LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

[email protected]

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

[email protected]

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

[email protected]

DENVER – The surgically implanted Inspire system for controlled upper airway stimulation as therapy for moderate to severe obstructive sleep apnea demonstrated sustained benefit at 42 months of prospective follow-up in the STAR trial, Dr. Patrick J. Strollo Jr. reported at the annual meeting of the Associated Professional Sleep Societies.

STAR was the pivotal trial whose previously reported 12-month outcomes led to Food and Drug Administration clearance of the device. Dr. Strollo was first author of that paper (N Engl J Med. 2014 Jan 9;370:139-49). At SLEEP 2016, he presented patient- and partner-reported outcomes at 42 months. Bottom line: The device had continued safety and no loss in efficacy.

“So far it seems to be a useful option for people who frequently didn’t have an option. And the technology is improving and will only get better,” said Dr. Strollo, professor of medicine and clinical and translational science, director of the Sleep Medicine Center, and codirector of the Sleep Medicine Institute at the University of Pittsburgh.

The Inspire system consists of three parts implanted by an otolaryngologist in an outpatient procedure: a small impulse generator, a breathing sensor lead inserted in the intercostal muscle, and a stimulator lead attached to the distal branch of the 10th cranial nerve, the hypoglossal nerve controlling the tongue muscles.

The device is programmed to discharge at the end of expiration and continue through the inspiratory phase, causing the tongue to move forward and the retrolingual and retropalatal airways to open, he explained in an interview.

Upper airway stimulation is approved for commercial use in patients such as those enrolled in the STAR trial on the basis of pilot studies that identified most likely responders. The key selection criteria include moderate to severe obstructive sleep apnea as defined by an apnea-hypopnea index of 20-50, nonadherence to continuous positive airway pressure (CPAP), a body mass index of 32 kg/m² or less, and absence of concentric collapse of the airway at the level of the palate during sedated endoscopy.

STAR included 126 participants who received the upper airway stimulation device. There have been two explants: one from septic arthritis, the other elective.

A total of 97 STAR participants had 42-month follow-up data available. Among the key findings were that:

• Mean scores on the Epworth Sleepiness Scale decreased from 11.6 at baseline to 7 at 12 months and 7.1 at 42 months.

• Scores on the Functional Outcomes of Sleep Questionnaire improved from 14.3 at baseline to 17.3 at 12 months and 17.5 at 42 months.

• The scores on both the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire were abnormal at baseline and converted to normal range at both 12 and 42 months of follow-up.

• At baseline, 29% of the patients’ sleeping partners characterized the snoring as loud, 24% rated it ‘very intense,’ and 30% left the bedroom. At 32 months, 11% of partners called the snoring loud, 3% deemed it very intense, and only 4% left the room.

• At 42 months, 81% of patients reported using the device nightly. That’s consistent with the objective evidence of adherence Dr. Strollo and his coinvestigators obtained in a study of postmarketing device implants in which they found device usage averaged about 7 hours per night.

“That’s much better than we see with CPAP in patients who can tolerate that therapy,” Dr. Strollo observed.

The planned 5-year follow-up of STAR participants includes a full laboratory polysomnography study to obtain objective apnea-hypopnea index figures.

The other major development is the launch of a comprehensive registry of patients who receive a post-marketing commercial implant. Roughly 1,000 implants have been done worldwide to date, but now that the device is approved, that number will quickly grow. The registry should prove a rich source for research.

“The goal is to try to refine the selection criteria,” according to Dr. Strollo.

Given that only about 50% of patients with moderate to severe sleep apnea are able to tolerate CPAP long term, where does the Inspire system fit into today’s practice of sleep medicine?

“Upper airway stimulation is another tool, another option for patients,” he said. “In my practice, normally I’d let patients try positive pressure first. I want to make sure they’ve tried CPAP, and they’ve tried more advanced therapy like autotitrating bilevel positive airway pressure, which is more comfortable than CPAP. Bilevel positive airway pressure allows you to salvage a fair number of patients who can’t tolerate CPAP. And I also offer an oral appliance, although the robustness of an oral appliance is not great as apnea becomes more severe.”

The STAR trial is supported by Inspire Medical Systems. Dr. Strollo reported receiving a research grant from the company.

[email protected]

DENVER – The surgically implanted Inspire system for controlled upper airway stimulation as therapy for moderate to severe obstructive sleep apnea demonstrated sustained benefit at 42 months of prospective follow-up in the STAR trial, Dr. Patrick J. Strollo Jr. reported at the annual meeting of the Associated Professional Sleep Societies.

STAR was the pivotal trial whose previously reported 12-month outcomes led to Food and Drug Administration clearance of the device. Dr. Strollo was first author of that paper (N Engl J Med. 2014 Jan 9;370:139-49). At SLEEP 2016, he presented patient- and partner-reported outcomes at 42 months. Bottom line: The device had continued safety and no loss in efficacy.

“So far it seems to be a useful option for people who frequently didn’t have an option. And the technology is improving and will only get better,” said Dr. Strollo, professor of medicine and clinical and translational science, director of the Sleep Medicine Center, and codirector of the Sleep Medicine Institute at the University of Pittsburgh.

The Inspire system consists of three parts implanted by an otolaryngologist in an outpatient procedure: a small impulse generator, a breathing sensor lead inserted in the intercostal muscle, and a stimulator lead attached to the distal branch of the 10th cranial nerve, the hypoglossal nerve controlling the tongue muscles.

The device is programmed to discharge at the end of expiration and continue through the inspiratory phase, causing the tongue to move forward and the retrolingual and retropalatal airways to open, he explained in an interview.

Upper airway stimulation is approved for commercial use in patients such as those enrolled in the STAR trial on the basis of pilot studies that identified most likely responders. The key selection criteria include moderate to severe obstructive sleep apnea as defined by an apnea-hypopnea index of 20-50, nonadherence to continuous positive airway pressure (CPAP), a body mass index of 32 kg/m² or less, and absence of concentric collapse of the airway at the level of the palate during sedated endoscopy.

STAR included 126 participants who received the upper airway stimulation device. There have been two explants: one from septic arthritis, the other elective.

A total of 97 STAR participants had 42-month follow-up data available. Among the key findings were that:

• Mean scores on the Epworth Sleepiness Scale decreased from 11.6 at baseline to 7 at 12 months and 7.1 at 42 months.

• Scores on the Functional Outcomes of Sleep Questionnaire improved from 14.3 at baseline to 17.3 at 12 months and 17.5 at 42 months.

• The scores on both the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire were abnormal at baseline and converted to normal range at both 12 and 42 months of follow-up.

• At baseline, 29% of the patients’ sleeping partners characterized the snoring as loud, 24% rated it ‘very intense,’ and 30% left the bedroom. At 32 months, 11% of partners called the snoring loud, 3% deemed it very intense, and only 4% left the room.

• At 42 months, 81% of patients reported using the device nightly. That’s consistent with the objective evidence of adherence Dr. Strollo and his coinvestigators obtained in a study of postmarketing device implants in which they found device usage averaged about 7 hours per night.

“That’s much better than we see with CPAP in patients who can tolerate that therapy,” Dr. Strollo observed.

The planned 5-year follow-up of STAR participants includes a full laboratory polysomnography study to obtain objective apnea-hypopnea index figures.

The other major development is the launch of a comprehensive registry of patients who receive a post-marketing commercial implant. Roughly 1,000 implants have been done worldwide to date, but now that the device is approved, that number will quickly grow. The registry should prove a rich source for research.

“The goal is to try to refine the selection criteria,” according to Dr. Strollo.

Given that only about 50% of patients with moderate to severe sleep apnea are able to tolerate CPAP long term, where does the Inspire system fit into today’s practice of sleep medicine?

“Upper airway stimulation is another tool, another option for patients,” he said. “In my practice, normally I’d let patients try positive pressure first. I want to make sure they’ve tried CPAP, and they’ve tried more advanced therapy like autotitrating bilevel positive airway pressure, which is more comfortable than CPAP. Bilevel positive airway pressure allows you to salvage a fair number of patients who can’t tolerate CPAP. And I also offer an oral appliance, although the robustness of an oral appliance is not great as apnea becomes more severe.”

The STAR trial is supported by Inspire Medical Systems. Dr. Strollo reported receiving a research grant from the company.

[email protected]

DENVER – The surgically implanted Inspire system for controlled upper airway stimulation as therapy for moderate to severe obstructive sleep apnea demonstrated sustained benefit at 42 months of prospective follow-up in the STAR trial, Dr. Patrick J. Strollo Jr. reported at the annual meeting of the Associated Professional Sleep Societies.

STAR was the pivotal trial whose previously reported 12-month outcomes led to Food and Drug Administration clearance of the device. Dr. Strollo was first author of that paper (N Engl J Med. 2014 Jan 9;370:139-49). At SLEEP 2016, he presented patient- and partner-reported outcomes at 42 months. Bottom line: The device had continued safety and no loss in efficacy.

“So far it seems to be a useful option for people who frequently didn’t have an option. And the technology is improving and will only get better,” said Dr. Strollo, professor of medicine and clinical and translational science, director of the Sleep Medicine Center, and codirector of the Sleep Medicine Institute at the University of Pittsburgh.

The Inspire system consists of three parts implanted by an otolaryngologist in an outpatient procedure: a small impulse generator, a breathing sensor lead inserted in the intercostal muscle, and a stimulator lead attached to the distal branch of the 10th cranial nerve, the hypoglossal nerve controlling the tongue muscles.

The device is programmed to discharge at the end of expiration and continue through the inspiratory phase, causing the tongue to move forward and the retrolingual and retropalatal airways to open, he explained in an interview.

Upper airway stimulation is approved for commercial use in patients such as those enrolled in the STAR trial on the basis of pilot studies that identified most likely responders. The key selection criteria include moderate to severe obstructive sleep apnea as defined by an apnea-hypopnea index of 20-50, nonadherence to continuous positive airway pressure (CPAP), a body mass index of 32 kg/m² or less, and absence of concentric collapse of the airway at the level of the palate during sedated endoscopy.

STAR included 126 participants who received the upper airway stimulation device. There have been two explants: one from septic arthritis, the other elective.

A total of 97 STAR participants had 42-month follow-up data available. Among the key findings were that:

• Mean scores on the Epworth Sleepiness Scale decreased from 11.6 at baseline to 7 at 12 months and 7.1 at 42 months.

• Scores on the Functional Outcomes of Sleep Questionnaire improved from 14.3 at baseline to 17.3 at 12 months and 17.5 at 42 months.

• The scores on both the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire were abnormal at baseline and converted to normal range at both 12 and 42 months of follow-up.

• At baseline, 29% of the patients’ sleeping partners characterized the snoring as loud, 24% rated it ‘very intense,’ and 30% left the bedroom. At 32 months, 11% of partners called the snoring loud, 3% deemed it very intense, and only 4% left the room.

• At 42 months, 81% of patients reported using the device nightly. That’s consistent with the objective evidence of adherence Dr. Strollo and his coinvestigators obtained in a study of postmarketing device implants in which they found device usage averaged about 7 hours per night.

“That’s much better than we see with CPAP in patients who can tolerate that therapy,” Dr. Strollo observed.

The planned 5-year follow-up of STAR participants includes a full laboratory polysomnography study to obtain objective apnea-hypopnea index figures.

The other major development is the launch of a comprehensive registry of patients who receive a post-marketing commercial implant. Roughly 1,000 implants have been done worldwide to date, but now that the device is approved, that number will quickly grow. The registry should prove a rich source for research.

“The goal is to try to refine the selection criteria,” according to Dr. Strollo.

Given that only about 50% of patients with moderate to severe sleep apnea are able to tolerate CPAP long term, where does the Inspire system fit into today’s practice of sleep medicine?

“Upper airway stimulation is another tool, another option for patients,” he said. “In my practice, normally I’d let patients try positive pressure first. I want to make sure they’ve tried CPAP, and they’ve tried more advanced therapy like autotitrating bilevel positive airway pressure, which is more comfortable than CPAP. Bilevel positive airway pressure allows you to salvage a fair number of patients who can’t tolerate CPAP. And I also offer an oral appliance, although the robustness of an oral appliance is not great as apnea becomes more severe.”

The STAR trial is supported by Inspire Medical Systems. Dr. Strollo reported receiving a research grant from the company.

[email protected]

CHICAGO – Physical function, role function, global health status and abdominal/gastrointestinal symptoms (AGIS) each predicted overall survival and were significantly associated with the early cessation of chemotherapy among women with platinum-resistant/refractory recurrent ovarian cancer in the Gynecologic Cancer InterGroup (GCIG) Symptom Benefit Study.

The findings from the international prospective cohort study suggest that baseline assessment of quality of life could help identify patients with platinum-resistant/refractory recurrent ovarian cancer (PRR-ROC) who are unlikely to benefit from palliative chemotherapy, Dr. Felicia Roncolato reported at the annual meeting of the American Society of Clinical Oncology.

In 570 women with PRR-ROC enrolled in the Symptom Benefit Study, median overall survival was 11.1 months and median progression-free survival was 3.6 months.

Factors shown on multivariable analysis to predict overall survival included hemoglobin (hazard ratio, 0.94 per 10 g/L increase), ascites (HR, 1.60), AGIS (HR, 1.24), platelets (HR, 1.10 per 100 x 10⁹ unit increase), Log CA125 (HR, 1.18 per unit increase), and neutrophil:lymphocyte ratio (HR, 1.79 for 5 or more). These were all statistically significant predictors of overall survival, said Dr. Roncolato of St. George Hospital, Sydney.

As for baseline quality of life data as a predictor of overall survival, the hazard ratios were 1.60 for low physical function, 1.54 for low role function, 1.55 for global health status, 2.37 for worst vs. least AGIS, and 1.75 for intermediate vs. least AGIS. After adjusting for all of these clinical factors, the multivariable analysis showed that low physical function, role function, and global health status, and worst AGIS remained statistically significant predictors of overall survival (HR, 1,45, 1.37, 1.34, 1.49, and 1.49, respectively). Median overall survival was 7 vs. 12 months in those with lower vs. higher physical function, role function, and global health status, 9 months vs. 14 months for those with lower vs. higher role function scores, and 8, 11, and 18 months in those with worst, intermediate, and least AGIS.

A sensitivity analysis supported the validity of the cut-points used for each of these scores, Dr. Roncolato noted.

As for early cessation of chemotherapy, 110 of the 570 women (19%) stopped chemotherapy within 8 weeks. Most (46%) stopped due to disease progression; other reasons for early cessation included death (18%), patient preference (12%), “other” (12%), adverse event (7%), and clinician preference (6%).

In these women, median progression-free survival and median overall survival were 1.3 months and 2.9 months, respectively, Dr. Roncolato said.

On univariable analysis, the same four quality of life domains (physical function, role function, global health status, and AGIS) each were significantly associated with overall survival (odds ratios were 2.45 for low physical function, 2.71 for low role function, 2.38 for global health status, 2.31 for worst vs. least AGIS, and 1.17 for intermediate vs. least AGIS).

Most patients with ovarian cancer have advanced stage disease at diagnosis and develop recurrent disease despite initial response, and most ultimately develop platinum resistant/refractory disease, Dr. Roncolato said.

The goals of treatment are to improve length and quality of life, but response rates are low; median progression-free survival is 3 months, and median overall survival is less than 12 months, she noted.

“To date there is no evidence that chemotherapy actually increases overall survival in the resistant/refractory setting, and one of our biggest challenges is identifying the patients who are most and least likely to benefit,” she said, adding that over the last decade, little has changed in terms of chemotherapy outcomes remaining poor in patients with PRR-ROC (median overall survival of about 45% at 12 months).

A substantial number of patients stop treatment early.

The Symptom Benefit Study was designed based on a recommendation of the 3rd GCIG Ovarian Cancer Consensus meeting, which called for more robust and reliable methods to quantify symptom improvement in patients with platinum-resistant/refractory ovarian cancer. The primary aim of the study was to develop criteria for quantifying symptom benefit for clinical trials in such patients. The initial portion of the study was known as MOST (Measure of Ovarian Cancer Symptoms and Treatment Concerns). The aim of the current portion of the study was to identify baseline characteristics associated with early cessation of chemotherapy and with poor overall survival.

Patients included in the study were women with PRR-ROC and patients receiving a third or subsequent line of treatment. All had a life expectancy of more than 3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3.

Quality of life measures, including EORTC QLQ-C30, QLQ-OV28, and others were performed at baseline and before each cycle of chemotherapy.

