The Diagnosis: Eccrine Poroma

A shave biopsy of the lesion was performed for definitive diagnosis and demonstrated a well-circumscribed tumor with cords and broad columns composed of uniform basaloid cells extending into the dermis and in areas connecting to the overlying epidermis (Figure). There also were small ducts and cysts admixed in the tumor columns that were embedded in a tumor stroma rich in blood vessels. A diagnosis of eccrine poroma was made based on these characteristic histologic features.

Biopsy revealed a basaloid tumor originating from the epidermis and extending into the dermis (A)(H&E, original magnification ×4). On higher magnification, ducts were evident amongst the tumor cells and a vascular rich stroma was revealed (B)(H&E, original magnification ×10).

First described by Pinkus et al¹ in 1956, eccrine poroma is a benign neoplasm of cells from the intraepidermal ductal portion of the eccrine sweat gland. Eccrine poroma (along with hidroacanthoma simplex, dermal duct tumor, and poroid hidradenoma) is one of the poroid neoplasms, which account for approximately 10% of all primary sweat gland tumors.² Eccrine poroma usually is seen in patients over 40 years of age without any predilection for race or sex.

Characteristically, eccrine poromas clinically manifest as solitary, firm, sharply demarcated papules or nodules that may be sessile or pedunculated and rarely exceed 2 cm in diameter. This entity classically presents on acral, non–hair-bearing areas (eg, palms and soles). Eccrine poromas have a wide range of clinical appearances that can lead to broad differential diagnoses³ and have been described as flesh-colored,³ pink to red,⁴ purple,⁵ and pigmented^3,4 papules or nodules depending on features such as blood vessel proliferation and pigment deposition.

Eccrine poromas also have been reported on hair-bearing areas of the body, including the head,³ neck,^3,6 chest,^4,6 hip,⁷ and pubic area,⁸ despite the paucity of eccrine glands in these areas on the body. These findings suggest that these neoplasms may not be purely eccrine in origin. The wide range of clinical presentations of eccrine poromas has prompted investigation into further classification and delineation of this neoplasm.³ The occurrence of eccrine poromas on areas of the skin known to have few eccrine glands suggests that eccrine poromas may not be purely comprised of eccrine ducts and instead may be of apocrine origin.^3,9,10 Histologic features of eccrine poromas that suggest apocrine origination include sebaceous and follicular differentiation (eg, folliculocentric distribution), the association with the follicular infundibulum, and the presence of follicular germ cells.^3,9,10 Thus, apocrine gland involvement in eccrine poromas may account for their appearance in anatomic areas that do not have high concentrations of eccrine glands, such as the trunk and pubic area.

Based on these findings, eccrine poromas may therefore be of eccrine and/or apocrine origin; however, the nomenclature of this neoplasm remains confusing and possibly misleading, as the term eccrine poroma continues to be accepted even in instances in which the differentiation appears to be largely apocrine. The terms poroma and eccrine poroma often are used interchangeably, which contributes to the confusion by failing to acknowledge the possibility of apocrine influence and possibly causing the clinician to exclude eccrine poromas from the differential diagnosis in areas that do not have high concentrations of eccrine glands.

Because of their high degree of clinical variability, characteristic acral location, and misleading nomenclature, eccrine poromas often are mistakenly confused with a long list of other cutaneous neoplasms, including hemangiomas, pyogenic granulomas, melanocytic nevi, warts, cysts, and other adnexal neoplasms.³ In our case, the lesion was abnormally large and was clinically concerning for an unusual sebaceous nevus. Its location on the lower back is not commonly noted and should remind the clinician of the possibility of apocrine differentiation. Clinicians should be aware of the wide phenotypic diversity of eccrine poromas, and therefore they should consider this diagnosis in their differential diagnosis for solitary papules or nodules occurring in any anatomic area.

The Diagnosis: Eccrine Poroma

A shave biopsy of the lesion was performed for definitive diagnosis and demonstrated a well-circumscribed tumor with cords and broad columns composed of uniform basaloid cells extending into the dermis and in areas connecting to the overlying epidermis (Figure). There also were small ducts and cysts admixed in the tumor columns that were embedded in a tumor stroma rich in blood vessels. A diagnosis of eccrine poroma was made based on these characteristic histologic features.

Biopsy revealed a basaloid tumor originating from the epidermis and extending into the dermis (A)(H&E, original magnification ×4). On higher magnification, ducts were evident amongst the tumor cells and a vascular rich stroma was revealed (B)(H&E, original magnification ×10).

First described by Pinkus et al¹ in 1956, eccrine poroma is a benign neoplasm of cells from the intraepidermal ductal portion of the eccrine sweat gland. Eccrine poroma (along with hidroacanthoma simplex, dermal duct tumor, and poroid hidradenoma) is one of the poroid neoplasms, which account for approximately 10% of all primary sweat gland tumors.² Eccrine poroma usually is seen in patients over 40 years of age without any predilection for race or sex.

Characteristically, eccrine poromas clinically manifest as solitary, firm, sharply demarcated papules or nodules that may be sessile or pedunculated and rarely exceed 2 cm in diameter. This entity classically presents on acral, non–hair-bearing areas (eg, palms and soles). Eccrine poromas have a wide range of clinical appearances that can lead to broad differential diagnoses³ and have been described as flesh-colored,³ pink to red,⁴ purple,⁵ and pigmented^3,4 papules or nodules depending on features such as blood vessel proliferation and pigment deposition.

Eccrine poromas also have been reported on hair-bearing areas of the body, including the head,³ neck,^3,6 chest,^4,6 hip,⁷ and pubic area,⁸ despite the paucity of eccrine glands in these areas on the body. These findings suggest that these neoplasms may not be purely eccrine in origin. The wide range of clinical presentations of eccrine poromas has prompted investigation into further classification and delineation of this neoplasm.³ The occurrence of eccrine poromas on areas of the skin known to have few eccrine glands suggests that eccrine poromas may not be purely comprised of eccrine ducts and instead may be of apocrine origin.^3,9,10 Histologic features of eccrine poromas that suggest apocrine origination include sebaceous and follicular differentiation (eg, folliculocentric distribution), the association with the follicular infundibulum, and the presence of follicular germ cells.^3,9,10 Thus, apocrine gland involvement in eccrine poromas may account for their appearance in anatomic areas that do not have high concentrations of eccrine glands, such as the trunk and pubic area.

Based on these findings, eccrine poromas may therefore be of eccrine and/or apocrine origin; however, the nomenclature of this neoplasm remains confusing and possibly misleading, as the term eccrine poroma continues to be accepted even in instances in which the differentiation appears to be largely apocrine. The terms poroma and eccrine poroma often are used interchangeably, which contributes to the confusion by failing to acknowledge the possibility of apocrine influence and possibly causing the clinician to exclude eccrine poromas from the differential diagnosis in areas that do not have high concentrations of eccrine glands.

