BIRMINGHAM, ENGLAND – Patients being treated with biologics for rheumatoid arthritis have a low risk for developing opportunistic infections, based on a new analysis of data from one of the largest and longest running biologics registers.

Data on 19,162 patients included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) showed that the incidence rate of opportunistic infections was 1.33 cases per 1,000 patient years when using any biologic drug, including anti–tumor necrosis factor (anti-TNF) drugs, rituximab (Rituxan/MabThera), or the interleukin-6 receptor inhibitor tocilizumab (Actemra).

Incidence rates for opportunistic infections appeared to be lowest with tocilizumab at 0.88 per 1,000 patient years, although the duration of follow-up with this drug was the shortest. Rates for anti-TNF drugs as a whole and rituximab were a respective 1.30 and 1.58 per 1,000 patient years.

“Opportunistic infections remain very rare events,” said Dr. Andrew Rutherford, a rheumatology clinical fellow at King’s College London, England.

The potential for serious infections to develop with biologic treatment is well known, and several analyses have already been performed on the BSRBR-RA data, Dr. Rutherford acknowledged at the British Society for Rheumatology annual conference. However, these prior analyses have become somewhat outdated and don’t reflect current practice or the current cohort of patients starting biologic therapy, he said.

“Using the old comparator arm of continuing patients on DMARD [disease-modifying anti-rheumatic drug] therapy isn’t really relevant for us in clinical practice any more,” he said. “I think for the majority of us, when we’re faced with a patient who’s got high disease activity, we are going to start them on a biologic, and the question is ‘Which biologic is safest or most effective?’ as opposed to ‘Should they just remain on DMARDs?’ ”

Patients currently starting biologic treatments who are included in the Register are also less likely to have been treated with steroids and more likely to have been diagnosed with RA for less than 5 years. Then, there are the newer biologics, such as tocilizumab and even more recently the Janus kinase (JAK) inhibitors.

“So, I think, clearly, there is a need to do updated analyses using the BSRBR,” Dr. Rutherford reasoned.

In the current analysis, which covers more than 99,000 patient years of follow-up overall, the primary aim was to estimate the incidence of opportunistic infections other than tuberculosis (TB) by biologic drug class.

Of 106 cases of opportunistic infections seen in patients treated with anti-TNF drugs, most (48%) resulted from herpes zoster, Pneumocystis pneumonia (PCP; 11.3%), or Aspergillus (11.3%).

There were 24 opportunistic infections in patients treated with rituximab, of which PCP (33.3%) or herpes zoster (29%) were the most common causes.

There were just three opportunistic infections in patients treated with tocilizumab, which were all different organisms, Dr. Rutherford reported.

Using anti-TNF therapy as the control, the unadjusted and adjusted hazard ratios for an opportunistic infection were a respective 1.21 and 0.92 for rituximab and 0.60 and 0.28 for tocilizumab. The confidence intervals were wide, however, crossing 1.0 in all comparisons, Dr. Rutherford emphasized.

PCP is rare with all biologics, but the incidence was almost four-times higher (HR, 3.91) with rituximab versus anti-TNF therapy, but the 95% CIs were wide (1.60–9.92) and probably not enough to influence practice.

A secondary analysis also looked at the incidence of TB by biologic drug class, although this was originally excluded from the study design. Not only has it been previously reported on from BSRBR, “guidelines have come into place that have probably changed the rates of TB dramatically over the years,” Dr. Rutherford said, so comparing older and new cohorts of biologic-treated patients might be “a little bit unfair.”

The incidence of TB per 100,000 patient years was 67.8 for all anti-TNF therapies, with a lower rate seen with rituximab (13.2 per 100,000 patient years) than any individual anti-TNF drug (48.9 for etanercept, 75.5 for infliximab, 84.6 for adalimumab, and 99.0 for certolizumab per 100,000 patient years).

These rates might potentially influence the choice of drug for a patient with a high-risk for reactivation of TB, Dr. Rutherford suggested.

Overall, rates of TB have fallen year over year in the Register. However, that likely reflects better screening and treatment of the infection, he added.

The BSRBR-RA is funded by the BSR through restricted grants from UK pharmaceutical companies. Past and present participating companies include Abbvie, Celltrion, Hospira, Pfizer, UCB, Roche, Merck and Samsung. Dr. Rutherford had no conflicts of interest.

BIRMINGHAM, ENGLAND – Patients being treated with biologics for rheumatoid arthritis have a low risk for developing opportunistic infections, based on a new analysis of data from one of the largest and longest running biologics registers.

Data on 19,162 patients included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) showed that the incidence rate of opportunistic infections was 1.33 cases per 1,000 patient years when using any biologic drug, including anti–tumor necrosis factor (anti-TNF) drugs, rituximab (Rituxan/MabThera), or the interleukin-6 receptor inhibitor tocilizumab (Actemra).

Incidence rates for opportunistic infections appeared to be lowest with tocilizumab at 0.88 per 1,000 patient years, although the duration of follow-up with this drug was the shortest. Rates for anti-TNF drugs as a whole and rituximab were a respective 1.30 and 1.58 per 1,000 patient years.

“Opportunistic infections remain very rare events,” said Dr. Andrew Rutherford, a rheumatology clinical fellow at King’s College London, England.

The potential for serious infections to develop with biologic treatment is well known, and several analyses have already been performed on the BSRBR-RA data, Dr. Rutherford acknowledged at the British Society for Rheumatology annual conference. However, these prior analyses have become somewhat outdated and don’t reflect current practice or the current cohort of patients starting biologic therapy, he said.

“Using the old comparator arm of continuing patients on DMARD [disease-modifying anti-rheumatic drug] therapy isn’t really relevant for us in clinical practice any more,” he said. “I think for the majority of us, when we’re faced with a patient who’s got high disease activity, we are going to start them on a biologic, and the question is ‘Which biologic is safest or most effective?’ as opposed to ‘Should they just remain on DMARDs?’ ”

Patients currently starting biologic treatments who are included in the Register are also less likely to have been treated with steroids and more likely to have been diagnosed with RA for less than 5 years. Then, there are the newer biologics, such as tocilizumab and even more recently the Janus kinase (JAK) inhibitors.

“So, I think, clearly, there is a need to do updated analyses using the BSRBR,” Dr. Rutherford reasoned.

In the current analysis, which covers more than 99,000 patient years of follow-up overall, the primary aim was to estimate the incidence of opportunistic infections other than tuberculosis (TB) by biologic drug class.

Of 106 cases of opportunistic infections seen in patients treated with anti-TNF drugs, most (48%) resulted from herpes zoster, Pneumocystis pneumonia (PCP; 11.3%), or Aspergillus (11.3%).

There were 24 opportunistic infections in patients treated with rituximab, of which PCP (33.3%) or herpes zoster (29%) were the most common causes.

There were just three opportunistic infections in patients treated with tocilizumab, which were all different organisms, Dr. Rutherford reported.

Using anti-TNF therapy as the control, the unadjusted and adjusted hazard ratios for an opportunistic infection were a respective 1.21 and 0.92 for rituximab and 0.60 and 0.28 for tocilizumab. The confidence intervals were wide, however, crossing 1.0 in all comparisons, Dr. Rutherford emphasized.

PCP is rare with all biologics, but the incidence was almost four-times higher (HR, 3.91) with rituximab versus anti-TNF therapy, but the 95% CIs were wide (1.60–9.92) and probably not enough to influence practice.

A secondary analysis also looked at the incidence of TB by biologic drug class, although this was originally excluded from the study design. Not only has it been previously reported on from BSRBR, “guidelines have come into place that have probably changed the rates of TB dramatically over the years,” Dr. Rutherford said, so comparing older and new cohorts of biologic-treated patients might be “a little bit unfair.”

The incidence of TB per 100,000 patient years was 67.8 for all anti-TNF therapies, with a lower rate seen with rituximab (13.2 per 100,000 patient years) than any individual anti-TNF drug (48.9 for etanercept, 75.5 for infliximab, 84.6 for adalimumab, and 99.0 for certolizumab per 100,000 patient years).