“The health-related quality of life scores identified a subset of women with resistant/refractory disease who have a very poor prognosis. It’s more informative than a clinician-assigned ECOG performance status, and including baseline health-related quality of life together with clinical prognostic factors improved the prediction of survival in women with PRR-ROC,” Dr. Roncolato said, adding that having this additional prognostic information could improve stratification in clinical trials, patient-doctor communication about prognosis, and clinical decision-making.

This study was funded by the Australian National Health and Medical Research Council. Dr. Roncolato reported having no disclosures.

[email protected]

CHICAGO – Physical function, role function, global health status and abdominal/gastrointestinal symptoms (AGIS) each predicted overall survival and were significantly associated with the early cessation of chemotherapy among women with platinum-resistant/refractory recurrent ovarian cancer in the Gynecologic Cancer InterGroup (GCIG) Symptom Benefit Study.

The findings from the international prospective cohort study suggest that baseline assessment of quality of life could help identify patients with platinum-resistant/refractory recurrent ovarian cancer (PRR-ROC) who are unlikely to benefit from palliative chemotherapy, Dr. Felicia Roncolato reported at the annual meeting of the American Society of Clinical Oncology.

In 570 women with PRR-ROC enrolled in the Symptom Benefit Study, median overall survival was 11.1 months and median progression-free survival was 3.6 months.

Factors shown on multivariable analysis to predict overall survival included hemoglobin (hazard ratio, 0.94 per 10 g/L increase), ascites (HR, 1.60), AGIS (HR, 1.24), platelets (HR, 1.10 per 100 x 10⁹ unit increase), Log CA125 (HR, 1.18 per unit increase), and neutrophil:lymphocyte ratio (HR, 1.79 for 5 or more). These were all statistically significant predictors of overall survival, said Dr. Roncolato of St. George Hospital, Sydney.

As for baseline quality of life data as a predictor of overall survival, the hazard ratios were 1.60 for low physical function, 1.54 for low role function, 1.55 for global health status, 2.37 for worst vs. least AGIS, and 1.75 for intermediate vs. least AGIS. After adjusting for all of these clinical factors, the multivariable analysis showed that low physical function, role function, and global health status, and worst AGIS remained statistically significant predictors of overall survival (HR, 1,45, 1.37, 1.34, 1.49, and 1.49, respectively). Median overall survival was 7 vs. 12 months in those with lower vs. higher physical function, role function, and global health status, 9 months vs. 14 months for those with lower vs. higher role function scores, and 8, 11, and 18 months in those with worst, intermediate, and least AGIS.

A sensitivity analysis supported the validity of the cut-points used for each of these scores, Dr. Roncolato noted.

As for early cessation of chemotherapy, 110 of the 570 women (19%) stopped chemotherapy within 8 weeks. Most (46%) stopped due to disease progression; other reasons for early cessation included death (18%), patient preference (12%), “other” (12%), adverse event (7%), and clinician preference (6%).

In these women, median progression-free survival and median overall survival were 1.3 months and 2.9 months, respectively, Dr. Roncolato said.

On univariable analysis, the same four quality of life domains (physical function, role function, global health status, and AGIS) each were significantly associated with overall survival (odds ratios were 2.45 for low physical function, 2.71 for low role function, 2.38 for global health status, 2.31 for worst vs. least AGIS, and 1.17 for intermediate vs. least AGIS).

Most patients with ovarian cancer have advanced stage disease at diagnosis and develop recurrent disease despite initial response, and most ultimately develop platinum resistant/refractory disease, Dr. Roncolato said.

The goals of treatment are to improve length and quality of life, but response rates are low; median progression-free survival is 3 months, and median overall survival is less than 12 months, she noted.

“To date there is no evidence that chemotherapy actually increases overall survival in the resistant/refractory setting, and one of our biggest challenges is identifying the patients who are most and least likely to benefit,” she said, adding that over the last decade, little has changed in terms of chemotherapy outcomes remaining poor in patients with PRR-ROC (median overall survival of about 45% at 12 months).

A substantial number of patients stop treatment early.

The Symptom Benefit Study was designed based on a recommendation of the 3rd GCIG Ovarian Cancer Consensus meeting, which called for more robust and reliable methods to quantify symptom improvement in patients with platinum-resistant/refractory ovarian cancer. The primary aim of the study was to develop criteria for quantifying symptom benefit for clinical trials in such patients. The initial portion of the study was known as MOST (Measure of Ovarian Cancer Symptoms and Treatment Concerns). The aim of the current portion of the study was to identify baseline characteristics associated with early cessation of chemotherapy and with poor overall survival.

Patients included in the study were women with PRR-ROC and patients receiving a third or subsequent line of treatment. All had a life expectancy of more than 3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3.

Quality of life measures, including EORTC QLQ-C30, QLQ-OV28, and others were performed at baseline and before each cycle of chemotherapy.

“The health-related quality of life scores identified a subset of women with resistant/refractory disease who have a very poor prognosis. It’s more informative than a clinician-assigned ECOG performance status, and including baseline health-related quality of life together with clinical prognostic factors improved the prediction of survival in women with PRR-ROC,” Dr. Roncolato said, adding that having this additional prognostic information could improve stratification in clinical trials, patient-doctor communication about prognosis, and clinical decision-making.

This study was funded by the Australian National Health and Medical Research Council. Dr. Roncolato reported having no disclosures.

[email protected]

CHICAGO – Physical function, role function, global health status and abdominal/gastrointestinal symptoms (AGIS) each predicted overall survival and were significantly associated with the early cessation of chemotherapy among women with platinum-resistant/refractory recurrent ovarian cancer in the Gynecologic Cancer InterGroup (GCIG) Symptom Benefit Study.

The findings from the international prospective cohort study suggest that baseline assessment of quality of life could help identify patients with platinum-resistant/refractory recurrent ovarian cancer (PRR-ROC) who are unlikely to benefit from palliative chemotherapy, Dr. Felicia Roncolato reported at the annual meeting of the American Society of Clinical Oncology.

In 570 women with PRR-ROC enrolled in the Symptom Benefit Study, median overall survival was 11.1 months and median progression-free survival was 3.6 months.

Factors shown on multivariable analysis to predict overall survival included hemoglobin (hazard ratio, 0.94 per 10 g/L increase), ascites (HR, 1.60), AGIS (HR, 1.24), platelets (HR, 1.10 per 100 x 10⁹ unit increase), Log CA125 (HR, 1.18 per unit increase), and neutrophil:lymphocyte ratio (HR, 1.79 for 5 or more). These were all statistically significant predictors of overall survival, said Dr. Roncolato of St. George Hospital, Sydney.

As for baseline quality of life data as a predictor of overall survival, the hazard ratios were 1.60 for low physical function, 1.54 for low role function, 1.55 for global health status, 2.37 for worst vs. least AGIS, and 1.75 for intermediate vs. least AGIS. After adjusting for all of these clinical factors, the multivariable analysis showed that low physical function, role function, and global health status, and worst AGIS remained statistically significant predictors of overall survival (HR, 1,45, 1.37, 1.34, 1.49, and 1.49, respectively). Median overall survival was 7 vs. 12 months in those with lower vs. higher physical function, role function, and global health status, 9 months vs. 14 months for those with lower vs. higher role function scores, and 8, 11, and 18 months in those with worst, intermediate, and least AGIS.

A sensitivity analysis supported the validity of the cut-points used for each of these scores, Dr. Roncolato noted.

As for early cessation of chemotherapy, 110 of the 570 women (19%) stopped chemotherapy within 8 weeks. Most (46%) stopped due to disease progression; other reasons for early cessation included death (18%), patient preference (12%), “other” (12%), adverse event (7%), and clinician preference (6%).

In these women, median progression-free survival and median overall survival were 1.3 months and 2.9 months, respectively, Dr. Roncolato said.

On univariable analysis, the same four quality of life domains (physical function, role function, global health status, and AGIS) each were significantly associated with overall survival (odds ratios were 2.45 for low physical function, 2.71 for low role function, 2.38 for global health status, 2.31 for worst vs. least AGIS, and 1.17 for intermediate vs. least AGIS).

Most patients with ovarian cancer have advanced stage disease at diagnosis and develop recurrent disease despite initial response, and most ultimately develop platinum resistant/refractory disease, Dr. Roncolato said.

The goals of treatment are to improve length and quality of life, but response rates are low; median progression-free survival is 3 months, and median overall survival is less than 12 months, she noted.

“To date there is no evidence that chemotherapy actually increases overall survival in the resistant/refractory setting, and one of our biggest challenges is identifying the patients who are most and least likely to benefit,” she said, adding that over the last decade, little has changed in terms of chemotherapy outcomes remaining poor in patients with PRR-ROC (median overall survival of about 45% at 12 months).

A substantial number of patients stop treatment early.

The Symptom Benefit Study was designed based on a recommendation of the 3rd GCIG Ovarian Cancer Consensus meeting, which called for more robust and reliable methods to quantify symptom improvement in patients with platinum-resistant/refractory ovarian cancer. The primary aim of the study was to develop criteria for quantifying symptom benefit for clinical trials in such patients. The initial portion of the study was known as MOST (Measure of Ovarian Cancer Symptoms and Treatment Concerns). The aim of the current portion of the study was to identify baseline characteristics associated with early cessation of chemotherapy and with poor overall survival.

Patients included in the study were women with PRR-ROC and patients receiving a third or subsequent line of treatment. All had a life expectancy of more than 3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3.

Quality of life measures, including EORTC QLQ-C30, QLQ-OV28, and others were performed at baseline and before each cycle of chemotherapy.

“The health-related quality of life scores identified a subset of women with resistant/refractory disease who have a very poor prognosis. It’s more informative than a clinician-assigned ECOG performance status, and including baseline health-related quality of life together with clinical prognostic factors improved the prediction of survival in women with PRR-ROC,” Dr. Roncolato said, adding that having this additional prognostic information could improve stratification in clinical trials, patient-doctor communication about prognosis, and clinical decision-making.

This study was funded by the Australian National Health and Medical Research Council. Dr. Roncolato reported having no disclosures.

[email protected]

Cognitive-behavioral therapy, lisdexamfetamine, and second-generation antidepressants are the most effective treatments for adult binge-eating disorder, a systematic review by Kimberly A. Brownley, PhD, and her associates found.

A total of 34 trials were included in the review. Patients who received therapist-led cognitive-behavioral therapy (CBT) achieved binge eating abstinence at a rate of 58.8%, compared with 11.2% of those on a wait list. Just over 40% of patients achieved abstinence on lisdexamfetamine, compared with 14.9% on a placebo, and 39.9% of patients achieved abstinence on second-generation antipsychotics (SGAs), compared with 23.6% on a placebo.

BananaStock/thinkstockphotos.com

Total eating-related obsessions and compulsions were significantly reduced in patients receiving lisdexamfetamine and SGAs, and CBT significantly improved eating-related psychopathology. Body mass index was not reduced in patients receiving SGAs or CBT, but was reduced in those receiving lisdexamfetamine and topiramate, compared with placebo. Symptoms of depression were reduced by SGAs, but not by CBT.

In a related editorial, Dr. Michael J. Devlin of the New York State Psychiatric Institute and Columbia University, New York, praised the review by Dr. Brownley and her associates as an expert summary of the “current evidence on binge-eating disorder.” He went on to make the connection between eating disorders and obesity, and discuss the prospects for interventions.

“The seeds of unhealthy eating that eventually lead to obesity, disordered eating, or both often are sown during childhood or adolescence, and interventions at the community and family levels in the context of enlightened public policy likely would yield significant benefit,” Dr. Devlin wrote. “Only by understanding binge-eating disorder at various levels of analysis and through different professional lenses will we ensure that its life span is shortened, to the benefit of our own.”

Find the full study (doi: 10.7326/M15-2455) and editorial (doi: 10.7326/M16-1398) in the Annals of Internal Medicine.

[email protected]

Cognitive-behavioral therapy, lisdexamfetamine, and second-generation antidepressants are the most effective treatments for adult binge-eating disorder, a systematic review by Kimberly A. Brownley, PhD, and her associates found.

A total of 34 trials were included in the review. Patients who received therapist-led cognitive-behavioral therapy (CBT) achieved binge eating abstinence at a rate of 58.8%, compared with 11.2% of those on a wait list. Just over 40% of patients achieved abstinence on lisdexamfetamine, compared with 14.9% on a placebo, and 39.9% of patients achieved abstinence on second-generation antipsychotics (SGAs), compared with 23.6% on a placebo.

BananaStock/thinkstockphotos.com

Total eating-related obsessions and compulsions were significantly reduced in patients receiving lisdexamfetamine and SGAs, and CBT significantly improved eating-related psychopathology. Body mass index was not reduced in patients receiving SGAs or CBT, but was reduced in those receiving lisdexamfetamine and topiramate, compared with placebo. Symptoms of depression were reduced by SGAs, but not by CBT.

In a related editorial, Dr. Michael J. Devlin of the New York State Psychiatric Institute and Columbia University, New York, praised the review by Dr. Brownley and her associates as an expert summary of the “current evidence on binge-eating disorder.” He went on to make the connection between eating disorders and obesity, and discuss the prospects for interventions.

“The seeds of unhealthy eating that eventually lead to obesity, disordered eating, or both often are sown during childhood or adolescence, and interventions at the community and family levels in the context of enlightened public policy likely would yield significant benefit,” Dr. Devlin wrote. “Only by understanding binge-eating disorder at various levels of analysis and through different professional lenses will we ensure that its life span is shortened, to the benefit of our own.”

Find the full study (doi: 10.7326/M15-2455) and editorial (doi: 10.7326/M16-1398) in the Annals of Internal Medicine.

[email protected]

Cognitive-behavioral therapy, lisdexamfetamine, and second-generation antidepressants are the most effective treatments for adult binge-eating disorder, a systematic review by Kimberly A. Brownley, PhD, and her associates found.

A total of 34 trials were included in the review. Patients who received therapist-led cognitive-behavioral therapy (CBT) achieved binge eating abstinence at a rate of 58.8%, compared with 11.2% of those on a wait list. Just over 40% of patients achieved abstinence on lisdexamfetamine, compared with 14.9% on a placebo, and 39.9% of patients achieved abstinence on second-generation antipsychotics (SGAs), compared with 23.6% on a placebo.

BananaStock/thinkstockphotos.com

Total eating-related obsessions and compulsions were significantly reduced in patients receiving lisdexamfetamine and SGAs, and CBT significantly improved eating-related psychopathology. Body mass index was not reduced in patients receiving SGAs or CBT, but was reduced in those receiving lisdexamfetamine and topiramate, compared with placebo. Symptoms of depression were reduced by SGAs, but not by CBT.

In a related editorial, Dr. Michael J. Devlin of the New York State Psychiatric Institute and Columbia University, New York, praised the review by Dr. Brownley and her associates as an expert summary of the “current evidence on binge-eating disorder.” He went on to make the connection between eating disorders and obesity, and discuss the prospects for interventions.

“The seeds of unhealthy eating that eventually lead to obesity, disordered eating, or both often are sown during childhood or adolescence, and interventions at the community and family levels in the context of enlightened public policy likely would yield significant benefit,” Dr. Devlin wrote. “Only by understanding binge-eating disorder at various levels of analysis and through different professional lenses will we ensure that its life span is shortened, to the benefit of our own.”

Find the full study (doi: 10.7326/M15-2455) and editorial (doi: 10.7326/M16-1398) in the Annals of Internal Medicine.

[email protected]

Lumbar radiculopathy is a common problem encountered by orthopedic surgeons, and typically presents with lower back or buttock pain radiating down the leg.¹ While the most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis, the differential diagnosis for lower extremity pain is broad and can be musculoskeletal, vascular, neurologic, or inflammatory in nature.^1,2 Differentiating between orthopedic, neurologic, and vascular causes of leg pain, such as peripheral artery disease (PAD), can sometimes be challenging. This is especially true in aortoiliac PAD, which can present with hip, buttock, and thigh pain. Dorsalis pedis pulses can be palpable due to collateral circulation. A careful history and physical examination is crucial to the correct diagnosis. The history should clearly document the nature of the pain, details of walking impairment, and the alleviating effects of standing still or positional changes. A complete neurovascular examination should include observations regarding the skin, hair, and nails, examination of dorsal pedis, popliteal, and femoral pulses in comparison to the contralateral side, and documentation of dural tension signs. Misdiagnoses can send the patient down a path of unnecessary tests, unindicated procedures, and ultimately, a delay in definitive diagnosis and treatment.¹

To our knowledge, this is the first report on a series of patients with thigh pain initially diagnosed as radiculopathy who underwent unproductive diagnostic tests and procedures, and ultimately were given delayed diagnoses of aortoiliac PAD. The patients provided written informed consent for print and electronic publication of these case reports.