Because of their high degree of clinical variability, characteristic acral location, and misleading nomenclature, eccrine poromas often are mistakenly confused with a long list of other cutaneous neoplasms, including hemangiomas, pyogenic granulomas, melanocytic nevi, warts, cysts, and other adnexal neoplasms.³ In our case, the lesion was abnormally large and was clinically concerning for an unusual sebaceous nevus. Its location on the lower back is not commonly noted and should remind the clinician of the possibility of apocrine differentiation. Clinicians should be aware of the wide phenotypic diversity of eccrine poromas, and therefore they should consider this diagnosis in their differential diagnosis for solitary papules or nodules occurring in any anatomic area.

The Diagnosis: Eccrine Poroma

A shave biopsy of the lesion was performed for definitive diagnosis and demonstrated a well-circumscribed tumor with cords and broad columns composed of uniform basaloid cells extending into the dermis and in areas connecting to the overlying epidermis (Figure). There also were small ducts and cysts admixed in the tumor columns that were embedded in a tumor stroma rich in blood vessels. A diagnosis of eccrine poroma was made based on these characteristic histologic features.

Biopsy revealed a basaloid tumor originating from the epidermis and extending into the dermis (A)(H&E, original magnification ×4). On higher magnification, ducts were evident amongst the tumor cells and a vascular rich stroma was revealed (B)(H&E, original magnification ×10).

First described by Pinkus et al¹ in 1956, eccrine poroma is a benign neoplasm of cells from the intraepidermal ductal portion of the eccrine sweat gland. Eccrine poroma (along with hidroacanthoma simplex, dermal duct tumor, and poroid hidradenoma) is one of the poroid neoplasms, which account for approximately 10% of all primary sweat gland tumors.² Eccrine poroma usually is seen in patients over 40 years of age without any predilection for race or sex.

Characteristically, eccrine poromas clinically manifest as solitary, firm, sharply demarcated papules or nodules that may be sessile or pedunculated and rarely exceed 2 cm in diameter. This entity classically presents on acral, non–hair-bearing areas (eg, palms and soles). Eccrine poromas have a wide range of clinical appearances that can lead to broad differential diagnoses³ and have been described as flesh-colored,³ pink to red,⁴ purple,⁵ and pigmented^3,4 papules or nodules depending on features such as blood vessel proliferation and pigment deposition.

Eccrine poromas also have been reported on hair-bearing areas of the body, including the head,³ neck,^3,6 chest,^4,6 hip,⁷ and pubic area,⁸ despite the paucity of eccrine glands in these areas on the body. These findings suggest that these neoplasms may not be purely eccrine in origin. The wide range of clinical presentations of eccrine poromas has prompted investigation into further classification and delineation of this neoplasm.³ The occurrence of eccrine poromas on areas of the skin known to have few eccrine glands suggests that eccrine poromas may not be purely comprised of eccrine ducts and instead may be of apocrine origin.^3,9,10 Histologic features of eccrine poromas that suggest apocrine origination include sebaceous and follicular differentiation (eg, folliculocentric distribution), the association with the follicular infundibulum, and the presence of follicular germ cells.^3,9,10 Thus, apocrine gland involvement in eccrine poromas may account for their appearance in anatomic areas that do not have high concentrations of eccrine glands, such as the trunk and pubic area.

Based on these findings, eccrine poromas may therefore be of eccrine and/or apocrine origin; however, the nomenclature of this neoplasm remains confusing and possibly misleading, as the term eccrine poroma continues to be accepted even in instances in which the differentiation appears to be largely apocrine. The terms poroma and eccrine poroma often are used interchangeably, which contributes to the confusion by failing to acknowledge the possibility of apocrine influence and possibly causing the clinician to exclude eccrine poromas from the differential diagnosis in areas that do not have high concentrations of eccrine glands.

Because of their high degree of clinical variability, characteristic acral location, and misleading nomenclature, eccrine poromas often are mistakenly confused with a long list of other cutaneous neoplasms, including hemangiomas, pyogenic granulomas, melanocytic nevi, warts, cysts, and other adnexal neoplasms.³ In our case, the lesion was abnormally large and was clinically concerning for an unusual sebaceous nevus. Its location on the lower back is not commonly noted and should remind the clinician of the possibility of apocrine differentiation. Clinicians should be aware of the wide phenotypic diversity of eccrine poromas, and therefore they should consider this diagnosis in their differential diagnosis for solitary papules or nodules occurring in any anatomic area.

Patients undergoing mitral valve replacement had a lower risk of regurgitation and heart failure–related adverse events at 2 years than those undergoing valve repair, according to the results of a trial presented at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

The results of the trial appear to associate mitral valve replacement with clinical advantages over mitral valve repair after 2 years of follow-up. However, replacement held no significant advantages over repair in the primary endpoint of left ventricular end-systolic volume index (LVESVI) or in overall survival, said Dr. Daniel Goldstein of the department of cardiothoracic surgery at Montefiore Medical Center, New York.

In the trial conducted by the Cardiothoracic Surgical Trials Network (CTSN), 251 patients with chronic severe ischemic mitral regurgitation were randomly assigned to undergo surgical repair of the mitral valve or to receive a mitral valve replacement with a prosthetic and procedure selected at the discretion of the surgeon.

In addition to the primary endpoint of LVESVI, the two approaches were also compared for survival, regurgitation recurrence, and heart failure events.

At 2 years, the mean change from baseline in LVESVI, a measure of remodeling, did not differ significantly between the repair and replacement arms (–9.0 vs. –6.5 mL/m², respectively). In addition, although the 2-year mortality rate was numerically lower in the repair arm relative to the replacement arm (19% vs. 23.2%, respectively), it was also not statistically different (P = .39).

However, the rate of recurrence of moderate or severe mitral regurgitation favored replacement over repair and was significant (3.8% vs. 58.8%, respectively; P less than .001). In addition, the rate of cardiovascular readmissions was significantly lower in the replacement group (P = .01).

For those in the repair group, there were significant trends for more serious adverse events related to heart failure (P = .05) and for a lower quality of life improvement (P = .07) on the Minnesota Living With Heart Failure questionnaire. There were no significant differences in rates of all serious adverse events or overall readmissions.

All of the differences between groups observed at 2 years amplify differences previously reported after 12 months (N Engl J Med. 2014 Jan 2;370[1]:23-32). For example, the difference in the rate of moderate to severe regurgitation favoring replacement over repair was already significant at that time (2.3% vs. 32.6%, respectively; P less than .001), even though the mortality rates were then, as now, numerically lower in the repair group versus the replacement group (14.3% vs. 17.6%, respectively; P = .45).

Dr. Goldstein reported no relevant financial relationships.

Patients undergoing mitral valve replacement had a lower risk of regurgitation and heart failure–related adverse events at 2 years than those undergoing valve repair, according to the results of a trial presented at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

The results of the trial appear to associate mitral valve replacement with clinical advantages over mitral valve repair after 2 years of follow-up. However, replacement held no significant advantages over repair in the primary endpoint of left ventricular end-systolic volume index (LVESVI) or in overall survival, said Dr. Daniel Goldstein of the department of cardiothoracic surgery at Montefiore Medical Center, New York.

In the trial conducted by the Cardiothoracic Surgical Trials Network (CTSN), 251 patients with chronic severe ischemic mitral regurgitation were randomly assigned to undergo surgical repair of the mitral valve or to receive a mitral valve replacement with a prosthetic and procedure selected at the discretion of the surgeon.