These rates might potentially influence the choice of drug for a patient with a high-risk for reactivation of TB, Dr. Rutherford suggested.

Overall, rates of TB have fallen year over year in the Register. However, that likely reflects better screening and treatment of the infection, he added.

The BSRBR-RA is funded by the BSR through restricted grants from UK pharmaceutical companies. Past and present participating companies include Abbvie, Celltrion, Hospira, Pfizer, UCB, Roche, Merck and Samsung. Dr. Rutherford had no conflicts of interest.

BIRMINGHAM, ENGLAND – Patients being treated with biologics for rheumatoid arthritis have a low risk for developing opportunistic infections, based on a new analysis of data from one of the largest and longest running biologics registers.

Data on 19,162 patients included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) showed that the incidence rate of opportunistic infections was 1.33 cases per 1,000 patient years when using any biologic drug, including anti–tumor necrosis factor (anti-TNF) drugs, rituximab (Rituxan/MabThera), or the interleukin-6 receptor inhibitor tocilizumab (Actemra).

Incidence rates for opportunistic infections appeared to be lowest with tocilizumab at 0.88 per 1,000 patient years, although the duration of follow-up with this drug was the shortest. Rates for anti-TNF drugs as a whole and rituximab were a respective 1.30 and 1.58 per 1,000 patient years.

“Opportunistic infections remain very rare events,” said Dr. Andrew Rutherford, a rheumatology clinical fellow at King’s College London, England.

The potential for serious infections to develop with biologic treatment is well known, and several analyses have already been performed on the BSRBR-RA data, Dr. Rutherford acknowledged at the British Society for Rheumatology annual conference. However, these prior analyses have become somewhat outdated and don’t reflect current practice or the current cohort of patients starting biologic therapy, he said.

“Using the old comparator arm of continuing patients on DMARD [disease-modifying anti-rheumatic drug] therapy isn’t really relevant for us in clinical practice any more,” he said. “I think for the majority of us, when we’re faced with a patient who’s got high disease activity, we are going to start them on a biologic, and the question is ‘Which biologic is safest or most effective?’ as opposed to ‘Should they just remain on DMARDs?’ ”

Patients currently starting biologic treatments who are included in the Register are also less likely to have been treated with steroids and more likely to have been diagnosed with RA for less than 5 years. Then, there are the newer biologics, such as tocilizumab and even more recently the Janus kinase (JAK) inhibitors.

“So, I think, clearly, there is a need to do updated analyses using the BSRBR,” Dr. Rutherford reasoned.

In the current analysis, which covers more than 99,000 patient years of follow-up overall, the primary aim was to estimate the incidence of opportunistic infections other than tuberculosis (TB) by biologic drug class.

Of 106 cases of opportunistic infections seen in patients treated with anti-TNF drugs, most (48%) resulted from herpes zoster, Pneumocystis pneumonia (PCP; 11.3%), or Aspergillus (11.3%).

There were 24 opportunistic infections in patients treated with rituximab, of which PCP (33.3%) or herpes zoster (29%) were the most common causes.

There were just three opportunistic infections in patients treated with tocilizumab, which were all different organisms, Dr. Rutherford reported.

Using anti-TNF therapy as the control, the unadjusted and adjusted hazard ratios for an opportunistic infection were a respective 1.21 and 0.92 for rituximab and 0.60 and 0.28 for tocilizumab. The confidence intervals were wide, however, crossing 1.0 in all comparisons, Dr. Rutherford emphasized.

PCP is rare with all biologics, but the incidence was almost four-times higher (HR, 3.91) with rituximab versus anti-TNF therapy, but the 95% CIs were wide (1.60–9.92) and probably not enough to influence practice.

A secondary analysis also looked at the incidence of TB by biologic drug class, although this was originally excluded from the study design. Not only has it been previously reported on from BSRBR, “guidelines have come into place that have probably changed the rates of TB dramatically over the years,” Dr. Rutherford said, so comparing older and new cohorts of biologic-treated patients might be “a little bit unfair.”

The incidence of TB per 100,000 patient years was 67.8 for all anti-TNF therapies, with a lower rate seen with rituximab (13.2 per 100,000 patient years) than any individual anti-TNF drug (48.9 for etanercept, 75.5 for infliximab, 84.6 for adalimumab, and 99.0 for certolizumab per 100,000 patient years).

These rates might potentially influence the choice of drug for a patient with a high-risk for reactivation of TB, Dr. Rutherford suggested.

Overall, rates of TB have fallen year over year in the Register. However, that likely reflects better screening and treatment of the infection, he added.

The BSRBR-RA is funded by the BSR through restricted grants from UK pharmaceutical companies. Past and present participating companies include Abbvie, Celltrion, Hospira, Pfizer, UCB, Roche, Merck and Samsung. Dr. Rutherford had no conflicts of interest.

Among children with nonalcoholic fatty liver disease (NAFLD), those with high birth weight had significantly greater odds of having more severe steatosis and nonalcoholic steatohepatitis (NASH) than those with normal birth weight, reported Kimberly P. Newton, MD, of the University of California, San Diego, and her associates.

In contrast, the children with low birth weight had twice the risk of advanced fibrosis, compared with those with normal birth weight.

Courtesy of Wikimedia / "Nephron" / Creative Commons License

[email protected]

Among children with nonalcoholic fatty liver disease (NAFLD), those with high birth weight had significantly greater odds of having more severe steatosis and nonalcoholic steatohepatitis (NASH) than those with normal birth weight, reported Kimberly P. Newton, MD, of the University of California, San Diego, and her associates.

In contrast, the children with low birth weight had twice the risk of advanced fibrosis, compared with those with normal birth weight.

Courtesy of Wikimedia / "Nephron" / Creative Commons License

[email protected]

Among children with nonalcoholic fatty liver disease (NAFLD), those with high birth weight had significantly greater odds of having more severe steatosis and nonalcoholic steatohepatitis (NASH) than those with normal birth weight, reported Kimberly P. Newton, MD, of the University of California, San Diego, and her associates.

In contrast, the children with low birth weight had twice the risk of advanced fibrosis, compared with those with normal birth weight.

Courtesy of Wikimedia / "Nephron" / Creative Commons License

[email protected]

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

Study Overview

Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.

Design. Meta-analysis.

Study selection. The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.

Main outcome measure. Severity of CRF.

Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.

Pharmaceutical interventions included the use of paroxetine hydrochloride (n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.

The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF (P < 0.001). Psychological interventions also yielded significant improvements in CRF (P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF (P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF (P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.

Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.

Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.

Commentary

Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.

According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.

Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.

There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.

Applications for Clinical Practice

CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].

—Daniel Isaac, DO, MS

The grip that opioid addiction has on adolescents often resembles that on addicted adults. Both groups crave the next high at all costs.

“Basically, they’re living to find their next heroin or opioids because their ‘feeling good’ completely depends on it,” Steven C. Matson, MD, , chief of the division of adolescent medicine at Nationwide Children’s Hospital, Columbus, Ohio, said in an interview. “They’re up in the morning, out trying to hustle money constantly, and then using and rebounding, and doing it over and over again. It gets to be a pretty dismal way of life.”

courtesy Lindsey Pulfer, RN

The scope of the problem

The 2015 National Survey on Drug Use and Health (NSDUH) found that 6.5 million Americans over the age of 12 years used controlled prescription medicines nonmedically during the past month, second only to marijuana and more than past-month users of cocaine, heroin, and hallucinogens combined. According to the Centers for Disease Control and Prevention, 91 Americans die every day from an overdose of opioids. In fact, opioid overdoses in the United States increased four times since 1999 and were highest among persons 25-54 years of age. In 2015, the five states with the highest rates of death resulting from drug overdose were West Virginia (41.5 per 100,000), New Hampshire (34.3 per 100,000), Kentucky (29.9 per 100,000), Ohio (29.9 per 100,000), and Rhode Island (28.2 per 100,000).