Case 1

An 81-year-old woman with a medical history notable for hypertension, hyperlipidemia, and stroke initially presented to an outside orthopedic institution with complaints of several months of lower back and right hip, thigh, and leg pain when walking. She did not report any history of night pain, weakness, or numbness. Examination at the time was notable for painful back extension, 4/5 hip flexion strength on the right compared to 5/5 on the left, but symmetric reflexes and negative dural tension signs. X-rays showed multilevel degenerative disc disease of the lumbar spine, and magnetic resonance imaging (MRI) showed a small L3/4 disc protrusion causing impingement of the L4 nerve root.

A transforaminal epidural steroid injection at the L4 level was performed with minimal resolution of symptoms. Several months later, right-sided intra-articular facet injections were performed at the L4/5 and L5/S1 levels, again with minimal relief of symptoms. At this point, the patient was sent for further physical therapy.

Over a year after symptom onset, the patient presented to our institution and was evaluated by a vascular surgeon. Physical examination was notable for 1+ femoral artery and dorsal pedis pulses on the right side, compared to 2+ on the left. An aortoiliac duplex ultrasound showed severe significant stenosis of the right common iliac artery (>75%).

The patient underwent a right common iliac artery angioplasty and stenting (Figures 1A, 1B), which resolved her symptoms.

Case 2

A 65-year-old man, who is a former smoker with a medical history notable for hyperlipidemia and coronary artery disease status post myocardial infarction, presented with a long history of right leg pain. He underwent a L5/S1 anterior posterior fusion at an outside institution and did well for about 5 years after the procedure (Figures 2A, 2B). The pain returned and he underwent several years of physical therapy, epidural steroid injections, and implantation of a spinal cord stimulator with no improvement. He reported right leg pain with minimal back pain, primarily in the thigh and not radiating to the feet and toes. The pain limited him from walking more than 1 block. On examination, strength was 5/5 bilaterally. Pulse examination was notable for lack of dorsalis pedis/posterior tibial pulses bilaterally. He had no bowel or bladder dysfunction.

Computed tomography myelogram showed a moderate amount of stenosis at L3/4 and L4/5. He was sent for evaluation by a vascular surgeon. Arterial duplex ultrasound showed significant stenosis of the right common iliac artery.

Angioplasty was attempted but vascular surgery was unable to cross the lesion (Figures 3A, 3B), and the patient ultimately had a femoral-femoral bypass, which resolved his leg pain.

Case 3

A 78-year-old woman, nonsmoker, presented with a 1-year history of left buttock and thigh pain exacerbated by ambulation. Ambulation was limited to 2 blocks. The patient was being worked up for spinal and hip etiologies of pain at an outside hospital. MRI revealed a mild posterior disc herniation at L3/4 and L4/5 and moderate narrowing of the spinal canal. She underwent 2 epidural steroid injections with no improvement. The patient’s relative, a physician, suggested that the patient receive a vascular surgery consultation, and the patient ultimately presented to our institution for evaluation by vascular surgery.

The physical examination was significant for a 1+ dorsal pedis pulse on the left compared to 2+ on the right. Moreover, the patient only demonstrated trace L femoral pulse compared to the right. Strength was 5/5 bilaterally.

The patient was taken to the operating room for angioplasty and stenting of the left common iliac artery (Figures 4A, 4B). This provided immediate symptom relief, and she has remained asymptomatic.

Discussion

Lumbar radiculopathy is a common diagnosis encountered by orthopedic surgeons. Although the diagnosis can appear to be straightforward in a patient presenting with lower back and leg pain, the etiology of lower back and leg pain can be extremely varied, and can be musculoskeletal, neurologic, vascular, rheumatologic, or oncologic in origin.¹ In particular, differentiating between radiculopathy and vascular claudication can sometimes be challenging.

The 2 most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis.¹ Lumbar disc herniation results from tear in the annulus of the intervertebral disc, resulting in herniation of disc material into the spinal canal causing compression and irritation of spinal nerve roots.¹ Spinal stenosis is narrowing of the spinal canal that produces compression of neural elements before they exit the neural foramen.³ Adult degenerative spinal stenosis is most often caused by osteophytes from the facet joints or hypertrophy of the ligamentum flavum, and can be broadly categorized into central spinal stenosis or lateral spinal stenosis.

PAD is defined as progressive stenosis or occlusion, or aneurysmal dilation of noncoronary arteries.² When PAD affects the vessels of the lower extremities, the symptoms typically manifest as intermittent claudication, which is exercise-induced ischemic pain in the lower extremity that is relieved by rest.² As the disease progresses, symptoms can progress to rest pain, ulceration, and, eventually, gangrene. The most common cause of PAD is atherosclerosis, and the risk factors include smoking, hypertension, diabetes, and hyperlipidemia. The prevalence of PAD rises sharply with age, starting from <3% in ages less than 60 years to >20% in ages 75 years and older.⁴

A detailed and pertinent history from the patient provides important information for differentiating radiculopathy and neurogenic claudication from vascular claudication. Patients with lumbar radiculopathy typically report pain in the lower back radiating down the leg past the knee in a dermatomal distribution. The pain often begins soon if not immediately after activity, but often takes time for relief onset after rest. Positional changes in the back such as flexion can provide relief.² Patients with neurogenic claudication from central spinal stenosis can present with bilateral thigh pain from prolonged standing and activity that is alleviated with flexion or stooping.³ Patients may admit to a positive “shopping cart sign,” with increased walking comfort stooped forward with hands on a shopping cart.

In contrast, patients with vascular claudication often report pain in the calf, thigh, or hip, but rarely in the foot. The location of pain varies with area of stenosis; generally, patients with superficial femoral artery occlusion present with calf claudication, while patients with aortoiliac disease present with buttock and thigh pain. The pain typically occurs after a very reproducible length of walking, and is relieved by cessation of walking, often even if the patient remains standing. Back positioning should have no effect on the pain.^2-5

Physical examination should begin with observation of the patient’s gait and posture, which may be hunched over in the setting of spinal stenosis. Examination of the patient’s skin may show loss of hair, shiny skin, or atrophic changes suggestive of vascular disease (Figure 5).¹ Prior to proceeding to a spine examination, palpating the trochanteric bursa and testing for hip range of motion is important to rule out intra-articular hip pathology and trochanteric bursitis as common causes of pain in the area. Patients with radiculopathy may show sensory disturbances in a dermatomal distribution, muscular weakness at the corresponding spinal level, and decreased deep tendon reflexes. The straight leg raise test can elicit signs of nerve root tension. A careful examination of bilateral lower extremity pulses at the dorsal pedis, popliteal, and femoral levels can help identify any asymmetric or decreased pulses that would indicate peripheral vascular disease. With chronic aortoiliac disease, it is important to check for femoral pulses, given the dorsal pedis pulse can be present due to collateral circulation. And finally, the ankle brachial index (ABI), measured as the ratio of the systolic pressure at the ankle divided by the systolic pressure at the arm, is a good screening test for PAD.⁶ A normal ABI is >1.

A thorough history and physical examination can elicit important information that is helpful in evaluating orthopedic patients, especially to differentiate between spinal and vascular causes of leg pain. This can help avoid misdiagnoses, which result in unnecessary tests, procedures, and wasted time. Don’t forget the pulses!

Lumbar radiculopathy is a common problem encountered by orthopedic surgeons, and typically presents with lower back or buttock pain radiating down the leg.¹ While the most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis, the differential diagnosis for lower extremity pain is broad and can be musculoskeletal, vascular, neurologic, or inflammatory in nature.^1,2 Differentiating between orthopedic, neurologic, and vascular causes of leg pain, such as peripheral artery disease (PAD), can sometimes be challenging. This is especially true in aortoiliac PAD, which can present with hip, buttock, and thigh pain. Dorsalis pedis pulses can be palpable due to collateral circulation. A careful history and physical examination is crucial to the correct diagnosis. The history should clearly document the nature of the pain, details of walking impairment, and the alleviating effects of standing still or positional changes. A complete neurovascular examination should include observations regarding the skin, hair, and nails, examination of dorsal pedis, popliteal, and femoral pulses in comparison to the contralateral side, and documentation of dural tension signs. Misdiagnoses can send the patient down a path of unnecessary tests, unindicated procedures, and ultimately, a delay in definitive diagnosis and treatment.¹

To our knowledge, this is the first report on a series of patients with thigh pain initially diagnosed as radiculopathy who underwent unproductive diagnostic tests and procedures, and ultimately were given delayed diagnoses of aortoiliac PAD. The patients provided written informed consent for print and electronic publication of these case reports.

Case 1

An 81-year-old woman with a medical history notable for hypertension, hyperlipidemia, and stroke initially presented to an outside orthopedic institution with complaints of several months of lower back and right hip, thigh, and leg pain when walking. She did not report any history of night pain, weakness, or numbness. Examination at the time was notable for painful back extension, 4/5 hip flexion strength on the right compared to 5/5 on the left, but symmetric reflexes and negative dural tension signs. X-rays showed multilevel degenerative disc disease of the lumbar spine, and magnetic resonance imaging (MRI) showed a small L3/4 disc protrusion causing impingement of the L4 nerve root.

A transforaminal epidural steroid injection at the L4 level was performed with minimal resolution of symptoms. Several months later, right-sided intra-articular facet injections were performed at the L4/5 and L5/S1 levels, again with minimal relief of symptoms. At this point, the patient was sent for further physical therapy.

Over a year after symptom onset, the patient presented to our institution and was evaluated by a vascular surgeon. Physical examination was notable for 1+ femoral artery and dorsal pedis pulses on the right side, compared to 2+ on the left. An aortoiliac duplex ultrasound showed severe significant stenosis of the right common iliac artery (>75%).

The patient underwent a right common iliac artery angioplasty and stenting (Figures 1A, 1B), which resolved her symptoms.

Case 2

A 65-year-old man, who is a former smoker with a medical history notable for hyperlipidemia and coronary artery disease status post myocardial infarction, presented with a long history of right leg pain. He underwent a L5/S1 anterior posterior fusion at an outside institution and did well for about 5 years after the procedure (Figures 2A, 2B). The pain returned and he underwent several years of physical therapy, epidural steroid injections, and implantation of a spinal cord stimulator with no improvement. He reported right leg pain with minimal back pain, primarily in the thigh and not radiating to the feet and toes. The pain limited him from walking more than 1 block. On examination, strength was 5/5 bilaterally. Pulse examination was notable for lack of dorsalis pedis/posterior tibial pulses bilaterally. He had no bowel or bladder dysfunction.

Computed tomography myelogram showed a moderate amount of stenosis at L3/4 and L4/5. He was sent for evaluation by a vascular surgeon. Arterial duplex ultrasound showed significant stenosis of the right common iliac artery.

Angioplasty was attempted but vascular surgery was unable to cross the lesion (Figures 3A, 3B), and the patient ultimately had a femoral-femoral bypass, which resolved his leg pain.

Case 3

A 78-year-old woman, nonsmoker, presented with a 1-year history of left buttock and thigh pain exacerbated by ambulation. Ambulation was limited to 2 blocks. The patient was being worked up for spinal and hip etiologies of pain at an outside hospital. MRI revealed a mild posterior disc herniation at L3/4 and L4/5 and moderate narrowing of the spinal canal. She underwent 2 epidural steroid injections with no improvement. The patient’s relative, a physician, suggested that the patient receive a vascular surgery consultation, and the patient ultimately presented to our institution for evaluation by vascular surgery.

The physical examination was significant for a 1+ dorsal pedis pulse on the left compared to 2+ on the right. Moreover, the patient only demonstrated trace L femoral pulse compared to the right. Strength was 5/5 bilaterally.

The patient was taken to the operating room for angioplasty and stenting of the left common iliac artery (Figures 4A, 4B). This provided immediate symptom relief, and she has remained asymptomatic.

Discussion

Lumbar radiculopathy is a common diagnosis encountered by orthopedic surgeons. Although the diagnosis can appear to be straightforward in a patient presenting with lower back and leg pain, the etiology of lower back and leg pain can be extremely varied, and can be musculoskeletal, neurologic, vascular, rheumatologic, or oncologic in origin.¹ In particular, differentiating between radiculopathy and vascular claudication can sometimes be challenging.

The 2 most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis.¹ Lumbar disc herniation results from tear in the annulus of the intervertebral disc, resulting in herniation of disc material into the spinal canal causing compression and irritation of spinal nerve roots.¹ Spinal stenosis is narrowing of the spinal canal that produces compression of neural elements before they exit the neural foramen.³ Adult degenerative spinal stenosis is most often caused by osteophytes from the facet joints or hypertrophy of the ligamentum flavum, and can be broadly categorized into central spinal stenosis or lateral spinal stenosis.

PAD is defined as progressive stenosis or occlusion, or aneurysmal dilation of noncoronary arteries.² When PAD affects the vessels of the lower extremities, the symptoms typically manifest as intermittent claudication, which is exercise-induced ischemic pain in the lower extremity that is relieved by rest.² As the disease progresses, symptoms can progress to rest pain, ulceration, and, eventually, gangrene. The most common cause of PAD is atherosclerosis, and the risk factors include smoking, hypertension, diabetes, and hyperlipidemia. The prevalence of PAD rises sharply with age, starting from <3% in ages less than 60 years to >20% in ages 75 years and older.⁴

A detailed and pertinent history from the patient provides important information for differentiating radiculopathy and neurogenic claudication from vascular claudication. Patients with lumbar radiculopathy typically report pain in the lower back radiating down the leg past the knee in a dermatomal distribution. The pain often begins soon if not immediately after activity, but often takes time for relief onset after rest. Positional changes in the back such as flexion can provide relief.² Patients with neurogenic claudication from central spinal stenosis can present with bilateral thigh pain from prolonged standing and activity that is alleviated with flexion or stooping.³ Patients may admit to a positive “shopping cart sign,” with increased walking comfort stooped forward with hands on a shopping cart.

In contrast, patients with vascular claudication often report pain in the calf, thigh, or hip, but rarely in the foot. The location of pain varies with area of stenosis; generally, patients with superficial femoral artery occlusion present with calf claudication, while patients with aortoiliac disease present with buttock and thigh pain. The pain typically occurs after a very reproducible length of walking, and is relieved by cessation of walking, often even if the patient remains standing. Back positioning should have no effect on the pain.^2-5

Physical examination should begin with observation of the patient’s gait and posture, which may be hunched over in the setting of spinal stenosis. Examination of the patient’s skin may show loss of hair, shiny skin, or atrophic changes suggestive of vascular disease (Figure 5).¹ Prior to proceeding to a spine examination, palpating the trochanteric bursa and testing for hip range of motion is important to rule out intra-articular hip pathology and trochanteric bursitis as common causes of pain in the area. Patients with radiculopathy may show sensory disturbances in a dermatomal distribution, muscular weakness at the corresponding spinal level, and decreased deep tendon reflexes. The straight leg raise test can elicit signs of nerve root tension. A careful examination of bilateral lower extremity pulses at the dorsal pedis, popliteal, and femoral levels can help identify any asymmetric or decreased pulses that would indicate peripheral vascular disease. With chronic aortoiliac disease, it is important to check for femoral pulses, given the dorsal pedis pulse can be present due to collateral circulation. And finally, the ankle brachial index (ABI), measured as the ratio of the systolic pressure at the ankle divided by the systolic pressure at the arm, is a good screening test for PAD.⁶ A normal ABI is >1.

A thorough history and physical examination can elicit important information that is helpful in evaluating orthopedic patients, especially to differentiate between spinal and vascular causes of leg pain. This can help avoid misdiagnoses, which result in unnecessary tests, procedures, and wasted time. Don’t forget the pulses!

Lumbar radiculopathy is a common problem encountered by orthopedic surgeons, and typically presents with lower back or buttock pain radiating down the leg.¹ While the most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis, the differential diagnosis for lower extremity pain is broad and can be musculoskeletal, vascular, neurologic, or inflammatory in nature.^1,2 Differentiating between orthopedic, neurologic, and vascular causes of leg pain, such as peripheral artery disease (PAD), can sometimes be challenging. This is especially true in aortoiliac PAD, which can present with hip, buttock, and thigh pain. Dorsalis pedis pulses can be palpable due to collateral circulation. A careful history and physical examination is crucial to the correct diagnosis. The history should clearly document the nature of the pain, details of walking impairment, and the alleviating effects of standing still or positional changes. A complete neurovascular examination should include observations regarding the skin, hair, and nails, examination of dorsal pedis, popliteal, and femoral pulses in comparison to the contralateral side, and documentation of dural tension signs. Misdiagnoses can send the patient down a path of unnecessary tests, unindicated procedures, and ultimately, a delay in definitive diagnosis and treatment.¹

To our knowledge, this is the first report on a series of patients with thigh pain initially diagnosed as radiculopathy who underwent unproductive diagnostic tests and procedures, and ultimately were given delayed diagnoses of aortoiliac PAD. The patients provided written informed consent for print and electronic publication of these case reports.