In addition to the primary endpoint of LVESVI, the two approaches were also compared for survival, regurgitation recurrence, and heart failure events.

At 2 years, the mean change from baseline in LVESVI, a measure of remodeling, did not differ significantly between the repair and replacement arms (–9.0 vs. –6.5 mL/m², respectively). In addition, although the 2-year mortality rate was numerically lower in the repair arm relative to the replacement arm (19% vs. 23.2%, respectively), it was also not statistically different (P = .39).

However, the rate of recurrence of moderate or severe mitral regurgitation favored replacement over repair and was significant (3.8% vs. 58.8%, respectively; P less than .001). In addition, the rate of cardiovascular readmissions was significantly lower in the replacement group (P = .01).

For those in the repair group, there were significant trends for more serious adverse events related to heart failure (P = .05) and for a lower quality of life improvement (P = .07) on the Minnesota Living With Heart Failure questionnaire. There were no significant differences in rates of all serious adverse events or overall readmissions.

All of the differences between groups observed at 2 years amplify differences previously reported after 12 months (N Engl J Med. 2014 Jan 2;370[1]:23-32). For example, the difference in the rate of moderate to severe regurgitation favoring replacement over repair was already significant at that time (2.3% vs. 32.6%, respectively; P less than .001), even though the mortality rates were then, as now, numerically lower in the repair group versus the replacement group (14.3% vs. 17.6%, respectively; P = .45).

Dr. Goldstein reported no relevant financial relationships.

Patients undergoing mitral valve replacement had a lower risk of regurgitation and heart failure–related adverse events at 2 years than those undergoing valve repair, according to the results of a trial presented at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

The results of the trial appear to associate mitral valve replacement with clinical advantages over mitral valve repair after 2 years of follow-up. However, replacement held no significant advantages over repair in the primary endpoint of left ventricular end-systolic volume index (LVESVI) or in overall survival, said Dr. Daniel Goldstein of the department of cardiothoracic surgery at Montefiore Medical Center, New York.

In the trial conducted by the Cardiothoracic Surgical Trials Network (CTSN), 251 patients with chronic severe ischemic mitral regurgitation were randomly assigned to undergo surgical repair of the mitral valve or to receive a mitral valve replacement with a prosthetic and procedure selected at the discretion of the surgeon.

In addition to the primary endpoint of LVESVI, the two approaches were also compared for survival, regurgitation recurrence, and heart failure events.

At 2 years, the mean change from baseline in LVESVI, a measure of remodeling, did not differ significantly between the repair and replacement arms (–9.0 vs. –6.5 mL/m², respectively). In addition, although the 2-year mortality rate was numerically lower in the repair arm relative to the replacement arm (19% vs. 23.2%, respectively), it was also not statistically different (P = .39).

However, the rate of recurrence of moderate or severe mitral regurgitation favored replacement over repair and was significant (3.8% vs. 58.8%, respectively; P less than .001). In addition, the rate of cardiovascular readmissions was significantly lower in the replacement group (P = .01).

For those in the repair group, there were significant trends for more serious adverse events related to heart failure (P = .05) and for a lower quality of life improvement (P = .07) on the Minnesota Living With Heart Failure questionnaire. There were no significant differences in rates of all serious adverse events or overall readmissions.

All of the differences between groups observed at 2 years amplify differences previously reported after 12 months (N Engl J Med. 2014 Jan 2;370[1]:23-32). For example, the difference in the rate of moderate to severe regurgitation favoring replacement over repair was already significant at that time (2.3% vs. 32.6%, respectively; P less than .001), even though the mortality rates were then, as now, numerically lower in the repair group versus the replacement group (14.3% vs. 17.6%, respectively; P = .45).

Dr. Goldstein reported no relevant financial relationships.

NEW YORK - Atrial fibrillation (AF) is associated with an increased risk of dementia, especially in younger individuals, according to results from the Rotterdam Study.

"When we started this study, we hypothesized that the hazard of atrial fibrillation would be higher with longer exposure, but to find such a strong exposure-time association in younger participants was striking," said Dr. Frank J. Wolters from Erasmus Medical Center in Rotterdam, the Netherlands.

"It emphasizes that prevention of dementia doesn't start when people report to their physician with mild memory complaints, but years, if not decades before, by identifying those at risk and optimizing preventive strategies," he said by email.

An earlier report from the Rotterdam Study showed that AF is more prevalent in people with dementia, but the cross-sectional design did not allow conclusions regarding a causal relationship.

Dr. Wolters's team investigated the association between AF and dementia during a follow up of 20 years of nearly 6,200 participants in the Rotterdam Study.

About 5% of the participants had AF at baseline, and 15.3% of these individuals developed dementia during more than 81,000 person-years of follow-up.

Another 11.7% developed AF later, and 15.0% developed dementia during more than 79,000 person-years, the researchers report in JAMA Neurology, online September 21.

People who had AF at the start of the study had a 34% increased risk of dementia (compared with those who did not have prevalent AF), and people who developed AF during follow-up had a 23% increased risk of dementia (compared with those who did not have incident AF).

The association between AF and dementia was strongest in persons younger than the median age (67 years), and in these younger participants, the risk of dementia was higher with increasing duration of AF.

"As we found atrial fibrillation to increase the risk of dementia independent of clinical stroke, either chronic hypoperfusion or more acutely silent infarcts or perhaps cortical microinfarcts could account for the increased risk of dementia," Dr. Wolters said.

"A few observational studies have suggested beneficialeffect of treatment of atrial fibrillation on the risk of dementia, but more evidence on treatment efficacy is sorely needed. This includes insight into whether optimal treatment consists of anticoagulation, heart rhythm, or rate control," he noted.

"With regard to treatment of atrial fibrillation, until further evidence on efficacy becomes available, it is worth realizing that optimal adherence to current guidelines may contribute to prevention of cognitive decline in addition to prevention of stroke," Dr. Wolters added. "Although we found the strongest associations between atrial fibrillation and dementia for younger people, the need to determine treatment efficacy is just as profound in the elderly."

Dr. Sanjay Dixit, director of cardiac electrophysiology at Philadelphia VA Medical Center in Pennsylvania, said by email, "Although the association between AF and dementia has been shown, it's difficult to establish cause and effect. As I point out in my previous review, obstructive sleep apnea (OSA) is considered to be a major contributor to the development of neurocognitive decline and dementia. OSA is very common in the AF population and many consider this to be (a) risk factor in the development of AF. So the question remains whether AF is the cause of dementia or other co-morbidities such as OSA that frequently co-exist in the AF population."

"Look for AF in patients with dementia and also caution patients with AF of the possibility of developing this condition in the future," Dr. Dixit advised. "Since catheter ablation therapy has been shown to have better outcomes for long-term control of AF than drugs, physicians should discuss this with patients and consider referring them to cardiac electrophysiologists early in the course of the disease."

Dr. T. Jared Bunch, director of heart rhythm services for Intermountain Healthcare, Murray, Utah, said by email, "It is great to see another confirmatory study that found essentially the same thing we did 5 years ago. These data in aggregate make the likelihood of the association much more compelling."