The CDC also found that, between 2013 and 2014, the number of children aged 0-14 years who died from a drug overdose increased slightly from 105 to 109. The number of children aged 15-24 years who died from a drug overdose rose from 3,664 to 3,798, an increase of 3.6%. While the precise path to opioid addiction differs from patient to patient, experts interviewed for this story noted that adolescents who currently smoke marijuana or drink alcohol on a regular basis face an increased risk of progressing to opioid use, compared with peers who lack substance abuse problems. In such cases, “go ahead and refer for substance abuse treatment at that point, rather than waiting for them to get into something much more dangerous,” Dr. Hulvershorn advised. “Neither of those drugs is good for adolescents either, but you could easily be preventing a worse outcome later. Sometimes physicians will ask, ‘You really want me to refer kids who are smoking pot?’ The answer is, ‘Absolutely.’ That’s probably our best shot at providing them with skills early on, before they get into heavier stuff.”

How to spot a troubled teen

Pediatricians can do their part to detect addiction by regularly asking about drug use during office visits. One quick screen Dr. Matson recommends is the HEADSS (Home, Education/employment, peer group Activities, Drugs, Sexuality, and Suicide/depression).

But, simply being attuned to how patients are performing in general domains can help you spot a troubled teen. “If a kid is still playing football and getting straight A’s, there’s probably a pretty low chance he’s having a serious problem,” he said. “A big part of addiction is secret, so I think when parents start to see their kids be more secretive, hiding their phone,” that’s a red flag. Or maybe their child has a new set of friends that “don’t seem as ‘good’ as the previous set of friends.” Other signs might be “losing a job that they were doing well at before, grades starting to go down, [or] loss of interest in the things they normally like to do. In general, I think kids work their way up to opioid addiction. If parents know their kids smoke cigarettes and think they might be doing some weed, those are the kids that are at risk for moving on to a bigger high.”

Many kids start with pills that they find or take from someone. “They may not think of them as a drug, so you would need to specifically ask, ‘Have you ever used a pill like a pain medication that you may have found or gotten from a family member or a friend for recreational use or for something other than how it was prescribed?’ ” Dr. Hulvershorn said.

The amount of parental supervision also factors in. “There’s been a lot of research showing that, if parents don’t have any idea where their kids are after school or what they’re up do, those kids are much more likely to be using,” she said. “So, you want to ask parents, ‘Are there times when your adolescent is unsupervised?’ ”

If you suspect that one of your adolescent patients is using opioids, but he or she won’t open up about it, consider intermittent urine screening, Dr. Hulvershorn said. If a screen comes back positive, be familiar with patient privacy regulations in your state, because special federal protections apply to adolescents and adults with respect to substance abuse disorder assessment and treatment. For example, in Indiana there is no age limit. Anyone under the age of 18 has the same protection as an adult. “I cannot legally release that information to the parent without the adolescent’s consent, which is really unusual,” she said. “Each state determines the age where that might apply. The best approach is to try to get the adolescent on board, and say, ‘Here’s what we found. We really need to get this out in the open and get you some treatment. I’d really like to have a conversation with your parents.’ Sometimes you can get them to agree, and sometimes you can’t. Nonetheless, you would try to proceed with treatment. You don’t need parental consent for treatment.”

Once Dr. Matson establishes confidentiality with patients, he spends time helping them understand where they fall in the “continuum of use.” He asks for permission to share information with them about the negative aspects of drug use instead of force-feeding it.

“A lot of these kids are hanging around the same kinds of kids and somehow, in their minds, think that what they’re doing is normal,” he said. “To me, somebody smoking weed twice a day every day is a problem, and they probably are addicted. It’s hard to know whether you’d be ready to pull a parent [into the room] at that point or at least give the kid a chance to think if they ... could cut down. If they would, maybe see them back with a warning that, if it’s not going to get much better, you might have to inform parents.

“Weed is always a big issue, especially in kids with ADHD. Those kids are at high risk for substance abuse, especially if they aren’t maintained on their [ADHD] drugs later on,” Dr. Matson said.

Adolescents on opioids “usually are going to present in a more dramatic fashion because they’re starting to get into trouble. They might have gotten arrested or might have been driving under the influence with both alcohol and opioids. To support their habit, a lot of kids have to steal things, so a kid who gets caught shoplifting is someone to be concerned about,” he said.

Treatment options

In 2016, the American Academy of Pediatrics issued a new policy statement, “Medication-Assisted Treatment for Adolescents with Opioid Disorders,” which recommends that pediatricians consider offering medication-assisted treatments to their adolescent and young adult patients with opioid use disorders or refer them to other providers who can. Ideally, pediatricians should refer patients to clinicians who have expertise in treating substance abuse disorders in adolescents, typically psychiatrists.

Psychiatrists “tend to have quite a bit of experience with addiction, but they can be very hard to find,” Dr. Hulvershorn said. “Sometimes, it’s a mental health center provider who treats adults with addiction. Addiction is a different beast in kids, but that might be the next best thing.”

Three medicines indicated for treating severe opioid disorder include buprenorphine (the “gold standard,” Dr. Matson said), methadone, and naltrexone, which is Dr. Hulvershorn’s typical drug of choice, “because it’s not a drug of abuse. It’s an opioid antagonist, so it blocks the euphoria that you might get when you are using a drug of abuse such as an opioid.”

Even though pediatricians have access to an American Academy of Pediatrics–endorsed buprenorphine waiver course, not all clinicians feel comfortable adding medication-assisted treatment to patients.

“It might mean that you partner with a substance use provider who can do more comprehensive services but not the prescribing,” Dr. Hulvershorn said. “You certainly don’t want to treat these kids in a vacuum by yourself, because it’s very complicated to treat them.”

Still, the office-based practice of prescribing opioid withdrawal medication “is a very successful approach and a reasonable alternative to other approaches that have been used historically, like methadone maintenance programs,” noted Dr. Potenza, emphasizing that physicians have to understand how to help patients with addiction.

Physicians interviewed for this story underscored the importance of a comprehensive approach that includes behavioral treatment, medication, and support from family and friends.

“A lot of kids who get into these problems come from families that don’t have many resources,” Dr. Matson said, noting that, often, it is a generational problem, in which grandparents and parents are drug users. “But, for kids who take a wrong path, encouraging words really can come true. It’s really a matter of how many people you have cheerleading for you and keeping an eye on you.”

When Dr. Matson’s clinic began treating patients with opioid use disorders 8 years ago, only about 25% of adolescents returned for a second visit, and the rate of abstinence at 1 year was only 9%. The clinic has undertake a large quality improvement project to improve that percentage. “We learned to not scare people right away with a bunch of assignments they have to get done but to just welcome them in, get them started on the medication, and give them positive messages. For short-term remission at 3 months, we’re at 50%-60%, which is pretty good. It’s probably as good as any adult program. I think we’re at 35%-40% remission at 1 year for people first time in recovery,” he said.

Where to go from here

Reflecting on what he’d like opioid use disorder treatment to look like 5 or 10 years down the road, Dr. Matson emphasized the prominent role that pediatricians can play.

“We’re really the ones that could make a difference if we can try to intervene,” he said. “I’m not sure I can prove it, but my pipe dream is, the earlier that we catch people and the less time they’ve been using drugs, it’s got to be easier to stop it then, than if they’ve been using for 5 or 10 years.”

That’s the kind of hope Dr. Hulvershorn holds for the17-year-old patient she’s treating who suffers from depression and PTSD.

“She has decided that it’s important for her to come clean,” said Dr. Hulvershorn, who added that the patient has received mental health and trauma counseling. “Part of our treatment program involves helping patients reorganize their life so that activities they’re involved with are not drug-related. That involves finding new friends and new activities, which can take some time. She is really committed to graduating from high school now that she’s clean. She’s really made a 180.”

Dr. Potenza disclosed having been a consultant to Jazz Pharmaceuticals and Opiant Pharmaceuticals. Dr. Matson and Dr. Hulvershorn reported having no relevant financial disclosures.

Role of a pediatrician’s support is vital

The way Deepa R. Camenga, MD, sees it, pediatricians play a vital role in not only counseling adolescents struggling with opioid use disorders but in helping to prevent it in the first place.