Case 1

An 81-year-old woman with a medical history notable for hypertension, hyperlipidemia, and stroke initially presented to an outside orthopedic institution with complaints of several months of lower back and right hip, thigh, and leg pain when walking. She did not report any history of night pain, weakness, or numbness. Examination at the time was notable for painful back extension, 4/5 hip flexion strength on the right compared to 5/5 on the left, but symmetric reflexes and negative dural tension signs. X-rays showed multilevel degenerative disc disease of the lumbar spine, and magnetic resonance imaging (MRI) showed a small L3/4 disc protrusion causing impingement of the L4 nerve root.

A transforaminal epidural steroid injection at the L4 level was performed with minimal resolution of symptoms. Several months later, right-sided intra-articular facet injections were performed at the L4/5 and L5/S1 levels, again with minimal relief of symptoms. At this point, the patient was sent for further physical therapy.

Over a year after symptom onset, the patient presented to our institution and was evaluated by a vascular surgeon. Physical examination was notable for 1+ femoral artery and dorsal pedis pulses on the right side, compared to 2+ on the left. An aortoiliac duplex ultrasound showed severe significant stenosis of the right common iliac artery (>75%).

The patient underwent a right common iliac artery angioplasty and stenting (Figures 1A, 1B), which resolved her symptoms.

Case 2

A 65-year-old man, who is a former smoker with a medical history notable for hyperlipidemia and coronary artery disease status post myocardial infarction, presented with a long history of right leg pain. He underwent a L5/S1 anterior posterior fusion at an outside institution and did well for about 5 years after the procedure (Figures 2A, 2B). The pain returned and he underwent several years of physical therapy, epidural steroid injections, and implantation of a spinal cord stimulator with no improvement. He reported right leg pain with minimal back pain, primarily in the thigh and not radiating to the feet and toes. The pain limited him from walking more than 1 block. On examination, strength was 5/5 bilaterally. Pulse examination was notable for lack of dorsalis pedis/posterior tibial pulses bilaterally. He had no bowel or bladder dysfunction.

Computed tomography myelogram showed a moderate amount of stenosis at L3/4 and L4/5. He was sent for evaluation by a vascular surgeon. Arterial duplex ultrasound showed significant stenosis of the right common iliac artery.

Angioplasty was attempted but vascular surgery was unable to cross the lesion (Figures 3A, 3B), and the patient ultimately had a femoral-femoral bypass, which resolved his leg pain.

Case 3

A 78-year-old woman, nonsmoker, presented with a 1-year history of left buttock and thigh pain exacerbated by ambulation. Ambulation was limited to 2 blocks. The patient was being worked up for spinal and hip etiologies of pain at an outside hospital. MRI revealed a mild posterior disc herniation at L3/4 and L4/5 and moderate narrowing of the spinal canal. She underwent 2 epidural steroid injections with no improvement. The patient’s relative, a physician, suggested that the patient receive a vascular surgery consultation, and the patient ultimately presented to our institution for evaluation by vascular surgery.

The physical examination was significant for a 1+ dorsal pedis pulse on the left compared to 2+ on the right. Moreover, the patient only demonstrated trace L femoral pulse compared to the right. Strength was 5/5 bilaterally.

The patient was taken to the operating room for angioplasty and stenting of the left common iliac artery (Figures 4A, 4B). This provided immediate symptom relief, and she has remained asymptomatic.

Discussion

Lumbar radiculopathy is a common diagnosis encountered by orthopedic surgeons. Although the diagnosis can appear to be straightforward in a patient presenting with lower back and leg pain, the etiology of lower back and leg pain can be extremely varied, and can be musculoskeletal, neurologic, vascular, rheumatologic, or oncologic in origin.¹ In particular, differentiating between radiculopathy and vascular claudication can sometimes be challenging.

The 2 most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis.¹ Lumbar disc herniation results from tear in the annulus of the intervertebral disc, resulting in herniation of disc material into the spinal canal causing compression and irritation of spinal nerve roots.¹ Spinal stenosis is narrowing of the spinal canal that produces compression of neural elements before they exit the neural foramen.³ Adult degenerative spinal stenosis is most often caused by osteophytes from the facet joints or hypertrophy of the ligamentum flavum, and can be broadly categorized into central spinal stenosis or lateral spinal stenosis.

PAD is defined as progressive stenosis or occlusion, or aneurysmal dilation of noncoronary arteries.² When PAD affects the vessels of the lower extremities, the symptoms typically manifest as intermittent claudication, which is exercise-induced ischemic pain in the lower extremity that is relieved by rest.² As the disease progresses, symptoms can progress to rest pain, ulceration, and, eventually, gangrene. The most common cause of PAD is atherosclerosis, and the risk factors include smoking, hypertension, diabetes, and hyperlipidemia. The prevalence of PAD rises sharply with age, starting from <3% in ages less than 60 years to >20% in ages 75 years and older.⁴

A detailed and pertinent history from the patient provides important information for differentiating radiculopathy and neurogenic claudication from vascular claudication. Patients with lumbar radiculopathy typically report pain in the lower back radiating down the leg past the knee in a dermatomal distribution. The pain often begins soon if not immediately after activity, but often takes time for relief onset after rest. Positional changes in the back such as flexion can provide relief.² Patients with neurogenic claudication from central spinal stenosis can present with bilateral thigh pain from prolonged standing and activity that is alleviated with flexion or stooping.³ Patients may admit to a positive “shopping cart sign,” with increased walking comfort stooped forward with hands on a shopping cart.

In contrast, patients with vascular claudication often report pain in the calf, thigh, or hip, but rarely in the foot. The location of pain varies with area of stenosis; generally, patients with superficial femoral artery occlusion present with calf claudication, while patients with aortoiliac disease present with buttock and thigh pain. The pain typically occurs after a very reproducible length of walking, and is relieved by cessation of walking, often even if the patient remains standing. Back positioning should have no effect on the pain.^2-5

Physical examination should begin with observation of the patient’s gait and posture, which may be hunched over in the setting of spinal stenosis. Examination of the patient’s skin may show loss of hair, shiny skin, or atrophic changes suggestive of vascular disease (Figure 5).¹ Prior to proceeding to a spine examination, palpating the trochanteric bursa and testing for hip range of motion is important to rule out intra-articular hip pathology and trochanteric bursitis as common causes of pain in the area. Patients with radiculopathy may show sensory disturbances in a dermatomal distribution, muscular weakness at the corresponding spinal level, and decreased deep tendon reflexes. The straight leg raise test can elicit signs of nerve root tension. A careful examination of bilateral lower extremity pulses at the dorsal pedis, popliteal, and femoral levels can help identify any asymmetric or decreased pulses that would indicate peripheral vascular disease. With chronic aortoiliac disease, it is important to check for femoral pulses, given the dorsal pedis pulse can be present due to collateral circulation. And finally, the ankle brachial index (ABI), measured as the ratio of the systolic pressure at the ankle divided by the systolic pressure at the arm, is a good screening test for PAD.⁶ A normal ABI is >1.

A thorough history and physical examination can elicit important information that is helpful in evaluating orthopedic patients, especially to differentiate between spinal and vascular causes of leg pain. This can help avoid misdiagnoses, which result in unnecessary tests, procedures, and wasted time. Don’t forget the pulses!

Review the PDF of the fact sheet on eye findings in dermatologic conditions with board-relevant, easy-to-review material. This month's fact sheet will review ophthalmologic findings associated with inherited dermatologic conditions.

Practice Questions

1. Which type of EDS is most characteristically associated with blue sclerae and globe rupture?

a. arthrochalasia

b. classical

c. dermatosparaxis

d. hypermobility

e. kyphoscoliosis

2. Ankyloblepharon may be associated with mutation of which gene?

a. fibrillin 1

b. LMX1B

c. NF1

d. p53

e. p63

3. Which is a characteristic ocular tumor in patients with tuberous sclerosis complex?

a. congenital hypertrophy of retinal pigment epithelium

b. phakoma

c. pigmented iris hamartoma

d. pinguecula

e. pterygium

4. Which syndrome is not associated with blue sclerae?

a. EDS type 6

b. lipoid proteinosis

c. Marfan syndrome

d. osteogenesis imperfecta type II

e. pseudoxanthoma elasticum

5. Which term describes white spots at the periphery of the iris?

a. Brushfield spots

b. coloboma

c. Kayser-Fleischer rings

d. Lester iris

e. Lisch nodules

Answers to practice questions provided on next page

Practice Question Answers

1. Which type of EDS is most characteristically associated with blue sclerae and globe rupture?

a. arthrochalasia

b. classical

c. dermatosparaxis

d. hypermobility

e. kyphoscoliosis

2. Ankyloblepharon may be associated with mutation of which gene?

a. fibrillin 1

b. LMX1B

c. NF1

d. p53

e. p63

3. Which is a characteristic ocular tumor in patients with tuberous sclerosis complex?

a. congenital hypertrophy of retinal pigment epithelium

b. phakoma

c. pigmented iris hamartoma

d. pinguecula

e. pterygium

4. Which syndrome is not associated with blue sclerae?

a. EDS type 6

b. lipoid proteinosis

c. Marfan syndrome

d. osteogenesis imperfecta type II

e. pseudoxanthoma elasticum

5. Which term describes white spots at the periphery of the iris?

a. Brushfield spots

b. coloboma

c. Kayser-Fleischer rings

d. Lester iris

e. Lisch nodules

Review the PDF of the fact sheet on eye findings in dermatologic conditions with board-relevant, easy-to-review material. This month's fact sheet will review ophthalmologic findings associated with inherited dermatologic conditions.

Practice Questions

1. Which type of EDS is most characteristically associated with blue sclerae and globe rupture?

a. arthrochalasia

b. classical

c. dermatosparaxis

d. hypermobility

e. kyphoscoliosis

2. Ankyloblepharon may be associated with mutation of which gene?

a. fibrillin 1

b. LMX1B

c. NF1

d. p53

e. p63

3. Which is a characteristic ocular tumor in patients with tuberous sclerosis complex?

a. congenital hypertrophy of retinal pigment epithelium

b. phakoma

c. pigmented iris hamartoma

d. pinguecula

e. pterygium

4. Which syndrome is not associated with blue sclerae?

a. EDS type 6

b. lipoid proteinosis

c. Marfan syndrome

d. osteogenesis imperfecta type II

e. pseudoxanthoma elasticum

5. Which term describes white spots at the periphery of the iris?

a. Brushfield spots

b. coloboma

c. Kayser-Fleischer rings

d. Lester iris

e. Lisch nodules

Answers to practice questions provided on next page

Practice Question Answers

1. Which type of EDS is most characteristically associated with blue sclerae and globe rupture?

a. arthrochalasia

b. classical

c. dermatosparaxis

d. hypermobility

e. kyphoscoliosis

2. Ankyloblepharon may be associated with mutation of which gene?

a. fibrillin 1

b. LMX1B

c. NF1

d. p53

e. p63

3. Which is a characteristic ocular tumor in patients with tuberous sclerosis complex?

a. congenital hypertrophy of retinal pigment epithelium

b. phakoma

c. pigmented iris hamartoma

d. pinguecula

e. pterygium

4. Which syndrome is not associated with blue sclerae?

a. EDS type 6

b. lipoid proteinosis

c. Marfan syndrome

d. osteogenesis imperfecta type II

e. pseudoxanthoma elasticum

5. Which term describes white spots at the periphery of the iris?

a. Brushfield spots

b. coloboma

c. Kayser-Fleischer rings

d. Lester iris

e. Lisch nodules

Review the PDF of the fact sheet on eye findings in dermatologic conditions with board-relevant, easy-to-review material. This month's fact sheet will review ophthalmologic findings associated with inherited dermatologic conditions.

Practice Questions

1. Which type of EDS is most characteristically associated with blue sclerae and globe rupture?

a. arthrochalasia

b. classical

c. dermatosparaxis

d. hypermobility

e. kyphoscoliosis

2. Ankyloblepharon may be associated with mutation of which gene?

a. fibrillin 1

b. LMX1B

c. NF1

d. p53

e. p63

3. Which is a characteristic ocular tumor in patients with tuberous sclerosis complex?

a. congenital hypertrophy of retinal pigment epithelium

b. phakoma

c. pigmented iris hamartoma

d. pinguecula

e. pterygium

4. Which syndrome is not associated with blue sclerae?

a. EDS type 6

b. lipoid proteinosis

c. Marfan syndrome

d. osteogenesis imperfecta type II

e. pseudoxanthoma elasticum

5. Which term describes white spots at the periphery of the iris?

a. Brushfield spots

b. coloboma

c. Kayser-Fleischer rings

d. Lester iris

e. Lisch nodules

Answers to practice questions provided on next page

Practice Question Answers

1. Which type of EDS is most characteristically associated with blue sclerae and globe rupture?

a. arthrochalasia

b. classical

c. dermatosparaxis

d. hypermobility

e. kyphoscoliosis

2. Ankyloblepharon may be associated with mutation of which gene?

a. fibrillin 1

b. LMX1B

c. NF1

d. p53

e. p63

3. Which is a characteristic ocular tumor in patients with tuberous sclerosis complex?

a. congenital hypertrophy of retinal pigment epithelium

b. phakoma

c. pigmented iris hamartoma

d. pinguecula

e. pterygium

4. Which syndrome is not associated with blue sclerae?

a. EDS type 6

b. lipoid proteinosis

c. Marfan syndrome

d. osteogenesis imperfecta type II

e. pseudoxanthoma elasticum

5. Which term describes white spots at the periphery of the iris?

a. Brushfield spots

b. coloboma

c. Kayser-Fleischer rings

d. Lester iris

e. Lisch nodules

Knee osteoarthritis (OA) is a progressive, degenerative joint disease characterized by pain and dysfunction. OA is a leading cause of disability in middle-aged and older adults,¹ affecting an estimated 27 million Americans.² With the continued aging of the baby boomer population and rising obesity rates, the incidence of OA is estimated to increase by 40% by 2025.³ The clinical and economic burdens of OA on our society—medical costs and workdays lost—are significant and will continue to be a problem for years to come.⁴

Total knee arthroplasty (TKA) is an option for severe end-stage OA. Most patients with mild to moderate OA follow nonsurgical strategies in an attempt to avoid invasive procedures. As there is no established cure, initial treatment of knee OA is geared toward alleviating pain and improving function. A multimodal approach is typically used and recommended.^5,6 Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and narcotic analgesics are commonly prescribed. NSAIDs can be effective⁷ but have well-known cardiovascular, renal, and gastrointestinal risks. If possible, narcotic analgesics should be avoided because of the risk of addiction and the problems associated with dependence. Intra-articular injections of corticosteroids or hyaluronic acid (viscosupplementation) are often recommended to reduce pain associated with arthritis. Braces designed to “off-load” the more diseased medial or lateral compartment of the knee have also been used in an effort to provide symptomatic relief. These low-risk, noninvasive unloader braces have increasingly been advanced as a conservative treatment modality for knee OA,^6,8-10despite modest evidence and lack of appropriately powered randomized controlled trials.¹¹ As more research on the efficacy of these braces is needed, we conducted a study to determine whether an unloader brace is an acceptable and valid treatment modality for knee OA.

Patients and Methods

This was a prospective, randomized, controlled trial of patients with symptomatic, predominantly unicompartmental OA involving the medial compartment of the knee. The study protocol was approved by the Institutional Review Board at Baptist Hospital in Pensacola, Florida. Patients were excluded if they had a rheumatologic disorder other than OA; a history of knee surgery other than a routine arthroscopic procedure; any soft-tissue, neurologic, or vascular compromise preventing long-term brace use; or obesity preventing effective or comfortable brace use. It is generally felt that unloader bracing may not be effective for patients with severe contractures or significant knee deformity; therefore, those lacking more than 10° of extension or 20° of flexion, or those who had a varus deformity of more than 8° of varus, were not offered enrollment.

Ideal sizes for the proposed study groups were determined through power analysis using standard deviations from prior similar investigations. The target was 30 patients per group.

Patients gave informed consent to the work. A computer-generated randomization schedule was used to randomize patients either to receive a medial unloader brace (Fusion OA; Breg, Inc) or not to receive a brace. Patients in these brace and control groups were allowed to continue their standard conservative OA treatment modalities, including NSAID use, home exercises, and joint supplement use. Patients were restricted from receiving any injection therapy or narcotic pain medication in an effort to isolate the effects of bracing on relief of pain and other symptoms.