"What is interesting in our subsequent work is the patients more sensitive to poor warfarin management (low times in therapeutic range) were at the highest relative risk of dementia compared to older patients," Dr. Bunch explained. "Now we all need to start to unravel the mechanisms behind it and find avenues of preventative treatment. The choice and manner of anticoagulant treatment is one and allowing faster heart rates is another."

Dr. Shih-An Chen and Dr. Tzu-Fan Chao from Taipei Veterans General Hospital, Taipei, Taiwan, who recently reported on the independent association between AF and dementia, struck a more cautious note.

"Only when a lower risk of dementia can be achieved by AF ablation in the prospective and randomized trial can we conclude that AF is the direct cause of dementia," they said in a joint email. "It should also be noted that the development of dementia is multifactorial, and AF only represents one of them."

NEW YORK - Atrial fibrillation (AF) is associated with an increased risk of dementia, especially in younger individuals, according to results from the Rotterdam Study.

"When we started this study, we hypothesized that the hazard of atrial fibrillation would be higher with longer exposure, but to find such a strong exposure-time association in younger participants was striking," said Dr. Frank J. Wolters from Erasmus Medical Center in Rotterdam, the Netherlands.

"It emphasizes that prevention of dementia doesn't start when people report to their physician with mild memory complaints, but years, if not decades before, by identifying those at risk and optimizing preventive strategies," he said by email.

An earlier report from the Rotterdam Study showed that AF is more prevalent in people with dementia, but the cross-sectional design did not allow conclusions regarding a causal relationship.

Dr. Wolters's team investigated the association between AF and dementia during a follow up of 20 years of nearly 6,200 participants in the Rotterdam Study.

About 5% of the participants had AF at baseline, and 15.3% of these individuals developed dementia during more than 81,000 person-years of follow-up.

Another 11.7% developed AF later, and 15.0% developed dementia during more than 79,000 person-years, the researchers report in JAMA Neurology, online September 21.

People who had AF at the start of the study had a 34% increased risk of dementia (compared with those who did not have prevalent AF), and people who developed AF during follow-up had a 23% increased risk of dementia (compared with those who did not have incident AF).

The association between AF and dementia was strongest in persons younger than the median age (67 years), and in these younger participants, the risk of dementia was higher with increasing duration of AF.

"As we found atrial fibrillation to increase the risk of dementia independent of clinical stroke, either chronic hypoperfusion or more acutely silent infarcts or perhaps cortical microinfarcts could account for the increased risk of dementia," Dr. Wolters said.

"A few observational studies have suggested beneficialeffect of treatment of atrial fibrillation on the risk of dementia, but more evidence on treatment efficacy is sorely needed. This includes insight into whether optimal treatment consists of anticoagulation, heart rhythm, or rate control," he noted.

"With regard to treatment of atrial fibrillation, until further evidence on efficacy becomes available, it is worth realizing that optimal adherence to current guidelines may contribute to prevention of cognitive decline in addition to prevention of stroke," Dr. Wolters added. "Although we found the strongest associations between atrial fibrillation and dementia for younger people, the need to determine treatment efficacy is just as profound in the elderly."

Dr. Sanjay Dixit, director of cardiac electrophysiology at Philadelphia VA Medical Center in Pennsylvania, said by email, "Although the association between AF and dementia has been shown, it's difficult to establish cause and effect. As I point out in my previous review, obstructive sleep apnea (OSA) is considered to be a major contributor to the development of neurocognitive decline and dementia. OSA is very common in the AF population and many consider this to be (a) risk factor in the development of AF. So the question remains whether AF is the cause of dementia or other co-morbidities such as OSA that frequently co-exist in the AF population."

"Look for AF in patients with dementia and also caution patients with AF of the possibility of developing this condition in the future," Dr. Dixit advised. "Since catheter ablation therapy has been shown to have better outcomes for long-term control of AF than drugs, physicians should discuss this with patients and consider referring them to cardiac electrophysiologists early in the course of the disease."

Dr. T. Jared Bunch, director of heart rhythm services for Intermountain Healthcare, Murray, Utah, said by email, "It is great to see another confirmatory study that found essentially the same thing we did 5 years ago. These data in aggregate make the likelihood of the association much more compelling."

"What is interesting in our subsequent work is the patients more sensitive to poor warfarin management (low times in therapeutic range) were at the highest relative risk of dementia compared to older patients," Dr. Bunch explained. "Now we all need to start to unravel the mechanisms behind it and find avenues of preventative treatment. The choice and manner of anticoagulant treatment is one and allowing faster heart rates is another."

Dr. Shih-An Chen and Dr. Tzu-Fan Chao from Taipei Veterans General Hospital, Taipei, Taiwan, who recently reported on the independent association between AF and dementia, struck a more cautious note.

"Only when a lower risk of dementia can be achieved by AF ablation in the prospective and randomized trial can we conclude that AF is the direct cause of dementia," they said in a joint email. "It should also be noted that the development of dementia is multifactorial, and AF only represents one of them."

NEW YORK - Atrial fibrillation (AF) is associated with an increased risk of dementia, especially in younger individuals, according to results from the Rotterdam Study.

"When we started this study, we hypothesized that the hazard of atrial fibrillation would be higher with longer exposure, but to find such a strong exposure-time association in younger participants was striking," said Dr. Frank J. Wolters from Erasmus Medical Center in Rotterdam, the Netherlands.

"It emphasizes that prevention of dementia doesn't start when people report to their physician with mild memory complaints, but years, if not decades before, by identifying those at risk and optimizing preventive strategies," he said by email.

An earlier report from the Rotterdam Study showed that AF is more prevalent in people with dementia, but the cross-sectional design did not allow conclusions regarding a causal relationship.

Dr. Wolters's team investigated the association between AF and dementia during a follow up of 20 years of nearly 6,200 participants in the Rotterdam Study.

About 5% of the participants had AF at baseline, and 15.3% of these individuals developed dementia during more than 81,000 person-years of follow-up.

Another 11.7% developed AF later, and 15.0% developed dementia during more than 79,000 person-years, the researchers report in JAMA Neurology, online September 21.

People who had AF at the start of the study had a 34% increased risk of dementia (compared with those who did not have prevalent AF), and people who developed AF during follow-up had a 23% increased risk of dementia (compared with those who did not have incident AF).

The association between AF and dementia was strongest in persons younger than the median age (67 years), and in these younger participants, the risk of dementia was higher with increasing duration of AF.

"As we found atrial fibrillation to increase the risk of dementia independent of clinical stroke, either chronic hypoperfusion or more acutely silent infarcts or perhaps cortical microinfarcts could account for the increased risk of dementia," Dr. Wolters said.

"A few observational studies have suggested beneficialeffect of treatment of atrial fibrillation on the risk of dementia, but more evidence on treatment efficacy is sorely needed. This includes insight into whether optimal treatment consists of anticoagulation, heart rhythm, or rate control," he noted.

"With regard to treatment of atrial fibrillation, until further evidence on efficacy becomes available, it is worth realizing that optimal adherence to current guidelines may contribute to prevention of cognitive decline in addition to prevention of stroke," Dr. Wolters added. "Although we found the strongest associations between atrial fibrillation and dementia for younger people, the need to determine treatment efficacy is just as profound in the elderly."