Prevention starts with advising parents or caregivers to manage any prescription medication that adolescents may receive for medical indications such as wisdom tooth extractions or sports injuries. “There is some risk for misuse or using it inappropriately or recreationally,” said Dr. Camenga, a pediatrician at Yale School of Medicine, New Haven, Conn., who is also board certified in addiction medicine. “The parents should be highly involved in the administration of these medications to teenagers.”

[email protected]

*This article was updated May 17, 2017.

The grip that opioid addiction has on adolescents often resembles that on addicted adults. Both groups crave the next high at all costs.

“Basically, they’re living to find their next heroin or opioids because their ‘feeling good’ completely depends on it,” Steven C. Matson, MD, , chief of the division of adolescent medicine at Nationwide Children’s Hospital, Columbus, Ohio, said in an interview. “They’re up in the morning, out trying to hustle money constantly, and then using and rebounding, and doing it over and over again. It gets to be a pretty dismal way of life.”

courtesy Lindsey Pulfer, RN

The scope of the problem

The 2015 National Survey on Drug Use and Health (NSDUH) found that 6.5 million Americans over the age of 12 years used controlled prescription medicines nonmedically during the past month, second only to marijuana and more than past-month users of cocaine, heroin, and hallucinogens combined. According to the Centers for Disease Control and Prevention, 91 Americans die every day from an overdose of opioids. In fact, opioid overdoses in the United States increased four times since 1999 and were highest among persons 25-54 years of age. In 2015, the five states with the highest rates of death resulting from drug overdose were West Virginia (41.5 per 100,000), New Hampshire (34.3 per 100,000), Kentucky (29.9 per 100,000), Ohio (29.9 per 100,000), and Rhode Island (28.2 per 100,000).

The CDC also found that, between 2013 and 2014, the number of children aged 0-14 years who died from a drug overdose increased slightly from 105 to 109. The number of children aged 15-24 years who died from a drug overdose rose from 3,664 to 3,798, an increase of 3.6%. While the precise path to opioid addiction differs from patient to patient, experts interviewed for this story noted that adolescents who currently smoke marijuana or drink alcohol on a regular basis face an increased risk of progressing to opioid use, compared with peers who lack substance abuse problems. In such cases, “go ahead and refer for substance abuse treatment at that point, rather than waiting for them to get into something much more dangerous,” Dr. Hulvershorn advised. “Neither of those drugs is good for adolescents either, but you could easily be preventing a worse outcome later. Sometimes physicians will ask, ‘You really want me to refer kids who are smoking pot?’ The answer is, ‘Absolutely.’ That’s probably our best shot at providing them with skills early on, before they get into heavier stuff.”

How to spot a troubled teen

Pediatricians can do their part to detect addiction by regularly asking about drug use during office visits. One quick screen Dr. Matson recommends is the HEADSS (Home, Education/employment, peer group Activities, Drugs, Sexuality, and Suicide/depression).

But, simply being attuned to how patients are performing in general domains can help you spot a troubled teen. “If a kid is still playing football and getting straight A’s, there’s probably a pretty low chance he’s having a serious problem,” he said. “A big part of addiction is secret, so I think when parents start to see their kids be more secretive, hiding their phone,” that’s a red flag. Or maybe their child has a new set of friends that “don’t seem as ‘good’ as the previous set of friends.” Other signs might be “losing a job that they were doing well at before, grades starting to go down, [or] loss of interest in the things they normally like to do. In general, I think kids work their way up to opioid addiction. If parents know their kids smoke cigarettes and think they might be doing some weed, those are the kids that are at risk for moving on to a bigger high.”

Many kids start with pills that they find or take from someone. “They may not think of them as a drug, so you would need to specifically ask, ‘Have you ever used a pill like a pain medication that you may have found or gotten from a family member or a friend for recreational use or for something other than how it was prescribed?’ ” Dr. Hulvershorn said.

The amount of parental supervision also factors in. “There’s been a lot of research showing that, if parents don’t have any idea where their kids are after school or what they’re up do, those kids are much more likely to be using,” she said. “So, you want to ask parents, ‘Are there times when your adolescent is unsupervised?’ ”

If you suspect that one of your adolescent patients is using opioids, but he or she won’t open up about it, consider intermittent urine screening, Dr. Hulvershorn said. If a screen comes back positive, be familiar with patient privacy regulations in your state, because special federal protections apply to adolescents and adults with respect to substance abuse disorder assessment and treatment. For example, in Indiana there is no age limit. Anyone under the age of 18 has the same protection as an adult. “I cannot legally release that information to the parent without the adolescent’s consent, which is really unusual,” she said. “Each state determines the age where that might apply. The best approach is to try to get the adolescent on board, and say, ‘Here’s what we found. We really need to get this out in the open and get you some treatment. I’d really like to have a conversation with your parents.’ Sometimes you can get them to agree, and sometimes you can’t. Nonetheless, you would try to proceed with treatment. You don’t need parental consent for treatment.”

Once Dr. Matson establishes confidentiality with patients, he spends time helping them understand where they fall in the “continuum of use.” He asks for permission to share information with them about the negative aspects of drug use instead of force-feeding it.

“A lot of these kids are hanging around the same kinds of kids and somehow, in their minds, think that what they’re doing is normal,” he said. “To me, somebody smoking weed twice a day every day is a problem, and they probably are addicted. It’s hard to know whether you’d be ready to pull a parent [into the room] at that point or at least give the kid a chance to think if they ... could cut down. If they would, maybe see them back with a warning that, if it’s not going to get much better, you might have to inform parents.

“Weed is always a big issue, especially in kids with ADHD. Those kids are at high risk for substance abuse, especially if they aren’t maintained on their [ADHD] drugs later on,” Dr. Matson said.

Adolescents on opioids “usually are going to present in a more dramatic fashion because they’re starting to get into trouble. They might have gotten arrested or might have been driving under the influence with both alcohol and opioids. To support their habit, a lot of kids have to steal things, so a kid who gets caught shoplifting is someone to be concerned about,” he said.

Treatment options

In 2016, the American Academy of Pediatrics issued a new policy statement, “Medication-Assisted Treatment for Adolescents with Opioid Disorders,” which recommends that pediatricians consider offering medication-assisted treatments to their adolescent and young adult patients with opioid use disorders or refer them to other providers who can. Ideally, pediatricians should refer patients to clinicians who have expertise in treating substance abuse disorders in adolescents, typically psychiatrists.

Psychiatrists “tend to have quite a bit of experience with addiction, but they can be very hard to find,” Dr. Hulvershorn said. “Sometimes, it’s a mental health center provider who treats adults with addiction. Addiction is a different beast in kids, but that might be the next best thing.”

Three medicines indicated for treating severe opioid disorder include buprenorphine (the “gold standard,” Dr. Matson said), methadone, and naltrexone, which is Dr. Hulvershorn’s typical drug of choice, “because it’s not a drug of abuse. It’s an opioid antagonist, so it blocks the euphoria that you might get when you are using a drug of abuse such as an opioid.”

Even though pediatricians have access to an American Academy of Pediatrics–endorsed buprenorphine waiver course, not all clinicians feel comfortable adding medication-assisted treatment to patients.

“It might mean that you partner with a substance use provider who can do more comprehensive services but not the prescribing,” Dr. Hulvershorn said. “You certainly don’t want to treat these kids in a vacuum by yourself, because it’s very complicated to treat them.”

Still, the office-based practice of prescribing opioid withdrawal medication “is a very successful approach and a reasonable alternative to other approaches that have been used historically, like methadone maintenance programs,” noted Dr. Potenza, emphasizing that physicians have to understand how to help patients with addiction.

Physicians interviewed for this story underscored the importance of a comprehensive approach that includes behavioral treatment, medication, and support from family and friends.

“A lot of kids who get into these problems come from families that don’t have many resources,” Dr. Matson said, noting that, often, it is a generational problem, in which grandparents and parents are drug users. “But, for kids who take a wrong path, encouraging words really can come true. It’s really a matter of how many people you have cheerleading for you and keeping an eye on you.”