All patients were examined by an orthopedic surgeon or fellowship-trained primary care sports medicine specialist. Age, sex, height, and weight data were recorded. Body mass index was calculated. Anteroposterior, lateral, flexion weight-bearing, and long-leg standing radiographs were obtained. Two orthopedic surgeons blindly graded OA¹² and calculated knee varus angles.¹³ Values were averaged, and intraobserver reliability and interobserver reliability were calculated.

Prospective subjective outcomes were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), administered on study entry and at 4, 8, 16, and 24 weeks during the study. The KOOS has 5 subscales: Pain, Symptoms, Function in Daily Living, Function in Sport and Recreation, and Knee-Related Quality of Life. Each subscale is scored separately. Items are rated 0 (extreme problems) to 100 (no problems). Patients were also asked to complete a weekly diary, which included visual analog scale (VAS) ratings of pain, NSAID use, sleep, and activity level. VAS items were rated 1 (extreme problems) to 100 (no problems). For brace-group patients, hours of brace use per day were recorded. Patients were required to use the brace for a minimum of 4 hours per day.

KOOS and VAS data were analyzed with repeated-measures analysis of variance. Significance level was set at P < .05.

Results

Of the 50 patients randomized, 31 (16 brace, 15 control) completed the study. Of the 19 dropouts, 10 were in the brace group (4 dropped out because of brace discomfort) and 9 in the control group (5 dropped out because of significant pain and the desire for more aggressive treatment with injections). The target patient numbers based on the power analysis were not achieved because of patient enrollment difficulties resulting from the strict criteria established in the study design.

The brace group consisted of 8 men and 8 women. Braces were worn an average of 6.7 hours per day. The control group consisted of 8 men and 7 women. The groups were not significantly different in age, height, weight, body mass index, measured varus knee angle, or arthritis grade (Table 1).

Radiographs were assessed by 2 orthopedic surgeons. Varus angle measurements showed high interobserver reliability (.904, P = .03) and high intraobserver reliability (.969, P = .05); arthritis grades showed low interobserver reliability (.469, P = .59) and high intraobserver reliability (.810, P = .001).

KOOS results showed that, compared with control patients, brace patients had significantly less pain (P < .001), fewer arthritis symptoms (P = .007), better ability to engage in activities of daily living (ADLs) (P = .008), and better total knee function (P = .004) (Figures 1-4). The groups did not differ in ability to engage in sport and recreation (P = .402) or in knee-related quality of life (P = .718), but each parameter showed a trend to be better in the brace group. There was no effect of time in any KOOS subscale. Confidence intervals for these data are listed in Table 2.

VAS results showed that, compared with control patients, brace patients had significantly less pain throughout the day (P = .021) and better activity levels (P = .035) (Figures 5, 6). The groups did not differ in ability to sleep (P = .117) or NSAID use (P = .138), but each parameter showed a trend to be better in the brace group. There was no effect of time in either VAS.

Discussion

We conducted this study to determine the efficacy of a medial unloader brace in reducing the pain and symptoms associated with varus knee OA.

Although TKA is an option for patients with significant end-stage knee OA, mild OA and moderate OA typically are managed with nonoperative modalities. These modalities can be effective and may delay or eliminate the need for surgery, which poses a small but definite risk. Delaying surgery, especially in younger, active patients, has the potential to reduce the number of wear-related revision surgeries.¹⁴

Braces designed to off-load the more diseased medial or lateral compartment of the knee have been used in an effort to provide relief from symptomatic OA. There is a lack of appropriately powered, randomized controlled studies on the efficacy of these braces. With the evidence being inconclusive, the American Academy of Orthopaedic Surgeons is unable to recommend for or against use of a brace in medial unicompartmental OA.¹¹ More research on the efficacy of these braces is needed. In the present study, we asked 2 questions: Does use of an unloader brace lessen the pain associated with knee OA? Is the unloader brace an acceptable and valid treatment modality for knee OA?

The 2 clinical outcome tools used in this study showed significant improvement in pain in brace patients compared with control patients. KOOS results showed reduced pain and arthritis symptoms. VAS results showed less pain experienced throughout the day. Pain reduction is probably the most important benefit of any nonoperative modality for knee OA. Pain typically is the driving force and the major indication for TKA. Other investigators have found pain reduced with use of unloader braces, but few long-term prospective randomized trials have been conducted. Ramsey and colleagues¹⁵ compared a neutral stabilizing brace with a medial unloading brace and found that both helped reduce pain and functional disability. This led to discussion about the 2 major potential mechanisms for symptom relief. One theory holds that bracing unloads the diseased portion of the joint and thereby helps improve symptoms.^16-18 According to the other theory, bracing stabilizes the knee, reducing muscle cocontractions and joint compression.^15,19,20 Draganich and colleagues²¹ found that both off-the-shelf and adjustable unloader braces reduced pain. In a short-term (8-week) study, Barnes and colleagues²² found substantial improvement in knee pain with use of an unloader brace. In one of the larger, better designed, prospective studies, Brouwer and colleagues²³ found borderline but significant improvements in pain. Larsen and colleagues,²⁴ in another short-term study, found no improvement in pain but did report improved activity levels with use of a medial unloader brace.

In addition to demonstrating pain reduction, our results showed that, compared with control patients, brace patients had fewer arthritis symptoms, better ability to engage in ADLs, and increased activity levels. Other studies have identified additional benefits of bracing for knee arthritis. Larsen and colleagues²⁴ found that valgus bracing for medial compartment knee OA improved walking and sit-to-stand activities. Although pain relief results were modest, Brouwer and colleagues²³ found significantly better knee function and longer walking distances for patients who used a medial unloader brace. Hewett and colleagues²⁵ found that pain, ADLs, and walking distance were all improved after 9 weeks of brace wear.

Our study had a few limitations. Although injections and narcotic pain medications were not allowed, NSAIDs, home exercises, and other modalities were permitted. We did not think it was reasonable to eliminate every nonoperative modality during the 6-month study period. Therefore, it is possible that some of the study population’s improvements are attributable to these other modalities, which were not rigidly controlled.

Patient enrollment was difficult because of the strict inclusion and exclusion criteria used. The result was a smaller than anticipated patient population. Although there were many excellent study candidates, most declined enrollment when they learned they could be randomized to the control group. These patients were not willing to forgo injections or bracing for 6 months. We thought it was important to maintain our study design because it allowed us to evaluate the true effect of brace use while eliminating confounding variables. Nearly equal numbers of brace and control patients dropped out of the study. The majority of control group dropouts wanted more treatment options, indicating that NSAIDs and exercises alone were not controlling patients’ symptoms. This finding supports recommendations for a multimodal approach to treatment. As expected, some patients dropped out because their brace was uncomfortable—an important finding that should be considered when counseling patients about treatment options for OA.

Not all patients are candidates for braces. Braces can be irritating and uncomfortable for obese patients and patients with skin or vascular issues. Some patients find braces inconvenient. As discussed, a multimodal OA treatment approach is encouraged, but not every mode fits every patient. Physician and patient should thoroughly discuss the benefits and potential problems of brace use before prescribing. Our study results showed trends toward better improvements for brace patients (compared with control patients) in quality of life, ability to engage in sport and recreation, ability to sleep, and need for NSAIDs. Had we enrolled more patients, we might have found statistical significance for these trends. Despite the challenges with patient enrollment and study population size, the data make clear that unloader braces can benefit appropriate patients.

Our findings support use of a medial unloader brace as an acceptable and valid treatment modality for mild and moderate knee OA. The medial unloader brace should be considered a reasonable alternative, as part of a multimodal approach, to more invasive options, such as TKA.

Knee osteoarthritis (OA) is a progressive, degenerative joint disease characterized by pain and dysfunction. OA is a leading cause of disability in middle-aged and older adults,¹ affecting an estimated 27 million Americans.² With the continued aging of the baby boomer population and rising obesity rates, the incidence of OA is estimated to increase by 40% by 2025.³ The clinical and economic burdens of OA on our society—medical costs and workdays lost—are significant and will continue to be a problem for years to come.⁴

Total knee arthroplasty (TKA) is an option for severe end-stage OA. Most patients with mild to moderate OA follow nonsurgical strategies in an attempt to avoid invasive procedures. As there is no established cure, initial treatment of knee OA is geared toward alleviating pain and improving function. A multimodal approach is typically used and recommended.^5,6 Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and narcotic analgesics are commonly prescribed. NSAIDs can be effective⁷ but have well-known cardiovascular, renal, and gastrointestinal risks. If possible, narcotic analgesics should be avoided because of the risk of addiction and the problems associated with dependence. Intra-articular injections of corticosteroids or hyaluronic acid (viscosupplementation) are often recommended to reduce pain associated with arthritis. Braces designed to “off-load” the more diseased medial or lateral compartment of the knee have also been used in an effort to provide symptomatic relief. These low-risk, noninvasive unloader braces have increasingly been advanced as a conservative treatment modality for knee OA,^6,8-10despite modest evidence and lack of appropriately powered randomized controlled trials.¹¹ As more research on the efficacy of these braces is needed, we conducted a study to determine whether an unloader brace is an acceptable and valid treatment modality for knee OA.

Patients and Methods

This was a prospective, randomized, controlled trial of patients with symptomatic, predominantly unicompartmental OA involving the medial compartment of the knee. The study protocol was approved by the Institutional Review Board at Baptist Hospital in Pensacola, Florida. Patients were excluded if they had a rheumatologic disorder other than OA; a history of knee surgery other than a routine arthroscopic procedure; any soft-tissue, neurologic, or vascular compromise preventing long-term brace use; or obesity preventing effective or comfortable brace use. It is generally felt that unloader bracing may not be effective for patients with severe contractures or significant knee deformity; therefore, those lacking more than 10° of extension or 20° of flexion, or those who had a varus deformity of more than 8° of varus, were not offered enrollment.

Ideal sizes for the proposed study groups were determined through power analysis using standard deviations from prior similar investigations. The target was 30 patients per group.

Patients gave informed consent to the work. A computer-generated randomization schedule was used to randomize patients either to receive a medial unloader brace (Fusion OA; Breg, Inc) or not to receive a brace. Patients in these brace and control groups were allowed to continue their standard conservative OA treatment modalities, including NSAID use, home exercises, and joint supplement use. Patients were restricted from receiving any injection therapy or narcotic pain medication in an effort to isolate the effects of bracing on relief of pain and other symptoms.

All patients were examined by an orthopedic surgeon or fellowship-trained primary care sports medicine specialist. Age, sex, height, and weight data were recorded. Body mass index was calculated. Anteroposterior, lateral, flexion weight-bearing, and long-leg standing radiographs were obtained. Two orthopedic surgeons blindly graded OA¹² and calculated knee varus angles.¹³ Values were averaged, and intraobserver reliability and interobserver reliability were calculated.

Prospective subjective outcomes were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), administered on study entry and at 4, 8, 16, and 24 weeks during the study. The KOOS has 5 subscales: Pain, Symptoms, Function in Daily Living, Function in Sport and Recreation, and Knee-Related Quality of Life. Each subscale is scored separately. Items are rated 0 (extreme problems) to 100 (no problems). Patients were also asked to complete a weekly diary, which included visual analog scale (VAS) ratings of pain, NSAID use, sleep, and activity level. VAS items were rated 1 (extreme problems) to 100 (no problems). For brace-group patients, hours of brace use per day were recorded. Patients were required to use the brace for a minimum of 4 hours per day.

KOOS and VAS data were analyzed with repeated-measures analysis of variance. Significance level was set at P < .05.

Results

Of the 50 patients randomized, 31 (16 brace, 15 control) completed the study. Of the 19 dropouts, 10 were in the brace group (4 dropped out because of brace discomfort) and 9 in the control group (5 dropped out because of significant pain and the desire for more aggressive treatment with injections). The target patient numbers based on the power analysis were not achieved because of patient enrollment difficulties resulting from the strict criteria established in the study design.

The brace group consisted of 8 men and 8 women. Braces were worn an average of 6.7 hours per day. The control group consisted of 8 men and 7 women. The groups were not significantly different in age, height, weight, body mass index, measured varus knee angle, or arthritis grade (Table 1).

Radiographs were assessed by 2 orthopedic surgeons. Varus angle measurements showed high interobserver reliability (.904, P = .03) and high intraobserver reliability (.969, P = .05); arthritis grades showed low interobserver reliability (.469, P = .59) and high intraobserver reliability (.810, P = .001).

KOOS results showed that, compared with control patients, brace patients had significantly less pain (P < .001), fewer arthritis symptoms (P = .007), better ability to engage in activities of daily living (ADLs) (P = .008), and better total knee function (P = .004) (Figures 1-4). The groups did not differ in ability to engage in sport and recreation (P = .402) or in knee-related quality of life (P = .718), but each parameter showed a trend to be better in the brace group. There was no effect of time in any KOOS subscale. Confidence intervals for these data are listed in Table 2.

VAS results showed that, compared with control patients, brace patients had significantly less pain throughout the day (P = .021) and better activity levels (P = .035) (Figures 5, 6). The groups did not differ in ability to sleep (P = .117) or NSAID use (P = .138), but each parameter showed a trend to be better in the brace group. There was no effect of time in either VAS.

Discussion

We conducted this study to determine the efficacy of a medial unloader brace in reducing the pain and symptoms associated with varus knee OA.

Although TKA is an option for patients with significant end-stage knee OA, mild OA and moderate OA typically are managed with nonoperative modalities. These modalities can be effective and may delay or eliminate the need for surgery, which poses a small but definite risk. Delaying surgery, especially in younger, active patients, has the potential to reduce the number of wear-related revision surgeries.¹⁴

Braces designed to off-load the more diseased medial or lateral compartment of the knee have been used in an effort to provide relief from symptomatic OA. There is a lack of appropriately powered, randomized controlled studies on the efficacy of these braces. With the evidence being inconclusive, the American Academy of Orthopaedic Surgeons is unable to recommend for or against use of a brace in medial unicompartmental OA.¹¹ More research on the efficacy of these braces is needed. In the present study, we asked 2 questions: Does use of an unloader brace lessen the pain associated with knee OA? Is the unloader brace an acceptable and valid treatment modality for knee OA?

The 2 clinical outcome tools used in this study showed significant improvement in pain in brace patients compared with control patients. KOOS results showed reduced pain and arthritis symptoms. VAS results showed less pain experienced throughout the day. Pain reduction is probably the most important benefit of any nonoperative modality for knee OA. Pain typically is the driving force and the major indication for TKA. Other investigators have found pain reduced with use of unloader braces, but few long-term prospective randomized trials have been conducted. Ramsey and colleagues¹⁵ compared a neutral stabilizing brace with a medial unloading brace and found that both helped reduce pain and functional disability. This led to discussion about the 2 major potential mechanisms for symptom relief. One theory holds that bracing unloads the diseased portion of the joint and thereby helps improve symptoms.^16-18 According to the other theory, bracing stabilizes the knee, reducing muscle cocontractions and joint compression.^15,19,20 Draganich and colleagues²¹ found that both off-the-shelf and adjustable unloader braces reduced pain. In a short-term (8-week) study, Barnes and colleagues²² found substantial improvement in knee pain with use of an unloader brace. In one of the larger, better designed, prospective studies, Brouwer and colleagues²³ found borderline but significant improvements in pain. Larsen and colleagues,²⁴ in another short-term study, found no improvement in pain but did report improved activity levels with use of a medial unloader brace.

In addition to demonstrating pain reduction, our results showed that, compared with control patients, brace patients had fewer arthritis symptoms, better ability to engage in ADLs, and increased activity levels. Other studies have identified additional benefits of bracing for knee arthritis. Larsen and colleagues²⁴ found that valgus bracing for medial compartment knee OA improved walking and sit-to-stand activities. Although pain relief results were modest, Brouwer and colleagues²³ found significantly better knee function and longer walking distances for patients who used a medial unloader brace. Hewett and colleagues²⁵ found that pain, ADLs, and walking distance were all improved after 9 weeks of brace wear.

Our study had a few limitations. Although injections and narcotic pain medications were not allowed, NSAIDs, home exercises, and other modalities were permitted. We did not think it was reasonable to eliminate every nonoperative modality during the 6-month study period. Therefore, it is possible that some of the study population’s improvements are attributable to these other modalities, which were not rigidly controlled.