Dr. Sanjay Dixit, director of cardiac electrophysiology at Philadelphia VA Medical Center in Pennsylvania, said by email, "Although the association between AF and dementia has been shown, it's difficult to establish cause and effect. As I point out in my previous review, obstructive sleep apnea (OSA) is considered to be a major contributor to the development of neurocognitive decline and dementia. OSA is very common in the AF population and many consider this to be (a) risk factor in the development of AF. So the question remains whether AF is the cause of dementia or other co-morbidities such as OSA that frequently co-exist in the AF population."

"Look for AF in patients with dementia and also caution patients with AF of the possibility of developing this condition in the future," Dr. Dixit advised. "Since catheter ablation therapy has been shown to have better outcomes for long-term control of AF than drugs, physicians should discuss this with patients and consider referring them to cardiac electrophysiologists early in the course of the disease."

Dr. T. Jared Bunch, director of heart rhythm services for Intermountain Healthcare, Murray, Utah, said by email, "It is great to see another confirmatory study that found essentially the same thing we did 5 years ago. These data in aggregate make the likelihood of the association much more compelling."

"What is interesting in our subsequent work is the patients more sensitive to poor warfarin management (low times in therapeutic range) were at the highest relative risk of dementia compared to older patients," Dr. Bunch explained. "Now we all need to start to unravel the mechanisms behind it and find avenues of preventative treatment. The choice and manner of anticoagulant treatment is one and allowing faster heart rates is another."

Dr. Shih-An Chen and Dr. Tzu-Fan Chao from Taipei Veterans General Hospital, Taipei, Taiwan, who recently reported on the independent association between AF and dementia, struck a more cautious note.

"Only when a lower risk of dementia can be achieved by AF ablation in the prospective and randomized trial can we conclude that AF is the direct cause of dementia," they said in a joint email. "It should also be noted that the development of dementia is multifactorial, and AF only represents one of them."

Click here to download the PDF.

Click here to download the PDF.

Click here to download the PDF.

Layla Richards, the first

person treated with UCART19

Photo courtesy of GOSH

A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.

The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.

Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla

is now free of leukemia.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.

“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”

Layla’s history

Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”

Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.

A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.

Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.

“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”

UCART19 treatment

Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.

But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.

Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 10⁶/kg) of UCART19.

After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.

The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.

She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.

More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.

Layla Richards, the first

person treated with UCART19

Photo courtesy of GOSH

A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.

The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.

Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla

is now free of leukemia.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.

“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”

Layla’s history

Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”

Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.

A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.

Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.

“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”

UCART19 treatment

Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.

But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.

Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 10⁶/kg) of UCART19.

After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.

The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.

She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.

More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.

Layla Richards, the first

person treated with UCART19

Photo courtesy of GOSH

A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.

The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.

Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla

is now free of leukemia.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.

“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”

Layla’s history

Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”

Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.

A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.

Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.

“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”

UCART19 treatment

Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.

But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.

Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 10⁶/kg) of UCART19.

After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.

The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.

She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.

More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.

John Dick, PhD

University Health Network

Results of a study published in Science challenge traditional ideas about how blood is made.

The findings suggest hematopoiesis does not occur through a gradual process consisting of multipotent, oligopotent, and unilineage progenitor stages.

Rather, hematopoietic stem cells (HSCs) mature into different types of blood cells quickly, and the process differs between early human development (fetal liver HSCs) and adulthood (HSCs from bone marrow).

The research indicates “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” said study investigator John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

He and his colleagues mapped the lineage potential of nearly 3000 single cells from 33 different populations of HSCs obtained from human blood samples taken at various life stages and ages.

The team’s discoveries build on research published in Science in 2011. In that paper, Dr Dick and his colleagues described isolating an HSC in its purest form—as a single cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” Dr Dick said.

“When we burrowed further to study these ‘daughters,’ we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.”

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

The investigators believe this work could help advance the manufacture of blood cells in the lab, and it should aid the study of blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases—from anemia . . . to leukemia,” Dr Dick said. “Think of it as moving from the old world of black-and-white television into the new world of high-definition.”

John Dick, PhD

University Health Network

Results of a study published in Science challenge traditional ideas about how blood is made.

The findings suggest hematopoiesis does not occur through a gradual process consisting of multipotent, oligopotent, and unilineage progenitor stages.

Rather, hematopoietic stem cells (HSCs) mature into different types of blood cells quickly, and the process differs between early human development (fetal liver HSCs) and adulthood (HSCs from bone marrow).

The research indicates “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” said study investigator John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

He and his colleagues mapped the lineage potential of nearly 3000 single cells from 33 different populations of HSCs obtained from human blood samples taken at various life stages and ages.

The team’s discoveries build on research published in Science in 2011. In that paper, Dr Dick and his colleagues described isolating an HSC in its purest form—as a single cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” Dr Dick said.

“When we burrowed further to study these ‘daughters,’ we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.”

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

The investigators believe this work could help advance the manufacture of blood cells in the lab, and it should aid the study of blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases—from anemia . . . to leukemia,” Dr Dick said. “Think of it as moving from the old world of black-and-white television into the new world of high-definition.”

John Dick, PhD

University Health Network

Results of a study published in Science challenge traditional ideas about how blood is made.

The findings suggest hematopoiesis does not occur through a gradual process consisting of multipotent, oligopotent, and unilineage progenitor stages.

Rather, hematopoietic stem cells (HSCs) mature into different types of blood cells quickly, and the process differs between early human development (fetal liver HSCs) and adulthood (HSCs from bone marrow).

The research indicates “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” said study investigator John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

He and his colleagues mapped the lineage potential of nearly 3000 single cells from 33 different populations of HSCs obtained from human blood samples taken at various life stages and ages.

The team’s discoveries build on research published in Science in 2011. In that paper, Dr Dick and his colleagues described isolating an HSC in its purest form—as a single cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” Dr Dick said.

“When we burrowed further to study these ‘daughters,’ we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.”

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

The investigators believe this work could help advance the manufacture of blood cells in the lab, and it should aid the study of blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases—from anemia . . . to leukemia,” Dr Dick said. “Think of it as moving from the old world of black-and-white television into the new world of high-definition.”

Only four short-term, randomized trials have addressed the safety, efficacy, and tolerability of cannabinoids for treating rheumatic diseases, and all have methodologic weaknesses and a high risk of bias, according to a qualitative review of data published since 1946.

“There is low-quality evidence suggesting that cannabinoids may be associated with improvements in pain and sleep quality in rheumatoid arthritis and fibromyalgia. Clinical positive effects for the studies assessed in this review must be balanced by the reported adverse events,” wrote Dr. Mary-Ann Fitzcharles of McGill University, Montreal, and her colleagues (Arthritis Care Res. 2015 Nov 9. doi: 10.1002/acr.22727).

©Thinkstock.com

The four randomized clinical trials, ranging in duration from 2 to 8 weeks, included one with 58 rheumatoid arthritis patients, two with a total of 71 fibromyalgia patients, and one with 74 osteoarthritis patients. Three trials met their respective primary endpoints and found a statistically significant effect of cannabinoids on pain (in two studies), sleep (in two studies), and improved quality of life (in one study). The investigators noted a high incidence (generally observed in 25%-50% of subjects) of mild to moderate side effects (dizziness, drowsiness, nausea, dry mouth) and many methodologic weaknesses in the evaluated data. The study that tested a fatty acid amide hydrolase inhibitor in osteoarthritis patients was stopped early due to futility. The other three completed studies were associated with an overall high risk of bias.