When Dr. Matson’s clinic began treating patients with opioid use disorders 8 years ago, only about 25% of adolescents returned for a second visit, and the rate of abstinence at 1 year was only 9%. The clinic has undertake a large quality improvement project to improve that percentage. “We learned to not scare people right away with a bunch of assignments they have to get done but to just welcome them in, get them started on the medication, and give them positive messages. For short-term remission at 3 months, we’re at 50%-60%, which is pretty good. It’s probably as good as any adult program. I think we’re at 35%-40% remission at 1 year for people first time in recovery,” he said.

Where to go from here

Reflecting on what he’d like opioid use disorder treatment to look like 5 or 10 years down the road, Dr. Matson emphasized the prominent role that pediatricians can play.

“We’re really the ones that could make a difference if we can try to intervene,” he said. “I’m not sure I can prove it, but my pipe dream is, the earlier that we catch people and the less time they’ve been using drugs, it’s got to be easier to stop it then, than if they’ve been using for 5 or 10 years.”

That’s the kind of hope Dr. Hulvershorn holds for the17-year-old patient she’s treating who suffers from depression and PTSD.

“She has decided that it’s important for her to come clean,” said Dr. Hulvershorn, who added that the patient has received mental health and trauma counseling. “Part of our treatment program involves helping patients reorganize their life so that activities they’re involved with are not drug-related. That involves finding new friends and new activities, which can take some time. She is really committed to graduating from high school now that she’s clean. She’s really made a 180.”

Dr. Potenza disclosed having been a consultant to Jazz Pharmaceuticals and Opiant Pharmaceuticals. Dr. Matson and Dr. Hulvershorn reported having no relevant financial disclosures.

Role of a pediatrician’s support is vital

The way Deepa R. Camenga, MD, sees it, pediatricians play a vital role in not only counseling adolescents struggling with opioid use disorders but in helping to prevent it in the first place.

Prevention starts with advising parents or caregivers to manage any prescription medication that adolescents may receive for medical indications such as wisdom tooth extractions or sports injuries. “There is some risk for misuse or using it inappropriately or recreationally,” said Dr. Camenga, a pediatrician at Yale School of Medicine, New Haven, Conn., who is also board certified in addiction medicine. “The parents should be highly involved in the administration of these medications to teenagers.”

[email protected]

*This article was updated May 17, 2017.

The grip that opioid addiction has on adolescents often resembles that on addicted adults. Both groups crave the next high at all costs.

“Basically, they’re living to find their next heroin or opioids because their ‘feeling good’ completely depends on it,” Steven C. Matson, MD, , chief of the division of adolescent medicine at Nationwide Children’s Hospital, Columbus, Ohio, said in an interview. “They’re up in the morning, out trying to hustle money constantly, and then using and rebounding, and doing it over and over again. It gets to be a pretty dismal way of life.”

courtesy Lindsey Pulfer, RN

The scope of the problem

The 2015 National Survey on Drug Use and Health (NSDUH) found that 6.5 million Americans over the age of 12 years used controlled prescription medicines nonmedically during the past month, second only to marijuana and more than past-month users of cocaine, heroin, and hallucinogens combined. According to the Centers for Disease Control and Prevention, 91 Americans die every day from an overdose of opioids. In fact, opioid overdoses in the United States increased four times since 1999 and were highest among persons 25-54 years of age. In 2015, the five states with the highest rates of death resulting from drug overdose were West Virginia (41.5 per 100,000), New Hampshire (34.3 per 100,000), Kentucky (29.9 per 100,000), Ohio (29.9 per 100,000), and Rhode Island (28.2 per 100,000).

The CDC also found that, between 2013 and 2014, the number of children aged 0-14 years who died from a drug overdose increased slightly from 105 to 109. The number of children aged 15-24 years who died from a drug overdose rose from 3,664 to 3,798, an increase of 3.6%. While the precise path to opioid addiction differs from patient to patient, experts interviewed for this story noted that adolescents who currently smoke marijuana or drink alcohol on a regular basis face an increased risk of progressing to opioid use, compared with peers who lack substance abuse problems. In such cases, “go ahead and refer for substance abuse treatment at that point, rather than waiting for them to get into something much more dangerous,” Dr. Hulvershorn advised. “Neither of those drugs is good for adolescents either, but you could easily be preventing a worse outcome later. Sometimes physicians will ask, ‘You really want me to refer kids who are smoking pot?’ The answer is, ‘Absolutely.’ That’s probably our best shot at providing them with skills early on, before they get into heavier stuff.”

How to spot a troubled teen

Pediatricians can do their part to detect addiction by regularly asking about drug use during office visits. One quick screen Dr. Matson recommends is the HEADSS (Home, Education/employment, peer group Activities, Drugs, Sexuality, and Suicide/depression).

But, simply being attuned to how patients are performing in general domains can help you spot a troubled teen. “If a kid is still playing football and getting straight A’s, there’s probably a pretty low chance he’s having a serious problem,” he said. “A big part of addiction is secret, so I think when parents start to see their kids be more secretive, hiding their phone,” that’s a red flag. Or maybe their child has a new set of friends that “don’t seem as ‘good’ as the previous set of friends.” Other signs might be “losing a job that they were doing well at before, grades starting to go down, [or] loss of interest in the things they normally like to do. In general, I think kids work their way up to opioid addiction. If parents know their kids smoke cigarettes and think they might be doing some weed, those are the kids that are at risk for moving on to a bigger high.”

Many kids start with pills that they find or take from someone. “They may not think of them as a drug, so you would need to specifically ask, ‘Have you ever used a pill like a pain medication that you may have found or gotten from a family member or a friend for recreational use or for something other than how it was prescribed?’ ” Dr. Hulvershorn said.

The amount of parental supervision also factors in. “There’s been a lot of research showing that, if parents don’t have any idea where their kids are after school or what they’re up do, those kids are much more likely to be using,” she said. “So, you want to ask parents, ‘Are there times when your adolescent is unsupervised?’ ”

If you suspect that one of your adolescent patients is using opioids, but he or she won’t open up about it, consider intermittent urine screening, Dr. Hulvershorn said. If a screen comes back positive, be familiar with patient privacy regulations in your state, because special federal protections apply to adolescents and adults with respect to substance abuse disorder assessment and treatment. For example, in Indiana there is no age limit. Anyone under the age of 18 has the same protection as an adult. “I cannot legally release that information to the parent without the adolescent’s consent, which is really unusual,” she said. “Each state determines the age where that might apply. The best approach is to try to get the adolescent on board, and say, ‘Here’s what we found. We really need to get this out in the open and get you some treatment. I’d really like to have a conversation with your parents.’ Sometimes you can get them to agree, and sometimes you can’t. Nonetheless, you would try to proceed with treatment. You don’t need parental consent for treatment.”

Once Dr. Matson establishes confidentiality with patients, he spends time helping them understand where they fall in the “continuum of use.” He asks for permission to share information with them about the negative aspects of drug use instead of force-feeding it.

“A lot of these kids are hanging around the same kinds of kids and somehow, in their minds, think that what they’re doing is normal,” he said. “To me, somebody smoking weed twice a day every day is a problem, and they probably are addicted. It’s hard to know whether you’d be ready to pull a parent [into the room] at that point or at least give the kid a chance to think if they ... could cut down. If they would, maybe see them back with a warning that, if it’s not going to get much better, you might have to inform parents.

“Weed is always a big issue, especially in kids with ADHD. Those kids are at high risk for substance abuse, especially if they aren’t maintained on their [ADHD] drugs later on,” Dr. Matson said.

Adolescents on opioids “usually are going to present in a more dramatic fashion because they’re starting to get into trouble. They might have gotten arrested or might have been driving under the influence with both alcohol and opioids. To support their habit, a lot of kids have to steal things, so a kid who gets caught shoplifting is someone to be concerned about,” he said.