Patient enrollment was difficult because of the strict inclusion and exclusion criteria used. The result was a smaller than anticipated patient population. Although there were many excellent study candidates, most declined enrollment when they learned they could be randomized to the control group. These patients were not willing to forgo injections or bracing for 6 months. We thought it was important to maintain our study design because it allowed us to evaluate the true effect of brace use while eliminating confounding variables. Nearly equal numbers of brace and control patients dropped out of the study. The majority of control group dropouts wanted more treatment options, indicating that NSAIDs and exercises alone were not controlling patients’ symptoms. This finding supports recommendations for a multimodal approach to treatment. As expected, some patients dropped out because their brace was uncomfortable—an important finding that should be considered when counseling patients about treatment options for OA.

Not all patients are candidates for braces. Braces can be irritating and uncomfortable for obese patients and patients with skin or vascular issues. Some patients find braces inconvenient. As discussed, a multimodal OA treatment approach is encouraged, but not every mode fits every patient. Physician and patient should thoroughly discuss the benefits and potential problems of brace use before prescribing. Our study results showed trends toward better improvements for brace patients (compared with control patients) in quality of life, ability to engage in sport and recreation, ability to sleep, and need for NSAIDs. Had we enrolled more patients, we might have found statistical significance for these trends. Despite the challenges with patient enrollment and study population size, the data make clear that unloader braces can benefit appropriate patients.

Our findings support use of a medial unloader brace as an acceptable and valid treatment modality for mild and moderate knee OA. The medial unloader brace should be considered a reasonable alternative, as part of a multimodal approach, to more invasive options, such as TKA.

Knee osteoarthritis (OA) is a progressive, degenerative joint disease characterized by pain and dysfunction. OA is a leading cause of disability in middle-aged and older adults,¹ affecting an estimated 27 million Americans.² With the continued aging of the baby boomer population and rising obesity rates, the incidence of OA is estimated to increase by 40% by 2025.³ The clinical and economic burdens of OA on our society—medical costs and workdays lost—are significant and will continue to be a problem for years to come.⁴

Total knee arthroplasty (TKA) is an option for severe end-stage OA. Most patients with mild to moderate OA follow nonsurgical strategies in an attempt to avoid invasive procedures. As there is no established cure, initial treatment of knee OA is geared toward alleviating pain and improving function. A multimodal approach is typically used and recommended.^5,6 Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and narcotic analgesics are commonly prescribed. NSAIDs can be effective⁷ but have well-known cardiovascular, renal, and gastrointestinal risks. If possible, narcotic analgesics should be avoided because of the risk of addiction and the problems associated with dependence. Intra-articular injections of corticosteroids or hyaluronic acid (viscosupplementation) are often recommended to reduce pain associated with arthritis. Braces designed to “off-load” the more diseased medial or lateral compartment of the knee have also been used in an effort to provide symptomatic relief. These low-risk, noninvasive unloader braces have increasingly been advanced as a conservative treatment modality for knee OA,^6,8-10despite modest evidence and lack of appropriately powered randomized controlled trials.¹¹ As more research on the efficacy of these braces is needed, we conducted a study to determine whether an unloader brace is an acceptable and valid treatment modality for knee OA.

Patients and Methods

This was a prospective, randomized, controlled trial of patients with symptomatic, predominantly unicompartmental OA involving the medial compartment of the knee. The study protocol was approved by the Institutional Review Board at Baptist Hospital in Pensacola, Florida. Patients were excluded if they had a rheumatologic disorder other than OA; a history of knee surgery other than a routine arthroscopic procedure; any soft-tissue, neurologic, or vascular compromise preventing long-term brace use; or obesity preventing effective or comfortable brace use. It is generally felt that unloader bracing may not be effective for patients with severe contractures or significant knee deformity; therefore, those lacking more than 10° of extension or 20° of flexion, or those who had a varus deformity of more than 8° of varus, were not offered enrollment.

Ideal sizes for the proposed study groups were determined through power analysis using standard deviations from prior similar investigations. The target was 30 patients per group.

Patients gave informed consent to the work. A computer-generated randomization schedule was used to randomize patients either to receive a medial unloader brace (Fusion OA; Breg, Inc) or not to receive a brace. Patients in these brace and control groups were allowed to continue their standard conservative OA treatment modalities, including NSAID use, home exercises, and joint supplement use. Patients were restricted from receiving any injection therapy or narcotic pain medication in an effort to isolate the effects of bracing on relief of pain and other symptoms.

All patients were examined by an orthopedic surgeon or fellowship-trained primary care sports medicine specialist. Age, sex, height, and weight data were recorded. Body mass index was calculated. Anteroposterior, lateral, flexion weight-bearing, and long-leg standing radiographs were obtained. Two orthopedic surgeons blindly graded OA¹² and calculated knee varus angles.¹³ Values were averaged, and intraobserver reliability and interobserver reliability were calculated.

Prospective subjective outcomes were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), administered on study entry and at 4, 8, 16, and 24 weeks during the study. The KOOS has 5 subscales: Pain, Symptoms, Function in Daily Living, Function in Sport and Recreation, and Knee-Related Quality of Life. Each subscale is scored separately. Items are rated 0 (extreme problems) to 100 (no problems). Patients were also asked to complete a weekly diary, which included visual analog scale (VAS) ratings of pain, NSAID use, sleep, and activity level. VAS items were rated 1 (extreme problems) to 100 (no problems). For brace-group patients, hours of brace use per day were recorded. Patients were required to use the brace for a minimum of 4 hours per day.

KOOS and VAS data were analyzed with repeated-measures analysis of variance. Significance level was set at P < .05.

Results

Of the 50 patients randomized, 31 (16 brace, 15 control) completed the study. Of the 19 dropouts, 10 were in the brace group (4 dropped out because of brace discomfort) and 9 in the control group (5 dropped out because of significant pain and the desire for more aggressive treatment with injections). The target patient numbers based on the power analysis were not achieved because of patient enrollment difficulties resulting from the strict criteria established in the study design.

The brace group consisted of 8 men and 8 women. Braces were worn an average of 6.7 hours per day. The control group consisted of 8 men and 7 women. The groups were not significantly different in age, height, weight, body mass index, measured varus knee angle, or arthritis grade (Table 1).

Radiographs were assessed by 2 orthopedic surgeons. Varus angle measurements showed high interobserver reliability (.904, P = .03) and high intraobserver reliability (.969, P = .05); arthritis grades showed low interobserver reliability (.469, P = .59) and high intraobserver reliability (.810, P = .001).

KOOS results showed that, compared with control patients, brace patients had significantly less pain (P < .001), fewer arthritis symptoms (P = .007), better ability to engage in activities of daily living (ADLs) (P = .008), and better total knee function (P = .004) (Figures 1-4). The groups did not differ in ability to engage in sport and recreation (P = .402) or in knee-related quality of life (P = .718), but each parameter showed a trend to be better in the brace group. There was no effect of time in any KOOS subscale. Confidence intervals for these data are listed in Table 2.

VAS results showed that, compared with control patients, brace patients had significantly less pain throughout the day (P = .021) and better activity levels (P = .035) (Figures 5, 6). The groups did not differ in ability to sleep (P = .117) or NSAID use (P = .138), but each parameter showed a trend to be better in the brace group. There was no effect of time in either VAS.

Discussion

We conducted this study to determine the efficacy of a medial unloader brace in reducing the pain and symptoms associated with varus knee OA.

Although TKA is an option for patients with significant end-stage knee OA, mild OA and moderate OA typically are managed with nonoperative modalities. These modalities can be effective and may delay or eliminate the need for surgery, which poses a small but definite risk. Delaying surgery, especially in younger, active patients, has the potential to reduce the number of wear-related revision surgeries.¹⁴

Braces designed to off-load the more diseased medial or lateral compartment of the knee have been used in an effort to provide relief from symptomatic OA. There is a lack of appropriately powered, randomized controlled studies on the efficacy of these braces. With the evidence being inconclusive, the American Academy of Orthopaedic Surgeons is unable to recommend for or against use of a brace in medial unicompartmental OA.¹¹ More research on the efficacy of these braces is needed. In the present study, we asked 2 questions: Does use of an unloader brace lessen the pain associated with knee OA? Is the unloader brace an acceptable and valid treatment modality for knee OA?

The 2 clinical outcome tools used in this study showed significant improvement in pain in brace patients compared with control patients. KOOS results showed reduced pain and arthritis symptoms. VAS results showed less pain experienced throughout the day. Pain reduction is probably the most important benefit of any nonoperative modality for knee OA. Pain typically is the driving force and the major indication for TKA. Other investigators have found pain reduced with use of unloader braces, but few long-term prospective randomized trials have been conducted. Ramsey and colleagues¹⁵ compared a neutral stabilizing brace with a medial unloading brace and found that both helped reduce pain and functional disability. This led to discussion about the 2 major potential mechanisms for symptom relief. One theory holds that bracing unloads the diseased portion of the joint and thereby helps improve symptoms.^16-18 According to the other theory, bracing stabilizes the knee, reducing muscle cocontractions and joint compression.^15,19,20 Draganich and colleagues²¹ found that both off-the-shelf and adjustable unloader braces reduced pain. In a short-term (8-week) study, Barnes and colleagues²² found substantial improvement in knee pain with use of an unloader brace. In one of the larger, better designed, prospective studies, Brouwer and colleagues²³ found borderline but significant improvements in pain. Larsen and colleagues,²⁴ in another short-term study, found no improvement in pain but did report improved activity levels with use of a medial unloader brace.

In addition to demonstrating pain reduction, our results showed that, compared with control patients, brace patients had fewer arthritis symptoms, better ability to engage in ADLs, and increased activity levels. Other studies have identified additional benefits of bracing for knee arthritis. Larsen and colleagues²⁴ found that valgus bracing for medial compartment knee OA improved walking and sit-to-stand activities. Although pain relief results were modest, Brouwer and colleagues²³ found significantly better knee function and longer walking distances for patients who used a medial unloader brace. Hewett and colleagues²⁵ found that pain, ADLs, and walking distance were all improved after 9 weeks of brace wear.

Our study had a few limitations. Although injections and narcotic pain medications were not allowed, NSAIDs, home exercises, and other modalities were permitted. We did not think it was reasonable to eliminate every nonoperative modality during the 6-month study period. Therefore, it is possible that some of the study population’s improvements are attributable to these other modalities, which were not rigidly controlled.

Patient enrollment was difficult because of the strict inclusion and exclusion criteria used. The result was a smaller than anticipated patient population. Although there were many excellent study candidates, most declined enrollment when they learned they could be randomized to the control group. These patients were not willing to forgo injections or bracing for 6 months. We thought it was important to maintain our study design because it allowed us to evaluate the true effect of brace use while eliminating confounding variables. Nearly equal numbers of brace and control patients dropped out of the study. The majority of control group dropouts wanted more treatment options, indicating that NSAIDs and exercises alone were not controlling patients’ symptoms. This finding supports recommendations for a multimodal approach to treatment. As expected, some patients dropped out because their brace was uncomfortable—an important finding that should be considered when counseling patients about treatment options for OA.

Not all patients are candidates for braces. Braces can be irritating and uncomfortable for obese patients and patients with skin or vascular issues. Some patients find braces inconvenient. As discussed, a multimodal OA treatment approach is encouraged, but not every mode fits every patient. Physician and patient should thoroughly discuss the benefits and potential problems of brace use before prescribing. Our study results showed trends toward better improvements for brace patients (compared with control patients) in quality of life, ability to engage in sport and recreation, ability to sleep, and need for NSAIDs. Had we enrolled more patients, we might have found statistical significance for these trends. Despite the challenges with patient enrollment and study population size, the data make clear that unloader braces can benefit appropriate patients.

Our findings support use of a medial unloader brace as an acceptable and valid treatment modality for mild and moderate knee OA. The medial unloader brace should be considered a reasonable alternative, as part of a multimodal approach, to more invasive options, such as TKA.

For overhead athletes, elbow ulnar collateral ligament (UCL) insufficiency is a potential career-ending injury. Baseball players with UCL insufficiency typically complain of medial-sided elbow pain that affects their ability to throw. Loss of velocity, loss of control, difficulty warming up, and pain while throwing are all symptoms of UCL injury.

Classically, nonoperative treatment of UCL injuries involves activity modification, use of anti-inflammatory medication, and a structured physical therapy program. Asymptomatic players can return to throwing after a structured interval throwing program. Rettig and colleagues¹ found a 42% rate of success in conservatively treating UCL injuries in throwing athletes. UCL reconstruction is reserved for players with complete tears of the UCL or with partial tears after failed conservative treatment. Several techniques have been used to reconstruct the ligament, but successful outcomes depend on a long rehabilitation process. According to most published series, 85% to 90% of athletes who had UCL reconstruction returned to their previous level of play, but it took, on average, 9 to 12 months.^2,3 This prolonged recovery period is one reason that some older professional baseball players, as well as casual high school and college players, elect to forgo surgery.

Over the past few years, platelet-rich plasma (PRP) has garnered attention as a bridge between conservative treatment and surgery. PRP refers to a sample of autologous blood that contains a platelet concentration higher than baseline levels. This sample often has a 3 to 5 times increase in growth factor concentration.^4-6 Initial studies focused on its ability to successfully treat lateral epicondylitis.^7-9 More recent clinical work has shown that PRP can potentially enhance healing after anterior cruciate ligament reconstruction,^10-14 rotator cuff repair,^15-17 and subacromial decompression.^11,18-23 If PRP could be used to successfully treat UCL insufficiency that is refractory to conservative treatment, then year-long recovery periods could be avoided. This could potentially prolong certain athletes’ careers or, at the very least, allow them to return to play much sooner. In the present case series, we hypothesized that PRP injections could be used to successfully treat partial UCL tears in high-level throwing athletes, obviating the need for surgery and its associated prolonged recovery period.

Materials and Methods

Institutional Review Board approval was obtained for this retrospective study of 44 baseball players treated with PRP injections for partial-thickness UCL tears.

Patients provided written informed consent. They were diagnosed with UCL insufficiency by physical examination, and findings were confirmed by magnetic resonance imaging (MRI). After diagnosis, all throwers underwent a trial of conservative treatment that included rest, activity modification, use of anti-inflammatory medication, and physical therapy followed by an attempt to return to throwing using an interval throwing program.

Study inclusion criteria were physical examinations and MRI results consistent with UCL insufficiency, and failure of the conservative treatment plan described.

Patients were injected using the Autologous Conditioned Plasma system (Arthrex). PRP solutions were prepared according to manufacturer guidelines. After the elbow was prepared sterilely, the UCL was injected at the location of the tear. Typically, 3 mL of PRP was injected into the elbow. Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Repeat injections were considered for recalcitrant pain after 3 weeks.

After injection, patients used acetaminophen and ice for pain control. Anti-inflammatory medications were avoided for a minimum of 2 weeks after injection. Typical postinjection therapy protocol consisted of rest followed by progressive stretching and strengthening for about 4 to 6 weeks before the start of an interval throwing program. Although there is no well-defined postinjection recovery protocol, as a general rule rest was prescribed for the first 2 weeks, followed by a progressive stretching and strengthening program for the next month. Patients who were asymptomatic subjectively and clinically—negative moving valgus stress test, negative milking maneuver, no pain with valgus stress—were started on an interval throwing program.

Final follow-up involved a physical examination. Results were classified according to a modified version of the Conway Scale^12,24-26: excellent (return to preinjury level of competition or performance), good (return to play at a lower level of competition or performance or, specifically for baseball players, ability to throw in daily batting practice), fair (able to play recreationally), and poor (unable to return to previous sport at any level).

By final follow-up, all patients had completed their postoperative rehabilitation protocol, and all had at least tried to return to their previous activities. No patients were lost to follow-up.

Results

Of the 44 baseball players, 6 were professional, 14 were in college, and 24 were in high school. There were 36 pitchers and 8 position players. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Fifteen of the 44 players had an excellent outcome (34%), 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional baseball players returned to professional play. Five (36%) of the 14 college players had an excellent outcome, and 4 (17%) of the 24 high school players had an excellent outcome. Of the 8 position players, 4 had an excellent outcome, 3 had a good outcome, and 1 had a poor outcome.

Before treatment, all patients had medial-sided elbow pain over the UCL inhibiting their ability to throw. Mean duration of symptoms before injection was 8.8 months (range, 1-36 months). There was no correlation between symptom duration and any outcome measure. On MRI, 29 patients showed partial tears: 22 proximally based and 7 distally based. The other 15 patients had diffuse signal without partial tear. All 7 patients with distally based partial tears and 3 of the patients with proximally based partial tears had a poor outcome. Overall, there were 6 excellent, 7 good, and 2 fair outcomes in the partial-tear group. In the patients with diffuse signal without partial tear, there were 9 excellent and 10 good outcomes.

Mean time from injection to return to throwing was 5 weeks, and mean time to return to competition was 12 weeks (range, 5-24 weeks). The 1 player who returned at 5 weeks was a professional relief pitcher whose team was in the playoffs. He has now pitched for an additional 2 baseball seasons without elbow difficulty.