One of the two fibromyalgia studies was a randomized, double-blind, placebo-controlled trial conducted in 2008 that assessed nabilone in 40 fibromyalgia patients. Nabilone treatment led to significant decreases in the visual analog scale for pain (–2.04, P less than .02) at 4 weeks. A second fibromyalgia trial from 2010 compared amitriptyline to nabilone in 31 subjects and found the latter agent to be superior on the primary endpoint of difference in score on the Insomnia Severity Index (difference = 3.2; 95% confidence interval, 1.2-5.3). A 2006 rheumatoid arthritis trial found that cannabis-based Sativex demonstrated a clinically meaningful advantage over placebo for the primary endpoint of morning pain on movement (difference of –0.95, 95% CI, –1.83 to –0.02; P = .044). No trials assessed herbal cannabis.

“It is not currently possible to recommend this category of treatments as therapy for patients with rheumatic diseases. Any conclusions based on these studies remain tenuous and call for larger, well controlled clinical trials to better understand potential benefits and risks as pertaining to rheumatic conditions,” Dr. Fitzcharles and her coauthors wrote.

No relevant financial disclosures were reported.

[email protected]

Only four short-term, randomized trials have addressed the safety, efficacy, and tolerability of cannabinoids for treating rheumatic diseases, and all have methodologic weaknesses and a high risk of bias, according to a qualitative review of data published since 1946.

“There is low-quality evidence suggesting that cannabinoids may be associated with improvements in pain and sleep quality in rheumatoid arthritis and fibromyalgia. Clinical positive effects for the studies assessed in this review must be balanced by the reported adverse events,” wrote Dr. Mary-Ann Fitzcharles of McGill University, Montreal, and her colleagues (Arthritis Care Res. 2015 Nov 9. doi: 10.1002/acr.22727).

©Thinkstock.com

The four randomized clinical trials, ranging in duration from 2 to 8 weeks, included one with 58 rheumatoid arthritis patients, two with a total of 71 fibromyalgia patients, and one with 74 osteoarthritis patients. Three trials met their respective primary endpoints and found a statistically significant effect of cannabinoids on pain (in two studies), sleep (in two studies), and improved quality of life (in one study). The investigators noted a high incidence (generally observed in 25%-50% of subjects) of mild to moderate side effects (dizziness, drowsiness, nausea, dry mouth) and many methodologic weaknesses in the evaluated data. The study that tested a fatty acid amide hydrolase inhibitor in osteoarthritis patients was stopped early due to futility. The other three completed studies were associated with an overall high risk of bias.

One of the two fibromyalgia studies was a randomized, double-blind, placebo-controlled trial conducted in 2008 that assessed nabilone in 40 fibromyalgia patients. Nabilone treatment led to significant decreases in the visual analog scale for pain (–2.04, P less than .02) at 4 weeks. A second fibromyalgia trial from 2010 compared amitriptyline to nabilone in 31 subjects and found the latter agent to be superior on the primary endpoint of difference in score on the Insomnia Severity Index (difference = 3.2; 95% confidence interval, 1.2-5.3). A 2006 rheumatoid arthritis trial found that cannabis-based Sativex demonstrated a clinically meaningful advantage over placebo for the primary endpoint of morning pain on movement (difference of –0.95, 95% CI, –1.83 to –0.02; P = .044). No trials assessed herbal cannabis.

“It is not currently possible to recommend this category of treatments as therapy for patients with rheumatic diseases. Any conclusions based on these studies remain tenuous and call for larger, well controlled clinical trials to better understand potential benefits and risks as pertaining to rheumatic conditions,” Dr. Fitzcharles and her coauthors wrote.

No relevant financial disclosures were reported.

[email protected]

Only four short-term, randomized trials have addressed the safety, efficacy, and tolerability of cannabinoids for treating rheumatic diseases, and all have methodologic weaknesses and a high risk of bias, according to a qualitative review of data published since 1946.

“There is low-quality evidence suggesting that cannabinoids may be associated with improvements in pain and sleep quality in rheumatoid arthritis and fibromyalgia. Clinical positive effects for the studies assessed in this review must be balanced by the reported adverse events,” wrote Dr. Mary-Ann Fitzcharles of McGill University, Montreal, and her colleagues (Arthritis Care Res. 2015 Nov 9. doi: 10.1002/acr.22727).

©Thinkstock.com

The four randomized clinical trials, ranging in duration from 2 to 8 weeks, included one with 58 rheumatoid arthritis patients, two with a total of 71 fibromyalgia patients, and one with 74 osteoarthritis patients. Three trials met their respective primary endpoints and found a statistically significant effect of cannabinoids on pain (in two studies), sleep (in two studies), and improved quality of life (in one study). The investigators noted a high incidence (generally observed in 25%-50% of subjects) of mild to moderate side effects (dizziness, drowsiness, nausea, dry mouth) and many methodologic weaknesses in the evaluated data. The study that tested a fatty acid amide hydrolase inhibitor in osteoarthritis patients was stopped early due to futility. The other three completed studies were associated with an overall high risk of bias.

One of the two fibromyalgia studies was a randomized, double-blind, placebo-controlled trial conducted in 2008 that assessed nabilone in 40 fibromyalgia patients. Nabilone treatment led to significant decreases in the visual analog scale for pain (–2.04, P less than .02) at 4 weeks. A second fibromyalgia trial from 2010 compared amitriptyline to nabilone in 31 subjects and found the latter agent to be superior on the primary endpoint of difference in score on the Insomnia Severity Index (difference = 3.2; 95% confidence interval, 1.2-5.3). A 2006 rheumatoid arthritis trial found that cannabis-based Sativex demonstrated a clinically meaningful advantage over placebo for the primary endpoint of morning pain on movement (difference of –0.95, 95% CI, –1.83 to –0.02; P = .044). No trials assessed herbal cannabis.

“It is not currently possible to recommend this category of treatments as therapy for patients with rheumatic diseases. Any conclusions based on these studies remain tenuous and call for larger, well controlled clinical trials to better understand potential benefits and risks as pertaining to rheumatic conditions,” Dr. Fitzcharles and her coauthors wrote.

No relevant financial disclosures were reported.

[email protected]

Regular corticosteroid injections over 2 years were relatively safe for osteoarthritic knees in a trial from Tufts Medical Center in Boston, but they did not slow the progression of joint damage or improve patient outcomes.

The findings come at a time when the role of intra-articular steroid shots is up for debate. They are widely used for knee osteoarthritis (OA) in the hopes of reducing cartilage damage from synovitis, but there’s also concern that they might actually harm cartilage and periarticular bone.

The investigators, led by Dr. Timothy McAlindon, chief of rheumatology at Tufts Medical Center, sought to bring some data to the table. “Our objective was to test the potential for disease modification of synovitic knee OA by triamcinolone hexacetonide [THA] in a clinical trial with comprehensive measurement of effects on cartilage and subchondral bone using MRI and DXA [dual-energy x-ray absorptiometry],” they said.