Treatment options

In 2016, the American Academy of Pediatrics issued a new policy statement, “Medication-Assisted Treatment for Adolescents with Opioid Disorders,” which recommends that pediatricians consider offering medication-assisted treatments to their adolescent and young adult patients with opioid use disorders or refer them to other providers who can. Ideally, pediatricians should refer patients to clinicians who have expertise in treating substance abuse disorders in adolescents, typically psychiatrists.

Psychiatrists “tend to have quite a bit of experience with addiction, but they can be very hard to find,” Dr. Hulvershorn said. “Sometimes, it’s a mental health center provider who treats adults with addiction. Addiction is a different beast in kids, but that might be the next best thing.”

Three medicines indicated for treating severe opioid disorder include buprenorphine (the “gold standard,” Dr. Matson said), methadone, and naltrexone, which is Dr. Hulvershorn’s typical drug of choice, “because it’s not a drug of abuse. It’s an opioid antagonist, so it blocks the euphoria that you might get when you are using a drug of abuse such as an opioid.”

Even though pediatricians have access to an American Academy of Pediatrics–endorsed buprenorphine waiver course, not all clinicians feel comfortable adding medication-assisted treatment to patients.

“It might mean that you partner with a substance use provider who can do more comprehensive services but not the prescribing,” Dr. Hulvershorn said. “You certainly don’t want to treat these kids in a vacuum by yourself, because it’s very complicated to treat them.”

Still, the office-based practice of prescribing opioid withdrawal medication “is a very successful approach and a reasonable alternative to other approaches that have been used historically, like methadone maintenance programs,” noted Dr. Potenza, emphasizing that physicians have to understand how to help patients with addiction.

Physicians interviewed for this story underscored the importance of a comprehensive approach that includes behavioral treatment, medication, and support from family and friends.

“A lot of kids who get into these problems come from families that don’t have many resources,” Dr. Matson said, noting that, often, it is a generational problem, in which grandparents and parents are drug users. “But, for kids who take a wrong path, encouraging words really can come true. It’s really a matter of how many people you have cheerleading for you and keeping an eye on you.”

When Dr. Matson’s clinic began treating patients with opioid use disorders 8 years ago, only about 25% of adolescents returned for a second visit, and the rate of abstinence at 1 year was only 9%. The clinic has undertake a large quality improvement project to improve that percentage. “We learned to not scare people right away with a bunch of assignments they have to get done but to just welcome them in, get them started on the medication, and give them positive messages. For short-term remission at 3 months, we’re at 50%-60%, which is pretty good. It’s probably as good as any adult program. I think we’re at 35%-40% remission at 1 year for people first time in recovery,” he said.

Where to go from here

Reflecting on what he’d like opioid use disorder treatment to look like 5 or 10 years down the road, Dr. Matson emphasized the prominent role that pediatricians can play.

“We’re really the ones that could make a difference if we can try to intervene,” he said. “I’m not sure I can prove it, but my pipe dream is, the earlier that we catch people and the less time they’ve been using drugs, it’s got to be easier to stop it then, than if they’ve been using for 5 or 10 years.”

That’s the kind of hope Dr. Hulvershorn holds for the17-year-old patient she’s treating who suffers from depression and PTSD.

“She has decided that it’s important for her to come clean,” said Dr. Hulvershorn, who added that the patient has received mental health and trauma counseling. “Part of our treatment program involves helping patients reorganize their life so that activities they’re involved with are not drug-related. That involves finding new friends and new activities, which can take some time. She is really committed to graduating from high school now that she’s clean. She’s really made a 180.”

Dr. Potenza disclosed having been a consultant to Jazz Pharmaceuticals and Opiant Pharmaceuticals. Dr. Matson and Dr. Hulvershorn reported having no relevant financial disclosures.

Role of a pediatrician’s support is vital

The way Deepa R. Camenga, MD, sees it, pediatricians play a vital role in not only counseling adolescents struggling with opioid use disorders but in helping to prevent it in the first place.

Prevention starts with advising parents or caregivers to manage any prescription medication that adolescents may receive for medical indications such as wisdom tooth extractions or sports injuries. “There is some risk for misuse or using it inappropriately or recreationally,” said Dr. Camenga, a pediatrician at Yale School of Medicine, New Haven, Conn., who is also board certified in addiction medicine. “The parents should be highly involved in the administration of these medications to teenagers.”

[email protected]

*This article was updated May 17, 2017.

GENEVA – Among older adults with stage III non–small cell lung cancer (NSCLC), the sequencing of chemotherapy and radiation has a significant effect on overall survival, a team of investigators from Hong Kong and the United States reported.

Among 2,033 adults who were 65 years or older with locally advanced NSCLC and treated with one of four combined-modality therapy (CMT) schedules, both chemotherapy induction followed by concurrent therapy (CMT-IND) and concurrent therapy followed by consolidation chemoradiation (CMT-CON) were associated with an approximately 30% improvement in survival, compared with either sequential chemotherapy followed by radiation (CMT-SEQ) or concurrent therapy only (CMT-ONLY), reported Hei Man Herbert Pang, MD, of the University of Hong Kong and his colleagues.

Neil Osterweil/Frontline Medical News

GENEVA – Among older adults with stage III non–small cell lung cancer (NSCLC), the sequencing of chemotherapy and radiation has a significant effect on overall survival, a team of investigators from Hong Kong and the United States reported.

Among 2,033 adults who were 65 years or older with locally advanced NSCLC and treated with one of four combined-modality therapy (CMT) schedules, both chemotherapy induction followed by concurrent therapy (CMT-IND) and concurrent therapy followed by consolidation chemoradiation (CMT-CON) were associated with an approximately 30% improvement in survival, compared with either sequential chemotherapy followed by radiation (CMT-SEQ) or concurrent therapy only (CMT-ONLY), reported Hei Man Herbert Pang, MD, of the University of Hong Kong and his colleagues.

Neil Osterweil/Frontline Medical News

GENEVA – Among older adults with stage III non–small cell lung cancer (NSCLC), the sequencing of chemotherapy and radiation has a significant effect on overall survival, a team of investigators from Hong Kong and the United States reported.

Among 2,033 adults who were 65 years or older with locally advanced NSCLC and treated with one of four combined-modality therapy (CMT) schedules, both chemotherapy induction followed by concurrent therapy (CMT-IND) and concurrent therapy followed by consolidation chemoradiation (CMT-CON) were associated with an approximately 30% improvement in survival, compared with either sequential chemotherapy followed by radiation (CMT-SEQ) or concurrent therapy only (CMT-ONLY), reported Hei Man Herbert Pang, MD, of the University of Hong Kong and his colleagues.

Neil Osterweil/Frontline Medical News

SAN DIEGO – Obese women with a body mass index of 40 or greater are more likely to experience expulsion of levonorgestrel IUDs than women with lower BMI, according to findings from a retrospective cohort study.

Women with class III obesity (a BMI of 40 or greater) had a 3.06-times higher odds of expulsion (95% confidence interval, 1.69-5.57) with a levonorgestrel IUD, compared with a control group of women with a BMI of less than 35, Lynne Saito-Tom, MD, of the University of Hawaii at Manoa, Honolulu, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

[email protected]

On Twitter @maryellenny

SAN DIEGO – Obese women with a body mass index of 40 or greater are more likely to experience expulsion of levonorgestrel IUDs than women with lower BMI, according to findings from a retrospective cohort study.

Women with class III obesity (a BMI of 40 or greater) had a 3.06-times higher odds of expulsion (95% confidence interval, 1.69-5.57) with a levonorgestrel IUD, compared with a control group of women with a BMI of less than 35, Lynne Saito-Tom, MD, of the University of Hawaii at Manoa, Honolulu, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

[email protected]

On Twitter @maryellenny

SAN DIEGO – Obese women with a body mass index of 40 or greater are more likely to experience expulsion of levonorgestrel IUDs than women with lower BMI, according to findings from a retrospective cohort study.

Women with class III obesity (a BMI of 40 or greater) had a 3.06-times higher odds of expulsion (95% confidence interval, 1.69-5.57) with a levonorgestrel IUD, compared with a control group of women with a BMI of less than 35, Lynne Saito-Tom, MD, of the University of Hawaii at Manoa, Honolulu, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

[email protected]

On Twitter @maryellenny

High mobility group box 1 (HMGB1) may be a new biomarker of celiac disease in children, said Sara Manti, MD, of the unit of pediatric genetics and immunology at the University of Messina, Italy, and her associates.