There were no injection-related complications.

Discussion

To our knowledge, this is the first report documenting successful PRP treatment of UCL insufficiency. In this study, 73% of players who had failed a course of conservative treatment had good to excellent outcomes with PRP injection.

Data on successful nonoperative treatment of UCL injuries are limited. Rettig and colleagues¹ treated 31 throwing athletes’ UCL injuries with a supervised rehabilitation program. Treatment included rest, use of anti-inflammatory medication, progressive strengthening, and an interval throwing program. Only 41% of the athletes returned to their previous level of play, and it took, on average, 24.5 weeks. There was no significant difference in age or in duration or acuity of symptoms between those who returned to play and those whose conservative treatment failed.

Surgical reconstruction of UCL injuries has been very successful, with upward of 90% of athletes returning to previous level of play.^3,27The procedure, however, is not without associated complications, including retear of the ligament, stiffness, ulnar nerve injury, and fracture.^27-29 In addition, even when successful, the procedure requires that athletes take 9 to 12 months to recover before returning to competition at their previous level.

Savoie and colleagues,³⁰ in their recent study on UCL repairs, highlighted an important fact that is often overlooked when reviewing the literature on UCL tears. Most of the literature on these injuries focuses on college and professional baseball players in whom ligament damage is often extensive, precluding repair. In contrast to prior reports, Savoie and colleagues³⁰ found excellent results in 93% of their young athletes who underwent UCL repair. It is possible that their results can be attributed to the fact that many of their athletes had tears isolated to one area of the ligament, as opposed to generalized ligament incompetence. Our improved results vis-à-vis other reports on conservative management may be attributable to the same phenomenon.

PRP has garnered much attention in the literature and media because of its potential to enhance healing of tendons and ligaments; in some cases, it can obviate the need for surgery. After failure of other nonoperative measures in 15 patients with elbow epicondylitis, Mishra and Pavelko⁸ treated each patient with a single PRP injection. They prepared the PRP using the GPS III system (Biomet). At final follow-up, 93% improvement was seen. Clearly, their experiment had design flaws: It was nonblinded, and 3 of the 5 patients in the control group treated with bupivacaine injection withdrew from the experiment. Despite its shortcomings, their study became the impetus for several other studies.

A larger, double-blinded, randomized controlled trial comparing PRP and cortisone injections for lateral epicondylitis in 100 patients is under way, and preliminary results have been published.⁹ A minimum of 6 months after injection, patients who received PRP showed more improvement in visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores. In another large, double-blinded, randomized controlled trial, patients with chronic lateral epicondylitis had significant improvements in VAS pain scores and DASH scores relative to patients injected with corticosteroids with a 2-year follow-up.³¹ Similarly, Thanasas and colleagues³² found significantly reduced VAS pain scores in patients injected with PRP versus autologous whole blood. Another study demonstrated improved tendon morphology using ultrasound imaging 6 months after PRP injection.³³

Contrary to these positive results, Krogh and colleagues³⁴ found that a single injection of PRP or glucocorticoid was not significantly superior to a saline injection for reducing pain and disability over a 3-month period in patients with lateral epicondylitis. Their study, however, had major flaws. Its original design called for a 12-month follow-up, but there was massive dropout in all 3 treatment arms, necessitating reporting of only 3-month data. In addition, 60% of the patients in the glucocorticoid group were not naïve to this treatment, so definitive conclusions about the efficacy of glucocorticoids could not be made.

In the present study, we successfully treated partial ligament tears with PRP injections. Sixty-seven percent of our baseball players returned to play at a mean of 4 months, much earlier than the 9 to 12 months typically required after ligament reconstruction. Many athletes, such as high school baseball players or aging veteran professional baseball players, do not have the luxury of 12 months for recovery. Therefore, this select group of patients clearly has a limited window of opportunity to return to play. In fact, these patients might be ideal candidates for PRP injections for UCL injuries. Return-to-play rates, however, differed significantly among professional players and nonprofessional players. The difference may be attributable to professional players’ conditioning, quality of physical therapy, extrinsic motivation, and other intangible factors. Four (67%) of our 6 professional baseball players returned to professional play after injection, whereas only 36% of college players and 17% of high school players had excellent outcomes.

Limitations

The present study had several weaknesses, several of which are inherent to PRP studies conducted so far. It was not a prospective, randomized controlled trial. It is important to note that PRP treatment in diseased tissue may have some drawbacks, as its success depends on the ability of healing tissue to use concentrated growth factors and cytokines to proliferate.³⁵ Thus, a chronically injured ligament with depleted active cells may have a diminished response to PRP. Another limitation of this study is that we evaluated outcomes based on return to play using the Conway Scale, which is well reported but not validated. Despite the potential weaknesses of this outcome scale, it has become the benchmark for measuring the success of outcomes of UCL reconstruction. Furthermore, we did not measure patients’ satisfaction with the treatment. Players who could not return to their preinjury level of play may have considered the treatment a failure regardless of their ability to continue throwing. Last, MRI was not repeated to document ligament healing. We did not routinely perform a second MRI because we thought it would not affect treatment. Several series have found a high incidence of abnormal signal in baseball players’ UCLs. In this group of patients, the most important outcome is return to previous level of competition.

This study raised several questions. Is one PRP brand better than another? Should more than 1 injection be given? What is the ideal postinjection protocol? Clearly, larger, prospective, randomized controlled studies are needed to truly elucidate the potential role of PRP in the treatment algorithm for UCL injury. Nevertheless, in certain cases in which traditional conservative measures have failed and patients do not have the luxury of rehabilitating for 9 to 12 months after surgery, PRP may be a viable treatment option.

Conclusion

In this study, use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.

For overhead athletes, elbow ulnar collateral ligament (UCL) insufficiency is a potential career-ending injury. Baseball players with UCL insufficiency typically complain of medial-sided elbow pain that affects their ability to throw. Loss of velocity, loss of control, difficulty warming up, and pain while throwing are all symptoms of UCL injury.

Classically, nonoperative treatment of UCL injuries involves activity modification, use of anti-inflammatory medication, and a structured physical therapy program. Asymptomatic players can return to throwing after a structured interval throwing program. Rettig and colleagues¹ found a 42% rate of success in conservatively treating UCL injuries in throwing athletes. UCL reconstruction is reserved for players with complete tears of the UCL or with partial tears after failed conservative treatment. Several techniques have been used to reconstruct the ligament, but successful outcomes depend on a long rehabilitation process. According to most published series, 85% to 90% of athletes who had UCL reconstruction returned to their previous level of play, but it took, on average, 9 to 12 months.^2,3 This prolonged recovery period is one reason that some older professional baseball players, as well as casual high school and college players, elect to forgo surgery.

Over the past few years, platelet-rich plasma (PRP) has garnered attention as a bridge between conservative treatment and surgery. PRP refers to a sample of autologous blood that contains a platelet concentration higher than baseline levels. This sample often has a 3 to 5 times increase in growth factor concentration.^4-6 Initial studies focused on its ability to successfully treat lateral epicondylitis.^7-9 More recent clinical work has shown that PRP can potentially enhance healing after anterior cruciate ligament reconstruction,^10-14 rotator cuff repair,^15-17 and subacromial decompression.^11,18-23 If PRP could be used to successfully treat UCL insufficiency that is refractory to conservative treatment, then year-long recovery periods could be avoided. This could potentially prolong certain athletes’ careers or, at the very least, allow them to return to play much sooner. In the present case series, we hypothesized that PRP injections could be used to successfully treat partial UCL tears in high-level throwing athletes, obviating the need for surgery and its associated prolonged recovery period.

Materials and Methods

Institutional Review Board approval was obtained for this retrospective study of 44 baseball players treated with PRP injections for partial-thickness UCL tears.

Patients provided written informed consent. They were diagnosed with UCL insufficiency by physical examination, and findings were confirmed by magnetic resonance imaging (MRI). After diagnosis, all throwers underwent a trial of conservative treatment that included rest, activity modification, use of anti-inflammatory medication, and physical therapy followed by an attempt to return to throwing using an interval throwing program.

Study inclusion criteria were physical examinations and MRI results consistent with UCL insufficiency, and failure of the conservative treatment plan described.

Patients were injected using the Autologous Conditioned Plasma system (Arthrex). PRP solutions were prepared according to manufacturer guidelines. After the elbow was prepared sterilely, the UCL was injected at the location of the tear. Typically, 3 mL of PRP was injected into the elbow. Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Repeat injections were considered for recalcitrant pain after 3 weeks.

After injection, patients used acetaminophen and ice for pain control. Anti-inflammatory medications were avoided for a minimum of 2 weeks after injection. Typical postinjection therapy protocol consisted of rest followed by progressive stretching and strengthening for about 4 to 6 weeks before the start of an interval throwing program. Although there is no well-defined postinjection recovery protocol, as a general rule rest was prescribed for the first 2 weeks, followed by a progressive stretching and strengthening program for the next month. Patients who were asymptomatic subjectively and clinically—negative moving valgus stress test, negative milking maneuver, no pain with valgus stress—were started on an interval throwing program.

Final follow-up involved a physical examination. Results were classified according to a modified version of the Conway Scale^12,24-26: excellent (return to preinjury level of competition or performance), good (return to play at a lower level of competition or performance or, specifically for baseball players, ability to throw in daily batting practice), fair (able to play recreationally), and poor (unable to return to previous sport at any level).

By final follow-up, all patients had completed their postoperative rehabilitation protocol, and all had at least tried to return to their previous activities. No patients were lost to follow-up.

Results

Of the 44 baseball players, 6 were professional, 14 were in college, and 24 were in high school. There were 36 pitchers and 8 position players. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Fifteen of the 44 players had an excellent outcome (34%), 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional baseball players returned to professional play. Five (36%) of the 14 college players had an excellent outcome, and 4 (17%) of the 24 high school players had an excellent outcome. Of the 8 position players, 4 had an excellent outcome, 3 had a good outcome, and 1 had a poor outcome.

Before treatment, all patients had medial-sided elbow pain over the UCL inhibiting their ability to throw. Mean duration of symptoms before injection was 8.8 months (range, 1-36 months). There was no correlation between symptom duration and any outcome measure. On MRI, 29 patients showed partial tears: 22 proximally based and 7 distally based. The other 15 patients had diffuse signal without partial tear. All 7 patients with distally based partial tears and 3 of the patients with proximally based partial tears had a poor outcome. Overall, there were 6 excellent, 7 good, and 2 fair outcomes in the partial-tear group. In the patients with diffuse signal without partial tear, there were 9 excellent and 10 good outcomes.

Mean time from injection to return to throwing was 5 weeks, and mean time to return to competition was 12 weeks (range, 5-24 weeks). The 1 player who returned at 5 weeks was a professional relief pitcher whose team was in the playoffs. He has now pitched for an additional 2 baseball seasons without elbow difficulty.

There were no injection-related complications.

Discussion

To our knowledge, this is the first report documenting successful PRP treatment of UCL insufficiency. In this study, 73% of players who had failed a course of conservative treatment had good to excellent outcomes with PRP injection.

Data on successful nonoperative treatment of UCL injuries are limited. Rettig and colleagues¹ treated 31 throwing athletes’ UCL injuries with a supervised rehabilitation program. Treatment included rest, use of anti-inflammatory medication, progressive strengthening, and an interval throwing program. Only 41% of the athletes returned to their previous level of play, and it took, on average, 24.5 weeks. There was no significant difference in age or in duration or acuity of symptoms between those who returned to play and those whose conservative treatment failed.

Surgical reconstruction of UCL injuries has been very successful, with upward of 90% of athletes returning to previous level of play.^3,27The procedure, however, is not without associated complications, including retear of the ligament, stiffness, ulnar nerve injury, and fracture.^27-29 In addition, even when successful, the procedure requires that athletes take 9 to 12 months to recover before returning to competition at their previous level.

Savoie and colleagues,³⁰ in their recent study on UCL repairs, highlighted an important fact that is often overlooked when reviewing the literature on UCL tears. Most of the literature on these injuries focuses on college and professional baseball players in whom ligament damage is often extensive, precluding repair. In contrast to prior reports, Savoie and colleagues³⁰ found excellent results in 93% of their young athletes who underwent UCL repair. It is possible that their results can be attributed to the fact that many of their athletes had tears isolated to one area of the ligament, as opposed to generalized ligament incompetence. Our improved results vis-à-vis other reports on conservative management may be attributable to the same phenomenon.

PRP has garnered much attention in the literature and media because of its potential to enhance healing of tendons and ligaments; in some cases, it can obviate the need for surgery. After failure of other nonoperative measures in 15 patients with elbow epicondylitis, Mishra and Pavelko⁸ treated each patient with a single PRP injection. They prepared the PRP using the GPS III system (Biomet). At final follow-up, 93% improvement was seen. Clearly, their experiment had design flaws: It was nonblinded, and 3 of the 5 patients in the control group treated with bupivacaine injection withdrew from the experiment. Despite its shortcomings, their study became the impetus for several other studies.

A larger, double-blinded, randomized controlled trial comparing PRP and cortisone injections for lateral epicondylitis in 100 patients is under way, and preliminary results have been published.⁹ A minimum of 6 months after injection, patients who received PRP showed more improvement in visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores. In another large, double-blinded, randomized controlled trial, patients with chronic lateral epicondylitis had significant improvements in VAS pain scores and DASH scores relative to patients injected with corticosteroids with a 2-year follow-up.³¹ Similarly, Thanasas and colleagues³² found significantly reduced VAS pain scores in patients injected with PRP versus autologous whole blood. Another study demonstrated improved tendon morphology using ultrasound imaging 6 months after PRP injection.³³

Contrary to these positive results, Krogh and colleagues³⁴ found that a single injection of PRP or glucocorticoid was not significantly superior to a saline injection for reducing pain and disability over a 3-month period in patients with lateral epicondylitis. Their study, however, had major flaws. Its original design called for a 12-month follow-up, but there was massive dropout in all 3 treatment arms, necessitating reporting of only 3-month data. In addition, 60% of the patients in the glucocorticoid group were not naïve to this treatment, so definitive conclusions about the efficacy of glucocorticoids could not be made.

In the present study, we successfully treated partial ligament tears with PRP injections. Sixty-seven percent of our baseball players returned to play at a mean of 4 months, much earlier than the 9 to 12 months typically required after ligament reconstruction. Many athletes, such as high school baseball players or aging veteran professional baseball players, do not have the luxury of 12 months for recovery. Therefore, this select group of patients clearly has a limited window of opportunity to return to play. In fact, these patients might be ideal candidates for PRP injections for UCL injuries. Return-to-play rates, however, differed significantly among professional players and nonprofessional players. The difference may be attributable to professional players’ conditioning, quality of physical therapy, extrinsic motivation, and other intangible factors. Four (67%) of our 6 professional baseball players returned to professional play after injection, whereas only 36% of college players and 17% of high school players had excellent outcomes.

Limitations

The present study had several weaknesses, several of which are inherent to PRP studies conducted so far. It was not a prospective, randomized controlled trial. It is important to note that PRP treatment in diseased tissue may have some drawbacks, as its success depends on the ability of healing tissue to use concentrated growth factors and cytokines to proliferate.³⁵ Thus, a chronically injured ligament with depleted active cells may have a diminished response to PRP. Another limitation of this study is that we evaluated outcomes based on return to play using the Conway Scale, which is well reported but not validated. Despite the potential weaknesses of this outcome scale, it has become the benchmark for measuring the success of outcomes of UCL reconstruction. Furthermore, we did not measure patients’ satisfaction with the treatment. Players who could not return to their preinjury level of play may have considered the treatment a failure regardless of their ability to continue throwing. Last, MRI was not repeated to document ligament healing. We did not routinely perform a second MRI because we thought it would not affect treatment. Several series have found a high incidence of abnormal signal in baseball players’ UCLs. In this group of patients, the most important outcome is return to previous level of competition.

This study raised several questions. Is one PRP brand better than another? Should more than 1 injection be given? What is the ideal postinjection protocol? Clearly, larger, prospective, randomized controlled studies are needed to truly elucidate the potential role of PRP in the treatment algorithm for UCL injury. Nevertheless, in certain cases in which traditional conservative measures have failed and patients do not have the luxury of rehabilitating for 9 to 12 months after surgery, PRP may be a viable treatment option.

Conclusion

In this study, use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.

For overhead athletes, elbow ulnar collateral ligament (UCL) insufficiency is a potential career-ending injury. Baseball players with UCL insufficiency typically complain of medial-sided elbow pain that affects their ability to throw. Loss of velocity, loss of control, difficulty warming up, and pain while throwing are all symptoms of UCL injury.