The investigators randomized 140 patients with symptomatic knee OA (Kellgren-Lawrence grade 2 or 3) and synovitis on ultrasound to either 40 mg THA or saline knee injections every 3 months for 2 years. Randomization was blocked and stratified by gender and Kellgren-Lawrence grade. Patients had clinical assessments at each visit and annual MRIs and DXA knee and hip scans.

There were no significant between-group differences over the course of the study in mean changes on Western Ontario and McMaster Universities Arthritis Index pain (–2.2 for THA vs. –2.8 for placebo; P = .3) and function scores (–7.1 for THA vs. –9.2 for placebo; P = .4), and no differences in chair stand (–1.1 for THA vs. –1.6 for placebo; P = .8) or walk time tests (–0.5 for THA vs. –0.03 for placebo; P = .5).

There were no significant differences on MRI or DXA, except that the steroid group had greater cartilage loss and the placebo group greater progression of fibrillation.

“The greater rate of loss of cartilage thickness ... in the treated group was small in magnitude and of uncertain clinical significance,” said Dr. McAlindon.

The mean body mass index in the study was 31.2 kg/m². Just over half the subjects were women, and about two-thirds were white. More than 90% of patients in both groups completed the study.

The work was funded by the National Institutes of Health. The investigators have no relevant disclosures.

[email protected]

Regular corticosteroid injections over 2 years were relatively safe for osteoarthritic knees in a trial from Tufts Medical Center in Boston, but they did not slow the progression of joint damage or improve patient outcomes.

The findings come at a time when the role of intra-articular steroid shots is up for debate. They are widely used for knee osteoarthritis (OA) in the hopes of reducing cartilage damage from synovitis, but there’s also concern that they might actually harm cartilage and periarticular bone.

The investigators, led by Dr. Timothy McAlindon, chief of rheumatology at Tufts Medical Center, sought to bring some data to the table. “Our objective was to test the potential for disease modification of synovitic knee OA by triamcinolone hexacetonide [THA] in a clinical trial with comprehensive measurement of effects on cartilage and subchondral bone using MRI and DXA [dual-energy x-ray absorptiometry],” they said.

The investigators randomized 140 patients with symptomatic knee OA (Kellgren-Lawrence grade 2 or 3) and synovitis on ultrasound to either 40 mg THA or saline knee injections every 3 months for 2 years. Randomization was blocked and stratified by gender and Kellgren-Lawrence grade. Patients had clinical assessments at each visit and annual MRIs and DXA knee and hip scans.

There were no significant between-group differences over the course of the study in mean changes on Western Ontario and McMaster Universities Arthritis Index pain (–2.2 for THA vs. –2.8 for placebo; P = .3) and function scores (–7.1 for THA vs. –9.2 for placebo; P = .4), and no differences in chair stand (–1.1 for THA vs. –1.6 for placebo; P = .8) or walk time tests (–0.5 for THA vs. –0.03 for placebo; P = .5).

There were no significant differences on MRI or DXA, except that the steroid group had greater cartilage loss and the placebo group greater progression of fibrillation.

“The greater rate of loss of cartilage thickness ... in the treated group was small in magnitude and of uncertain clinical significance,” said Dr. McAlindon.

The mean body mass index in the study was 31.2 kg/m². Just over half the subjects were women, and about two-thirds were white. More than 90% of patients in both groups completed the study.

The work was funded by the National Institutes of Health. The investigators have no relevant disclosures.

[email protected]

Regular corticosteroid injections over 2 years were relatively safe for osteoarthritic knees in a trial from Tufts Medical Center in Boston, but they did not slow the progression of joint damage or improve patient outcomes.

The findings come at a time when the role of intra-articular steroid shots is up for debate. They are widely used for knee osteoarthritis (OA) in the hopes of reducing cartilage damage from synovitis, but there’s also concern that they might actually harm cartilage and periarticular bone.

The investigators, led by Dr. Timothy McAlindon, chief of rheumatology at Tufts Medical Center, sought to bring some data to the table. “Our objective was to test the potential for disease modification of synovitic knee OA by triamcinolone hexacetonide [THA] in a clinical trial with comprehensive measurement of effects on cartilage and subchondral bone using MRI and DXA [dual-energy x-ray absorptiometry],” they said.

The investigators randomized 140 patients with symptomatic knee OA (Kellgren-Lawrence grade 2 or 3) and synovitis on ultrasound to either 40 mg THA or saline knee injections every 3 months for 2 years. Randomization was blocked and stratified by gender and Kellgren-Lawrence grade. Patients had clinical assessments at each visit and annual MRIs and DXA knee and hip scans.

There were no significant between-group differences over the course of the study in mean changes on Western Ontario and McMaster Universities Arthritis Index pain (–2.2 for THA vs. –2.8 for placebo; P = .3) and function scores (–7.1 for THA vs. –9.2 for placebo; P = .4), and no differences in chair stand (–1.1 for THA vs. –1.6 for placebo; P = .8) or walk time tests (–0.5 for THA vs. –0.03 for placebo; P = .5).

There were no significant differences on MRI or DXA, except that the steroid group had greater cartilage loss and the placebo group greater progression of fibrillation.

“The greater rate of loss of cartilage thickness ... in the treated group was small in magnitude and of uncertain clinical significance,” said Dr. McAlindon.

The mean body mass index in the study was 31.2 kg/m². Just over half the subjects were women, and about two-thirds were white. More than 90% of patients in both groups completed the study.

The work was funded by the National Institutes of Health. The investigators have no relevant disclosures.

[email protected]

SAN DIEGO – Neither fish oil nor aspirin can be recommended for prevention of primary arteriovenous fistula failure in patients with advanced renal disease, a randomized trial showed.

“AVF failure increases patient morbidity and health provider costs,” Dr. Ashley B. Irish said during a press briefing at a meeting sponsored by the American Society of Nephrology. “Therefore, therapies to reduce AVF failure may reduce patient outcomes and reduce costs. But it remains uncertain whether targeting antiplatelet agents to affect thrombosis is going to improve the numbers of AVFs you can actually use.”

In a randomized trial known as Fish Oils and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED), Dr. Irish and his associates set out to determine whether omega-3 polyunsaturated fatty acids (fish oil) can reduce new AVF access failure at 12 months. The secondary outcome was to determine if aspirin would have the same effect.

Doug Brunk/Frontline Medical News

The intervention consisted of 12 weeks of fish oil 4 g or placebo (olive oil) divided in two doses. A subset of patients were randomized to aspirin 100 mg or matching placebo in addition to fish oil or placebo in a factorial design, said Dr, Irish, of the department of nephrology at Fiona Stanley Hospital, Perth, Australia. AVF failure was defined as AVF thrombosis and/or abandonment and/or cannulation formation.

The study was carried out at centers in Australia, Malaysia, and the United Kingdom, and included 567 patients with stage 4 or stage 5 chronic kidney disease who were either on dialysis or who were expected to start within 12 months. Their mean age was 55 years, 63% were male, 46% had diabetes, but only 16% were on vascular dialysis. “So, these patients were a little bit healthier than you might expect in usual populations of people on dialysis,” Dr. Irish said.