Serum HMGB1 levels were significantly higher in 49 children with celiac disease, compared with 44 healthy children in the control group (16.4 ng/mL vs. 6.23 ng/mL; P less than .001). Children with typical form celiac disease had significantly higher serum HMGB1 levels (22.03 ng/mL) than both children with atypical form (14.83 ng/mL) and silent form celiac disease (12.3 ng/mL). There was no statistically significant difference in serum HMGB1 levels between children with atypical form and silent form celiac disease.

Higher serum HMGB1 levels were correlated with severity of Marsh-Oberhüber classification. 

These data, which need to be confirmed in further studies, suggest that HMGB1 is upregulated and linked to the severity of histologic damage in celiac disease. If other studies confirm these findings, it could be hypothesized that “asymptomatic children only with positive familial history and abnormal serum anti–tTG-IgA levels as well as normal serum HMGB1 levels need not be subjected to endoscopy to rule out the CD diagnosis,” the investigators said.

Perhaps, “neutralizing HMGB1 activity might be identified as a potential therapeutic target,” Dr. Manti and her associates noted.

Read more in the journal Nutrition (2017 May;37:18-21).

[email protected]

High mobility group box 1 (HMGB1) may be a new biomarker of celiac disease in children, said Sara Manti, MD, of the unit of pediatric genetics and immunology at the University of Messina, Italy, and her associates.

Serum HMGB1 levels were significantly higher in 49 children with celiac disease, compared with 44 healthy children in the control group (16.4 ng/mL vs. 6.23 ng/mL; P less than .001). Children with typical form celiac disease had significantly higher serum HMGB1 levels (22.03 ng/mL) than both children with atypical form (14.83 ng/mL) and silent form celiac disease (12.3 ng/mL). There was no statistically significant difference in serum HMGB1 levels between children with atypical form and silent form celiac disease.

Higher serum HMGB1 levels were correlated with severity of Marsh-Oberhüber classification. 

These data, which need to be confirmed in further studies, suggest that HMGB1 is upregulated and linked to the severity of histologic damage in celiac disease. If other studies confirm these findings, it could be hypothesized that “asymptomatic children only with positive familial history and abnormal serum anti–tTG-IgA levels as well as normal serum HMGB1 levels need not be subjected to endoscopy to rule out the CD diagnosis,” the investigators said.

Perhaps, “neutralizing HMGB1 activity might be identified as a potential therapeutic target,” Dr. Manti and her associates noted.

Read more in the journal Nutrition (2017 May;37:18-21).

[email protected]

High mobility group box 1 (HMGB1) may be a new biomarker of celiac disease in children, said Sara Manti, MD, of the unit of pediatric genetics and immunology at the University of Messina, Italy, and her associates.

Serum HMGB1 levels were significantly higher in 49 children with celiac disease, compared with 44 healthy children in the control group (16.4 ng/mL vs. 6.23 ng/mL; P less than .001). Children with typical form celiac disease had significantly higher serum HMGB1 levels (22.03 ng/mL) than both children with atypical form (14.83 ng/mL) and silent form celiac disease (12.3 ng/mL). There was no statistically significant difference in serum HMGB1 levels between children with atypical form and silent form celiac disease.

Higher serum HMGB1 levels were correlated with severity of Marsh-Oberhüber classification. 

These data, which need to be confirmed in further studies, suggest that HMGB1 is upregulated and linked to the severity of histologic damage in celiac disease. If other studies confirm these findings, it could be hypothesized that “asymptomatic children only with positive familial history and abnormal serum anti–tTG-IgA levels as well as normal serum HMGB1 levels need not be subjected to endoscopy to rule out the CD diagnosis,” the investigators said.

Perhaps, “neutralizing HMGB1 activity might be identified as a potential therapeutic target,” Dr. Manti and her associates noted.

Read more in the journal Nutrition (2017 May;37:18-21).

[email protected]

LAS VEGAS – Bisphosphonates may slow the onset and progression of osteoarthritis (OA), according to data from the National Institutes of Health–sponsored Osteoarthritis Initiative. “Bisphosphonates warrant further study as potential disease-modifying agents in osteoarthritis,” Tuhina Neogi, MD, declared in presenting the study findings at the World Congress on Osteoarthritis.

In addition to the promising signal of a preventive effect for bisphosphonates, her analysis of Osteoarthritis Initiative data yielded two other major findings: Changes over time in the MRI-based three-dimensional bone shape of the knee constitute a novel structural imaging biomarker that appears to be of value in monitoring patients with OA or at high risk for the joint disease, and bisphosphonate-induced suppression of bone turnover had no adverse long-term impact on osteoarthritis risk.

“While bisphosphonates may have beneficial articular cartilage effects, there are potential theoretical concerns regarding long-term effects of bone turnover. This issue hasn’t previously been addressed. Bone turnover suppression may lead to more bone deposition and bone stiffness, with adverse biomechanical consequences. But it did not appear, in this sample at least, that suppression of bone turnover had a negative impact over the long term,” said Dr. Neogi, professor of medicine at Boston University.

The Osteoarthritis Initiative is a multicenter, longitudinal, prospective, observational study of knee osteoarthritis launched by the NIH in 2002. Dr. Neogi’s analysis was limited to the 1,071 female participants free of radiographic knee OA at baseline and who had 3-Tesla MRIs of the right knee at baseline and annually thereafter for 4 years. They were at increased risk for OA on the basis of their age – a mean of 62 years – along with their mean body mass index of 28.3 kg/m2. Just under one-quarter of the women were on bisphosphonate therapy.

Prior studies of the effects of bisphosphonates in patients with knee OA have yielded conflicting results, in part because radiographic findings are a relatively crude indicator of bone and joint changes. 3D bone shape of the knee has been shown to change much more quickly than traditional radiographic measures. These changes predict the incidence of knee OA even years later, the rheumatologist explained at the congress sponsored by the Osteoarthritis Research Society International.

Using bone shape analytic software developed by England-based Imorphics, she and her coinvestigators categorized the women into three distinct groups on the basis of the trajectory of MRI changes toward a more osteoarthritic bone shape over time. Of them, 23% fell into the fast-change group, 49% were in the intermediate group, and 28% were in the slowest-changing group. The rate of MRI bone shape progression toward knee OA was 2.7-times higher in the fastest, compared with the slowest, group.

The incidence of radiographic OA during 4 years of prospective follow-up was 14% in the fastest bone shape-changing group, 8% in the intermediate-speed group, and 4% in the slowest-changing group.

In a multivariate analysis adjusted for age, BMI, education, race, quadriceps strength, and history of knee injury, bisphosphonate users were 41% less likely to be in the fastest bone shape–changing group and 32% less likely to be in the intermediate group, compared with the slowest-changing group.

As a rheumatologist with a PhD in epidemiology, Dr. Neogi was readily prepared to critique her own study. The major limitation in her view was the potential for residual confounding, which is inherent in observational studies. In this instance, the possibility of confounding by indication cannot be excluded. Also, bone mineral density data wasn’t collected in the Osteoarthritis Initiative. Future studies should evaluate the impact over time of new-onset bisphosphonate therapy as a means of altering the slope of the trajectory of MRI-based 3D bone shape of the knee, Dr. Neogi said.

She reported having no financial conflicts regarding the NIH-sponsored study.

[email protected]

LAS VEGAS – Bisphosphonates may slow the onset and progression of osteoarthritis (OA), according to data from the National Institutes of Health–sponsored Osteoarthritis Initiative. “Bisphosphonates warrant further study as potential disease-modifying agents in osteoarthritis,” Tuhina Neogi, MD, declared in presenting the study findings at the World Congress on Osteoarthritis.