Classically, nonoperative treatment of UCL injuries involves activity modification, use of anti-inflammatory medication, and a structured physical therapy program. Asymptomatic players can return to throwing after a structured interval throwing program. Rettig and colleagues¹ found a 42% rate of success in conservatively treating UCL injuries in throwing athletes. UCL reconstruction is reserved for players with complete tears of the UCL or with partial tears after failed conservative treatment. Several techniques have been used to reconstruct the ligament, but successful outcomes depend on a long rehabilitation process. According to most published series, 85% to 90% of athletes who had UCL reconstruction returned to their previous level of play, but it took, on average, 9 to 12 months.^2,3 This prolonged recovery period is one reason that some older professional baseball players, as well as casual high school and college players, elect to forgo surgery.

Over the past few years, platelet-rich plasma (PRP) has garnered attention as a bridge between conservative treatment and surgery. PRP refers to a sample of autologous blood that contains a platelet concentration higher than baseline levels. This sample often has a 3 to 5 times increase in growth factor concentration.^4-6 Initial studies focused on its ability to successfully treat lateral epicondylitis.^7-9 More recent clinical work has shown that PRP can potentially enhance healing after anterior cruciate ligament reconstruction,^10-14 rotator cuff repair,^15-17 and subacromial decompression.^11,18-23 If PRP could be used to successfully treat UCL insufficiency that is refractory to conservative treatment, then year-long recovery periods could be avoided. This could potentially prolong certain athletes’ careers or, at the very least, allow them to return to play much sooner. In the present case series, we hypothesized that PRP injections could be used to successfully treat partial UCL tears in high-level throwing athletes, obviating the need for surgery and its associated prolonged recovery period.

Materials and Methods

Institutional Review Board approval was obtained for this retrospective study of 44 baseball players treated with PRP injections for partial-thickness UCL tears.

Patients provided written informed consent. They were diagnosed with UCL insufficiency by physical examination, and findings were confirmed by magnetic resonance imaging (MRI). After diagnosis, all throwers underwent a trial of conservative treatment that included rest, activity modification, use of anti-inflammatory medication, and physical therapy followed by an attempt to return to throwing using an interval throwing program.

Study inclusion criteria were physical examinations and MRI results consistent with UCL insufficiency, and failure of the conservative treatment plan described.

Patients were injected using the Autologous Conditioned Plasma system (Arthrex). PRP solutions were prepared according to manufacturer guidelines. After the elbow was prepared sterilely, the UCL was injected at the location of the tear. Typically, 3 mL of PRP was injected into the elbow. Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Repeat injections were considered for recalcitrant pain after 3 weeks.

After injection, patients used acetaminophen and ice for pain control. Anti-inflammatory medications were avoided for a minimum of 2 weeks after injection. Typical postinjection therapy protocol consisted of rest followed by progressive stretching and strengthening for about 4 to 6 weeks before the start of an interval throwing program. Although there is no well-defined postinjection recovery protocol, as a general rule rest was prescribed for the first 2 weeks, followed by a progressive stretching and strengthening program for the next month. Patients who were asymptomatic subjectively and clinically—negative moving valgus stress test, negative milking maneuver, no pain with valgus stress—were started on an interval throwing program.

Final follow-up involved a physical examination. Results were classified according to a modified version of the Conway Scale^12,24-26: excellent (return to preinjury level of competition or performance), good (return to play at a lower level of competition or performance or, specifically for baseball players, ability to throw in daily batting practice), fair (able to play recreationally), and poor (unable to return to previous sport at any level).

By final follow-up, all patients had completed their postoperative rehabilitation protocol, and all had at least tried to return to their previous activities. No patients were lost to follow-up.

Results

Of the 44 baseball players, 6 were professional, 14 were in college, and 24 were in high school. There were 36 pitchers and 8 position players. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Fifteen of the 44 players had an excellent outcome (34%), 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional baseball players returned to professional play. Five (36%) of the 14 college players had an excellent outcome, and 4 (17%) of the 24 high school players had an excellent outcome. Of the 8 position players, 4 had an excellent outcome, 3 had a good outcome, and 1 had a poor outcome.

Before treatment, all patients had medial-sided elbow pain over the UCL inhibiting their ability to throw. Mean duration of symptoms before injection was 8.8 months (range, 1-36 months). There was no correlation between symptom duration and any outcome measure. On MRI, 29 patients showed partial tears: 22 proximally based and 7 distally based. The other 15 patients had diffuse signal without partial tear. All 7 patients with distally based partial tears and 3 of the patients with proximally based partial tears had a poor outcome. Overall, there were 6 excellent, 7 good, and 2 fair outcomes in the partial-tear group. In the patients with diffuse signal without partial tear, there were 9 excellent and 10 good outcomes.

Mean time from injection to return to throwing was 5 weeks, and mean time to return to competition was 12 weeks (range, 5-24 weeks). The 1 player who returned at 5 weeks was a professional relief pitcher whose team was in the playoffs. He has now pitched for an additional 2 baseball seasons without elbow difficulty.

There were no injection-related complications.

Discussion

To our knowledge, this is the first report documenting successful PRP treatment of UCL insufficiency. In this study, 73% of players who had failed a course of conservative treatment had good to excellent outcomes with PRP injection.

Data on successful nonoperative treatment of UCL injuries are limited. Rettig and colleagues¹ treated 31 throwing athletes’ UCL injuries with a supervised rehabilitation program. Treatment included rest, use of anti-inflammatory medication, progressive strengthening, and an interval throwing program. Only 41% of the athletes returned to their previous level of play, and it took, on average, 24.5 weeks. There was no significant difference in age or in duration or acuity of symptoms between those who returned to play and those whose conservative treatment failed.

Surgical reconstruction of UCL injuries has been very successful, with upward of 90% of athletes returning to previous level of play.^3,27The procedure, however, is not without associated complications, including retear of the ligament, stiffness, ulnar nerve injury, and fracture.^27-29 In addition, even when successful, the procedure requires that athletes take 9 to 12 months to recover before returning to competition at their previous level.

Savoie and colleagues,³⁰ in their recent study on UCL repairs, highlighted an important fact that is often overlooked when reviewing the literature on UCL tears. Most of the literature on these injuries focuses on college and professional baseball players in whom ligament damage is often extensive, precluding repair. In contrast to prior reports, Savoie and colleagues³⁰ found excellent results in 93% of their young athletes who underwent UCL repair. It is possible that their results can be attributed to the fact that many of their athletes had tears isolated to one area of the ligament, as opposed to generalized ligament incompetence. Our improved results vis-à-vis other reports on conservative management may be attributable to the same phenomenon.

PRP has garnered much attention in the literature and media because of its potential to enhance healing of tendons and ligaments; in some cases, it can obviate the need for surgery. After failure of other nonoperative measures in 15 patients with elbow epicondylitis, Mishra and Pavelko⁸ treated each patient with a single PRP injection. They prepared the PRP using the GPS III system (Biomet). At final follow-up, 93% improvement was seen. Clearly, their experiment had design flaws: It was nonblinded, and 3 of the 5 patients in the control group treated with bupivacaine injection withdrew from the experiment. Despite its shortcomings, their study became the impetus for several other studies.

A larger, double-blinded, randomized controlled trial comparing PRP and cortisone injections for lateral epicondylitis in 100 patients is under way, and preliminary results have been published.⁹ A minimum of 6 months after injection, patients who received PRP showed more improvement in visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores. In another large, double-blinded, randomized controlled trial, patients with chronic lateral epicondylitis had significant improvements in VAS pain scores and DASH scores relative to patients injected with corticosteroids with a 2-year follow-up.³¹ Similarly, Thanasas and colleagues³² found significantly reduced VAS pain scores in patients injected with PRP versus autologous whole blood. Another study demonstrated improved tendon morphology using ultrasound imaging 6 months after PRP injection.³³

Contrary to these positive results, Krogh and colleagues³⁴ found that a single injection of PRP or glucocorticoid was not significantly superior to a saline injection for reducing pain and disability over a 3-month period in patients with lateral epicondylitis. Their study, however, had major flaws. Its original design called for a 12-month follow-up, but there was massive dropout in all 3 treatment arms, necessitating reporting of only 3-month data. In addition, 60% of the patients in the glucocorticoid group were not naïve to this treatment, so definitive conclusions about the efficacy of glucocorticoids could not be made.

In the present study, we successfully treated partial ligament tears with PRP injections. Sixty-seven percent of our baseball players returned to play at a mean of 4 months, much earlier than the 9 to 12 months typically required after ligament reconstruction. Many athletes, such as high school baseball players or aging veteran professional baseball players, do not have the luxury of 12 months for recovery. Therefore, this select group of patients clearly has a limited window of opportunity to return to play. In fact, these patients might be ideal candidates for PRP injections for UCL injuries. Return-to-play rates, however, differed significantly among professional players and nonprofessional players. The difference may be attributable to professional players’ conditioning, quality of physical therapy, extrinsic motivation, and other intangible factors. Four (67%) of our 6 professional baseball players returned to professional play after injection, whereas only 36% of college players and 17% of high school players had excellent outcomes.

Limitations

The present study had several weaknesses, several of which are inherent to PRP studies conducted so far. It was not a prospective, randomized controlled trial. It is important to note that PRP treatment in diseased tissue may have some drawbacks, as its success depends on the ability of healing tissue to use concentrated growth factors and cytokines to proliferate.³⁵ Thus, a chronically injured ligament with depleted active cells may have a diminished response to PRP. Another limitation of this study is that we evaluated outcomes based on return to play using the Conway Scale, which is well reported but not validated. Despite the potential weaknesses of this outcome scale, it has become the benchmark for measuring the success of outcomes of UCL reconstruction. Furthermore, we did not measure patients’ satisfaction with the treatment. Players who could not return to their preinjury level of play may have considered the treatment a failure regardless of their ability to continue throwing. Last, MRI was not repeated to document ligament healing. We did not routinely perform a second MRI because we thought it would not affect treatment. Several series have found a high incidence of abnormal signal in baseball players’ UCLs. In this group of patients, the most important outcome is return to previous level of competition.

This study raised several questions. Is one PRP brand better than another? Should more than 1 injection be given? What is the ideal postinjection protocol? Clearly, larger, prospective, randomized controlled studies are needed to truly elucidate the potential role of PRP in the treatment algorithm for UCL injury. Nevertheless, in certain cases in which traditional conservative measures have failed and patients do not have the luxury of rehabilitating for 9 to 12 months after surgery, PRP may be a viable treatment option.

Conclusion

In this study, use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.

Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.^1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.^1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.^5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.⁶ The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.

The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.^7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.^11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.^13-19

An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.^20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.^21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.^23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

Emerging Evidence

Multiple biomechanical studies have evaluated ADMs in RC models.^24-28 Barber and colleagues²⁴ demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues²⁵ subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).

A subsequent study by Barber and Aziz-Jacobo²⁶ compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.²⁶ Beitzel and colleagues²⁷ evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues²⁸ also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.

These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues²⁹ evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.³⁰ At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal³¹ retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues³² evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.^1-6

Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.^14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues¹⁴ obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues¹⁷ obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues¹⁹ evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues³³ evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.^{13,16,18,34,35} Bond and colleagues¹³ reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.¹³ These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.

Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.^36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.³⁸ This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.

Conclusion

The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.

Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.^1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.^1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.^5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.⁶ The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.

The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.^7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.^11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.^13-19

An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.^20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.^21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.^23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

Emerging Evidence

Multiple biomechanical studies have evaluated ADMs in RC models.^24-28 Barber and colleagues²⁴ demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues²⁵ subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).

A subsequent study by Barber and Aziz-Jacobo²⁶ compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.²⁶ Beitzel and colleagues²⁷ evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues²⁸ also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.

These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues²⁹ evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.³⁰ At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal³¹ retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues³² evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.^1-6

Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.^14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues¹⁴ obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues¹⁷ obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues¹⁹ evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues³³ evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.^{13,16,18,34,35} Bond and colleagues¹³ reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.¹³ These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.

Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.^36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.³⁸ This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.

Conclusion

The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.

Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.^1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.^1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.^5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.⁶ The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.

The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.^7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.^11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.^13-19

An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.^20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.^21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.^23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

Emerging Evidence

Multiple biomechanical studies have evaluated ADMs in RC models.^24-28 Barber and colleagues²⁴ demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues²⁵ subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).

A subsequent study by Barber and Aziz-Jacobo²⁶ compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.²⁶ Beitzel and colleagues²⁷ evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues²⁸ also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.

These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues²⁹ evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.³⁰ At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal³¹ retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues³² evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.^1-6

Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.^14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues¹⁴ obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues¹⁷ obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues¹⁹ evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues³³ evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.^{13,16,18,34,35} Bond and colleagues¹³ reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.¹³ These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.

Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.^36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.³⁸ This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.

Conclusion

The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.

Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.¹ It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.² However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.

Rotator Cuff Tears

Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.³ Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.^4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.^8-10

Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.^11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues¹⁶ performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).¹⁶ Zhao and colleagues¹⁷ reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.

Knee Osteoarthritis

Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.¹⁸ The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.

A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.^19-22 Campbell and colleagues²³ published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues²⁴ reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith²⁵ conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.

Ulnar Collateral Ligament Injuries

The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.

Podesta and colleagues²⁶ published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.

Lateral Elbow Epicondylitis

Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.^27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.³⁰ For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.^31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.³⁴ The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.^35-37

In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.³⁸ These physiologic changes may precede observable clinical improvements. Brklijac and colleagues³⁹ prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.

Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).^40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.^42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues⁴⁴ compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.

Hamstring Injuries

Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.⁴⁵ The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.⁴⁶ The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.⁴⁷ PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.

Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.^48,49 Wetzel and colleagues⁴⁸ retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues⁴⁹ conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).

Mejia and Bradley⁵⁰ have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues⁴⁹ performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.^51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.⁵³ In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.⁵⁴ Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.

Achilles Tendinopathy

Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.⁵⁵ Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.⁵⁶ For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.

In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues⁵⁷ conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues^58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.

Summary

In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.

Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.¹ It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.² However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.

Rotator Cuff Tears

Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.³ Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.^4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.^8-10

Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.^11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues¹⁶ performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).¹⁶ Zhao and colleagues¹⁷ reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.

Knee Osteoarthritis

Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.¹⁸ The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.

A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.^19-22 Campbell and colleagues²³ published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues²⁴ reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith²⁵ conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.

Ulnar Collateral Ligament Injuries

The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.

Podesta and colleagues²⁶ published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.

Lateral Elbow Epicondylitis

Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.^27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.³⁰ For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.^31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.³⁴ The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.^35-37

In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.³⁸ These physiologic changes may precede observable clinical improvements. Brklijac and colleagues³⁹ prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.

Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).^40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.^42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues⁴⁴ compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.

Hamstring Injuries

Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.⁴⁵ The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.⁴⁶ The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.⁴⁷ PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.

Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.^48,49 Wetzel and colleagues⁴⁸ retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues⁴⁹ conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).

Mejia and Bradley⁵⁰ have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues⁴⁹ performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.^51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.⁵³ In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.⁵⁴ Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.

Achilles Tendinopathy

Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.⁵⁵ Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.⁵⁶ For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.

In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues⁵⁷ conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues^58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.

Summary

In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.

Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.¹ It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.² However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.

Rotator Cuff Tears

Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.³ Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.^4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.^8-10

Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.^11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues¹⁶ performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).¹⁶ Zhao and colleagues¹⁷ reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.

Knee Osteoarthritis

Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.¹⁸ The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.

A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.^19-22 Campbell and colleagues²³ published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues²⁴ reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith²⁵ conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.

Ulnar Collateral Ligament Injuries

The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.

Podesta and colleagues²⁶ published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.

Lateral Elbow Epicondylitis

Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.^27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.³⁰ For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.^31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.³⁴ The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.^35-37

In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.³⁸ These physiologic changes may precede observable clinical improvements. Brklijac and colleagues³⁹ prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.

Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).^40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.^42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues⁴⁴ compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.

Hamstring Injuries

Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.⁴⁵ The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.⁴⁶ The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.⁴⁷ PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.

Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.^48,49 Wetzel and colleagues⁴⁸ retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues⁴⁹ conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).

Mejia and Bradley⁵⁰ have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues⁴⁹ performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.^51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.⁵³ In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.⁵⁴ Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.

Achilles Tendinopathy

Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.⁵⁵ Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.⁵⁶ For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.

In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues⁵⁷ conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues^58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.

Summary

In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.