The researchers found that fish oil had no effect on preventing AVF failure. In fact, 47% of patients who received fish oil had a failed AVF at 12 months, compared with 47% of those who received placebo (relative risk after adjusting for aspirin use was 1.03).

“So, nearly half of all patients in this trial had no usable AVF at 12 months after surgery,” Dr. Irish said. “It didn’t matter whether you were old or young, had vascular disease, or were diabetic or not. Fish oil didn’t help.”

Aspirin didn’t work, either. In fact, 45% of those who received aspirin had a failed AVF at 12 months, compared with 43% of those who received placebo (RR, 1.05).

Dr. Irish noted that the proportion of serious adverse events was low and similar between patients who received fish oil and those who received or aspirin. “The treatment was safe; it just didn’t work,” he said.

“This study and others have shown that trying to prevent AVFs from clotting or promoting their development by inhibiting platelets and blood vessel changes is not effective,” Dr. Irish explained. “The focus might need to shift to other strategies, such as preserving blood vessels from damage, surgical techniques, and modification of vessel walls by infrared and other pharmacological treatments.”

Dr. Irish characterized the study results as “disappointing, because these therapies are cheap, safe, and readily available. But it’s not a waste of time, because now we know that this avenue of approach in research is not going to lead us anywhere. It’s time to move on. This information will help us inform practice and plan new trials.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Neither fish oil nor aspirin can be recommended for prevention of primary arteriovenous fistula failure in patients with advanced renal disease, a randomized trial showed.

“AVF failure increases patient morbidity and health provider costs,” Dr. Ashley B. Irish said during a press briefing at a meeting sponsored by the American Society of Nephrology. “Therefore, therapies to reduce AVF failure may reduce patient outcomes and reduce costs. But it remains uncertain whether targeting antiplatelet agents to affect thrombosis is going to improve the numbers of AVFs you can actually use.”

In a randomized trial known as Fish Oils and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED), Dr. Irish and his associates set out to determine whether omega-3 polyunsaturated fatty acids (fish oil) can reduce new AVF access failure at 12 months. The secondary outcome was to determine if aspirin would have the same effect.

Doug Brunk/Frontline Medical News

The intervention consisted of 12 weeks of fish oil 4 g or placebo (olive oil) divided in two doses. A subset of patients were randomized to aspirin 100 mg or matching placebo in addition to fish oil or placebo in a factorial design, said Dr, Irish, of the department of nephrology at Fiona Stanley Hospital, Perth, Australia. AVF failure was defined as AVF thrombosis and/or abandonment and/or cannulation formation.

The study was carried out at centers in Australia, Malaysia, and the United Kingdom, and included 567 patients with stage 4 or stage 5 chronic kidney disease who were either on dialysis or who were expected to start within 12 months. Their mean age was 55 years, 63% were male, 46% had diabetes, but only 16% were on vascular dialysis. “So, these patients were a little bit healthier than you might expect in usual populations of people on dialysis,” Dr. Irish said.

The researchers found that fish oil had no effect on preventing AVF failure. In fact, 47% of patients who received fish oil had a failed AVF at 12 months, compared with 47% of those who received placebo (relative risk after adjusting for aspirin use was 1.03).

“So, nearly half of all patients in this trial had no usable AVF at 12 months after surgery,” Dr. Irish said. “It didn’t matter whether you were old or young, had vascular disease, or were diabetic or not. Fish oil didn’t help.”

Aspirin didn’t work, either. In fact, 45% of those who received aspirin had a failed AVF at 12 months, compared with 43% of those who received placebo (RR, 1.05).

Dr. Irish noted that the proportion of serious adverse events was low and similar between patients who received fish oil and those who received or aspirin. “The treatment was safe; it just didn’t work,” he said.

“This study and others have shown that trying to prevent AVFs from clotting or promoting their development by inhibiting platelets and blood vessel changes is not effective,” Dr. Irish explained. “The focus might need to shift to other strategies, such as preserving blood vessels from damage, surgical techniques, and modification of vessel walls by infrared and other pharmacological treatments.”

Dr. Irish characterized the study results as “disappointing, because these therapies are cheap, safe, and readily available. But it’s not a waste of time, because now we know that this avenue of approach in research is not going to lead us anywhere. It’s time to move on. This information will help us inform practice and plan new trials.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Neither fish oil nor aspirin can be recommended for prevention of primary arteriovenous fistula failure in patients with advanced renal disease, a randomized trial showed.

“AVF failure increases patient morbidity and health provider costs,” Dr. Ashley B. Irish said during a press briefing at a meeting sponsored by the American Society of Nephrology. “Therefore, therapies to reduce AVF failure may reduce patient outcomes and reduce costs. But it remains uncertain whether targeting antiplatelet agents to affect thrombosis is going to improve the numbers of AVFs you can actually use.”

In a randomized trial known as Fish Oils and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED), Dr. Irish and his associates set out to determine whether omega-3 polyunsaturated fatty acids (fish oil) can reduce new AVF access failure at 12 months. The secondary outcome was to determine if aspirin would have the same effect.

Doug Brunk/Frontline Medical News

The intervention consisted of 12 weeks of fish oil 4 g or placebo (olive oil) divided in two doses. A subset of patients were randomized to aspirin 100 mg or matching placebo in addition to fish oil or placebo in a factorial design, said Dr, Irish, of the department of nephrology at Fiona Stanley Hospital, Perth, Australia. AVF failure was defined as AVF thrombosis and/or abandonment and/or cannulation formation.

The study was carried out at centers in Australia, Malaysia, and the United Kingdom, and included 567 patients with stage 4 or stage 5 chronic kidney disease who were either on dialysis or who were expected to start within 12 months. Their mean age was 55 years, 63% were male, 46% had diabetes, but only 16% were on vascular dialysis. “So, these patients were a little bit healthier than you might expect in usual populations of people on dialysis,” Dr. Irish said.

The researchers found that fish oil had no effect on preventing AVF failure. In fact, 47% of patients who received fish oil had a failed AVF at 12 months, compared with 47% of those who received placebo (relative risk after adjusting for aspirin use was 1.03).

“So, nearly half of all patients in this trial had no usable AVF at 12 months after surgery,” Dr. Irish said. “It didn’t matter whether you were old or young, had vascular disease, or were diabetic or not. Fish oil didn’t help.”

Aspirin didn’t work, either. In fact, 45% of those who received aspirin had a failed AVF at 12 months, compared with 43% of those who received placebo (RR, 1.05).

Dr. Irish noted that the proportion of serious adverse events was low and similar between patients who received fish oil and those who received or aspirin. “The treatment was safe; it just didn’t work,” he said.

“This study and others have shown that trying to prevent AVFs from clotting or promoting their development by inhibiting platelets and blood vessel changes is not effective,” Dr. Irish explained. “The focus might need to shift to other strategies, such as preserving blood vessels from damage, surgical techniques, and modification of vessel walls by infrared and other pharmacological treatments.”

Dr. Irish characterized the study results as “disappointing, because these therapies are cheap, safe, and readily available. But it’s not a waste of time, because now we know that this avenue of approach in research is not going to lead us anywhere. It’s time to move on. This information will help us inform practice and plan new trials.”

The researchers reported having no financial disclosures.

[email protected]