In addition to the promising signal of a preventive effect for bisphosphonates, her analysis of Osteoarthritis Initiative data yielded two other major findings: Changes over time in the MRI-based three-dimensional bone shape of the knee constitute a novel structural imaging biomarker that appears to be of value in monitoring patients with OA or at high risk for the joint disease, and bisphosphonate-induced suppression of bone turnover had no adverse long-term impact on osteoarthritis risk.

“While bisphosphonates may have beneficial articular cartilage effects, there are potential theoretical concerns regarding long-term effects of bone turnover. This issue hasn’t previously been addressed. Bone turnover suppression may lead to more bone deposition and bone stiffness, with adverse biomechanical consequences. But it did not appear, in this sample at least, that suppression of bone turnover had a negative impact over the long term,” said Dr. Neogi, professor of medicine at Boston University.

The Osteoarthritis Initiative is a multicenter, longitudinal, prospective, observational study of knee osteoarthritis launched by the NIH in 2002. Dr. Neogi’s analysis was limited to the 1,071 female participants free of radiographic knee OA at baseline and who had 3-Tesla MRIs of the right knee at baseline and annually thereafter for 4 years. They were at increased risk for OA on the basis of their age – a mean of 62 years – along with their mean body mass index of 28.3 kg/m2. Just under one-quarter of the women were on bisphosphonate therapy.

Prior studies of the effects of bisphosphonates in patients with knee OA have yielded conflicting results, in part because radiographic findings are a relatively crude indicator of bone and joint changes. 3D bone shape of the knee has been shown to change much more quickly than traditional radiographic measures. These changes predict the incidence of knee OA even years later, the rheumatologist explained at the congress sponsored by the Osteoarthritis Research Society International.

Using bone shape analytic software developed by England-based Imorphics, she and her coinvestigators categorized the women into three distinct groups on the basis of the trajectory of MRI changes toward a more osteoarthritic bone shape over time. Of them, 23% fell into the fast-change group, 49% were in the intermediate group, and 28% were in the slowest-changing group. The rate of MRI bone shape progression toward knee OA was 2.7-times higher in the fastest, compared with the slowest, group.

The incidence of radiographic OA during 4 years of prospective follow-up was 14% in the fastest bone shape-changing group, 8% in the intermediate-speed group, and 4% in the slowest-changing group.

In a multivariate analysis adjusted for age, BMI, education, race, quadriceps strength, and history of knee injury, bisphosphonate users were 41% less likely to be in the fastest bone shape–changing group and 32% less likely to be in the intermediate group, compared with the slowest-changing group.

As a rheumatologist with a PhD in epidemiology, Dr. Neogi was readily prepared to critique her own study. The major limitation in her view was the potential for residual confounding, which is inherent in observational studies. In this instance, the possibility of confounding by indication cannot be excluded. Also, bone mineral density data wasn’t collected in the Osteoarthritis Initiative. Future studies should evaluate the impact over time of new-onset bisphosphonate therapy as a means of altering the slope of the trajectory of MRI-based 3D bone shape of the knee, Dr. Neogi said.

She reported having no financial conflicts regarding the NIH-sponsored study.

[email protected]

LAS VEGAS – Bisphosphonates may slow the onset and progression of osteoarthritis (OA), according to data from the National Institutes of Health–sponsored Osteoarthritis Initiative. “Bisphosphonates warrant further study as potential disease-modifying agents in osteoarthritis,” Tuhina Neogi, MD, declared in presenting the study findings at the World Congress on Osteoarthritis.

In addition to the promising signal of a preventive effect for bisphosphonates, her analysis of Osteoarthritis Initiative data yielded two other major findings: Changes over time in the MRI-based three-dimensional bone shape of the knee constitute a novel structural imaging biomarker that appears to be of value in monitoring patients with OA or at high risk for the joint disease, and bisphosphonate-induced suppression of bone turnover had no adverse long-term impact on osteoarthritis risk.

“While bisphosphonates may have beneficial articular cartilage effects, there are potential theoretical concerns regarding long-term effects of bone turnover. This issue hasn’t previously been addressed. Bone turnover suppression may lead to more bone deposition and bone stiffness, with adverse biomechanical consequences. But it did not appear, in this sample at least, that suppression of bone turnover had a negative impact over the long term,” said Dr. Neogi, professor of medicine at Boston University.

The Osteoarthritis Initiative is a multicenter, longitudinal, prospective, observational study of knee osteoarthritis launched by the NIH in 2002. Dr. Neogi’s analysis was limited to the 1,071 female participants free of radiographic knee OA at baseline and who had 3-Tesla MRIs of the right knee at baseline and annually thereafter for 4 years. They were at increased risk for OA on the basis of their age – a mean of 62 years – along with their mean body mass index of 28.3 kg/m2. Just under one-quarter of the women were on bisphosphonate therapy.

Prior studies of the effects of bisphosphonates in patients with knee OA have yielded conflicting results, in part because radiographic findings are a relatively crude indicator of bone and joint changes. 3D bone shape of the knee has been shown to change much more quickly than traditional radiographic measures. These changes predict the incidence of knee OA even years later, the rheumatologist explained at the congress sponsored by the Osteoarthritis Research Society International.

Using bone shape analytic software developed by England-based Imorphics, she and her coinvestigators categorized the women into three distinct groups on the basis of the trajectory of MRI changes toward a more osteoarthritic bone shape over time. Of them, 23% fell into the fast-change group, 49% were in the intermediate group, and 28% were in the slowest-changing group. The rate of MRI bone shape progression toward knee OA was 2.7-times higher in the fastest, compared with the slowest, group.

The incidence of radiographic OA during 4 years of prospective follow-up was 14% in the fastest bone shape-changing group, 8% in the intermediate-speed group, and 4% in the slowest-changing group.

In a multivariate analysis adjusted for age, BMI, education, race, quadriceps strength, and history of knee injury, bisphosphonate users were 41% less likely to be in the fastest bone shape–changing group and 32% less likely to be in the intermediate group, compared with the slowest-changing group.

As a rheumatologist with a PhD in epidemiology, Dr. Neogi was readily prepared to critique her own study. The major limitation in her view was the potential for residual confounding, which is inherent in observational studies. In this instance, the possibility of confounding by indication cannot be excluded. Also, bone mineral density data wasn’t collected in the Osteoarthritis Initiative. Future studies should evaluate the impact over time of new-onset bisphosphonate therapy as a means of altering the slope of the trajectory of MRI-based 3D bone shape of the knee, Dr. Neogi said.

She reported having no financial conflicts regarding the NIH-sponsored study.

[email protected]

SAN DIEGO – Just over half of women who requested immediate postpartum sterilization received it in a prospective study of 334 women, with Medicaid paperwork serving as a barrier for many of the unfulfilled requests.

All of the women in the study delivered a baby and had requested immediate postpartum sterilization at some point before delivery, but just 173 women (52%) received the procedure, Taylor Hahn, MD, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. A total of 161 women (48%) did not receive the procedure.

[email protected]

On Twitter @maryellenny

SAN DIEGO – Just over half of women who requested immediate postpartum sterilization received it in a prospective study of 334 women, with Medicaid paperwork serving as a barrier for many of the unfulfilled requests.

All of the women in the study delivered a baby and had requested immediate postpartum sterilization at some point before delivery, but just 173 women (52%) received the procedure, Taylor Hahn, MD, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. A total of 161 women (48%) did not receive the procedure.

[email protected]

On Twitter @maryellenny

SAN DIEGO – Just over half of women who requested immediate postpartum sterilization received it in a prospective study of 334 women, with Medicaid paperwork serving as a barrier for many of the unfulfilled requests.

All of the women in the study delivered a baby and had requested immediate postpartum sterilization at some point before delivery, but just 173 women (52%) received the procedure, Taylor Hahn, MD, reported at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. A total of 161 women (48%) did not receive the procedure.

[email protected]

On Twitter @maryellenny

LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.

This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.

Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.

Bruce Jancin/Frontline Medical News

[email protected]

LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.

This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.

Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.

Bruce Jancin/Frontline Medical News

[email protected]

LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.

This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.

Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.

Bruce Jancin/Frontline Medical News

[email protected]