SNPs increased four-fold the risk for bladder cancer.

NMIBC affected just more than half (52%; n = 421) of the bladder cancer patients, with 11 SNPs linked to disease recurrence and 13 to disease progression to MIBC.

Of patients who presented with MIBC, 10 SNPs were found that either increased or decreased the risk of death. Of these, two SNPs, and rs234473 on the RGS5 gene in particular, conferred the greatest risk of a poor survival outcome. Indeed, patients who had rs234473 had a lower median overall survival of 13.3 months, compared with 81.9 months in those where the genetic variant was absent.

The study was funded by several grants from the National Cancer Institute and by the University of Texas MD Anderson Cancer Center Research Trust. The authors made no conflict of interest disclosures.

The study was funded by the National Cancer Institute and by the University of Texas MD Anderson Cancer Center Research Trust. The authors made no conflict of interest disclosures.

An alteration in the gene that regulates the G-protein signaling pathway has been linked to a reduced risk for bladder cancer in a case-control study.

The single nucleotide polymorphism (SNP) rs10759 found on the RGS4 gene conferred a 0.77-fold reduced risk for nonmuscle-invasive bladder cancer (NMIBC).

Other alterations in the regulator of the G-protein signaling (RGS) pathway were linked to NMIBC recurrence and progression and to patient survival in muscle-invasive bladder cancer (MIBC).

"Our current findings have significant clinical implications in personalized medicine," Dr. Eugene Lee and his colleagues report in an early online edition of Cancer (March 25; doi:10.1002/cncr.27871).

"By identifying individuals at increased risk for bladder cancer, we have the ability to initiate comprehensive screening," wrote the authors from the University of Texas MD Anderson Cancer Center in Houston. In addition, the findings could lead to better treatment, with the potential to target patients who may require earlier systemic chemotherapy or treatment with novel targeted agents.

"Furthermore," Dr. Lee noted in a press statement, "we can identify patients who already have a diagnosis of bladder cancer that are at increased risk of worsening of disease or dying."

The ultimate goal, he adds, "is to find as many genetic alterations that confer risk and create a panel of markers that would aid in diagnosis, treatment, and follow-up."

The RGS pathway produces a heterogeneous group of proteins that are involved in cell signaling. Genetic alterations in the pathway have already been linked to several tumors, including breast, prostate, lung cancers, and squamous cell cancer of the head and neck.

The study population consisted of 1,606 individuals, 803 of whom had newly-diagnosed, histologically confirmed, untreated bladder cancer. Each of these individuals was matched, based on age, gender, and ethnicity, to a healthy individual without a history of cancer.

Cases and controls were demographically similar, with a mean age of about 64 years; 79% of participants in each group were men and all were white. Not surprisingly, a higher percentage of patients than of controls were current (23% vs. 8%) or former (50% vs. 47%) smokers.

A total of 85 SNPs in 17 RGS genes were assessed for their potential association with bladder cancer risk, recurrence and progression in nonmuscle-invasive disease, and survival in muscle-invasive.

Bladder cancer risk was associated with six SNPs, including rs10759, which had the only, and the strongest, association for a positive outcome. Individuals with two or more of the five unfavorable SNPs were twice as likely as those without the SNPs to have bladder cancer. The presence of all five unfavorable SNPs increased four-fold the risk for bladder cancer.

NMIBC affected just more than half (52%; n = 421) of the bladder cancer patients, with 11 SNPs linked to disease recurrence and 13 to disease progression to MIBC.

Of patients who presented with MIBC, 10 SNPs were found that either increased or decreased the risk of death. Of these, two SNPs, and rs234473 on the RGS5 gene in particular, conferred the greatest risk of a poor survival outcome. Indeed, patients who had rs234473 had a lower median overall survival of 13.3 months, compared with 81.9 months in those where the genetic variant was absent.

The study was funded by several grants from the National Cancer Institute and by the University of Texas MD Anderson Cancer Center Research Trust. The authors made no conflict of interest disclosures.

The study was funded by the National Cancer Institute and by the University of Texas MD Anderson Cancer Center Research Trust. The authors made no conflict of interest disclosures.

An alteration in the gene that regulates the G-protein signaling pathway has been linked to a reduced risk for bladder cancer in a case-control study.

The single nucleotide polymorphism (SNP) rs10759 found on the RGS4 gene conferred a 0.77-fold reduced risk for nonmuscle-invasive bladder cancer (NMIBC).

Other alterations in the regulator of the G-protein signaling (RGS) pathway were linked to NMIBC recurrence and progression and to patient survival in muscle-invasive bladder cancer (MIBC).

"Our current findings have significant clinical implications in personalized medicine," Dr. Eugene Lee and his colleagues report in an early online edition of Cancer (March 25; doi:10.1002/cncr.27871).

"By identifying individuals at increased risk for bladder cancer, we have the ability to initiate comprehensive screening," wrote the authors from the University of Texas MD Anderson Cancer Center in Houston. In addition, the findings could lead to better treatment, with the potential to target patients who may require earlier systemic chemotherapy or treatment with novel targeted agents.

"Furthermore," Dr. Lee noted in a press statement, "we can identify patients who already have a diagnosis of bladder cancer that are at increased risk of worsening of disease or dying."

The ultimate goal, he adds, "is to find as many genetic alterations that confer risk and create a panel of markers that would aid in diagnosis, treatment, and follow-up."

The RGS pathway produces a heterogeneous group of proteins that are involved in cell signaling. Genetic alterations in the pathway have already been linked to several tumors, including breast, prostate, lung cancers, and squamous cell cancer of the head and neck.

The study population consisted of 1,606 individuals, 803 of whom had newly-diagnosed, histologically confirmed, untreated bladder cancer. Each of these individuals was matched, based on age, gender, and ethnicity, to a healthy individual without a history of cancer.

Cases and controls were demographically similar, with a mean age of about 64 years; 79% of participants in each group were men and all were white. Not surprisingly, a higher percentage of patients than of controls were current (23% vs. 8%) or former (50% vs. 47%) smokers.

A total of 85 SNPs in 17 RGS genes were assessed for their potential association with bladder cancer risk, recurrence and progression in nonmuscle-invasive disease, and survival in muscle-invasive.

Bladder cancer risk was associated with six SNPs, including rs10759, which had the only, and the strongest, association for a positive outcome. Individuals with two or more of the five unfavorable SNPs were twice as likely as those without the SNPs to have bladder cancer. The presence of all five unfavorable SNPs increased four-fold the risk for bladder cancer.

NMIBC affected just more than half (52%; n = 421) of the bladder cancer patients, with 11 SNPs linked to disease recurrence and 13 to disease progression to MIBC.

Of patients who presented with MIBC, 10 SNPs were found that either increased or decreased the risk of death. Of these, two SNPs, and rs234473 on the RGS5 gene in particular, conferred the greatest risk of a poor survival outcome. Indeed, patients who had rs234473 had a lower median overall survival of 13.3 months, compared with 81.9 months in those where the genetic variant was absent.

The study was funded by several grants from the National Cancer Institute and by the University of Texas MD Anderson Cancer Center Research Trust. The authors made no conflict of interest disclosures.

The study was funded by the National Cancer Institute and by the University of Texas MD Anderson Cancer Center Research Trust. The authors made no conflict of interest disclosures.