The TPA ambulance, armed with its own CT scanner, has arrived in the United States after several successful years in Germany.

Now what?

Like all new advances, it’s a difficult balance between costs and benefits. The money, in the end, is what it really comes down to. Will the cost of a CT ambulance, the equipment needed to send images to a radiologist, the extra training for EMTs, the price of stocking TPA on board, and maybe even having a neurologist on the ride (or telemedicine for one to see the patient) be offset by money saved on rehabilitation costs, better recoveries, fewer complications, even returning a patient to work?

I have no idea. I’m not sure anyone else does, either.

Certainly, I support the idea of improved stroke care. Although far from ideal, TPA is the only thing we have right now, and the sooner it’s given, the better. Most neurologists will agree. But who’s going to pay for this?

The insurance companies, obviously. But money is finite. What if we upgrade all these ambulances, only to find that there’s no significant cost savings on rehab and recovery when TPA is used in the field? Then the money comes out of doctors’ and nurses’ salaries, higher premiums for everyone, and a cutback in treatment for some other disorder. I’m pretty sure it won’t be taken out of an insurance executive’s year-end bonus.

And just try explaining that to the family of a stroke victim.

It’s not practical to put a CT scanner in every ambulance, so where do we put those so equipped? Again, there’s no easy answer. In areas with large retirement communities? Seems like a safe bet, but young people have strokes, too. Only in cities? More people live in cities, but those in rural areas may be too far from a hospital to receive TPA early. Shouldn’t they have one, too?

Who’s going to make the decision to send the TPA ambulance vs. the regular ambulance? That’s another tough question. The layman who calls in usually isn’t sure what’s going on, only that an ambulance is needed. The dispatcher often can’t tell over the phone if the patient has had a stroke, seizure, or psychogenic event. Should a neurologist or emergency medicine physician make the decision? Maybe, but how much extra time will it take to get one on the line? And, even then, they’ll be making a critical decision with sparse, secondhand information. What if the special ambulance is mistakenly sent to deal with a conversion disorder, only to have a legitimate stroke occur elsewhere when it’s no longer immediately available? That, inevitably, will lead to a lawsuit because the wrong ambulance was sent.

I’m not against the stroke ambulance – far from it – but there are still a lot questions to be answered. Putting a CT scanner and TPA in an ambulance is, comparatively, the easiest part.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The TPA ambulance, armed with its own CT scanner, has arrived in the United States after several successful years in Germany.

Now what?

Like all new advances, it’s a difficult balance between costs and benefits. The money, in the end, is what it really comes down to. Will the cost of a CT ambulance, the equipment needed to send images to a radiologist, the extra training for EMTs, the price of stocking TPA on board, and maybe even having a neurologist on the ride (or telemedicine for one to see the patient) be offset by money saved on rehabilitation costs, better recoveries, fewer complications, even returning a patient to work?

I have no idea. I’m not sure anyone else does, either.

Certainly, I support the idea of improved stroke care. Although far from ideal, TPA is the only thing we have right now, and the sooner it’s given, the better. Most neurologists will agree. But who’s going to pay for this?

The insurance companies, obviously. But money is finite. What if we upgrade all these ambulances, only to find that there’s no significant cost savings on rehab and recovery when TPA is used in the field? Then the money comes out of doctors’ and nurses’ salaries, higher premiums for everyone, and a cutback in treatment for some other disorder. I’m pretty sure it won’t be taken out of an insurance executive’s year-end bonus.

And just try explaining that to the family of a stroke victim.

It’s not practical to put a CT scanner in every ambulance, so where do we put those so equipped? Again, there’s no easy answer. In areas with large retirement communities? Seems like a safe bet, but young people have strokes, too. Only in cities? More people live in cities, but those in rural areas may be too far from a hospital to receive TPA early. Shouldn’t they have one, too?

Who’s going to make the decision to send the TPA ambulance vs. the regular ambulance? That’s another tough question. The layman who calls in usually isn’t sure what’s going on, only that an ambulance is needed. The dispatcher often can’t tell over the phone if the patient has had a stroke, seizure, or psychogenic event. Should a neurologist or emergency medicine physician make the decision? Maybe, but how much extra time will it take to get one on the line? And, even then, they’ll be making a critical decision with sparse, secondhand information. What if the special ambulance is mistakenly sent to deal with a conversion disorder, only to have a legitimate stroke occur elsewhere when it’s no longer immediately available? That, inevitably, will lead to a lawsuit because the wrong ambulance was sent.

I’m not against the stroke ambulance – far from it – but there are still a lot questions to be answered. Putting a CT scanner and TPA in an ambulance is, comparatively, the easiest part.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The TPA ambulance, armed with its own CT scanner, has arrived in the United States after several successful years in Germany.

Now what?

Like all new advances, it’s a difficult balance between costs and benefits. The money, in the end, is what it really comes down to. Will the cost of a CT ambulance, the equipment needed to send images to a radiologist, the extra training for EMTs, the price of stocking TPA on board, and maybe even having a neurologist on the ride (or telemedicine for one to see the patient) be offset by money saved on rehabilitation costs, better recoveries, fewer complications, even returning a patient to work?

I have no idea. I’m not sure anyone else does, either.

Certainly, I support the idea of improved stroke care. Although far from ideal, TPA is the only thing we have right now, and the sooner it’s given, the better. Most neurologists will agree. But who’s going to pay for this?

The insurance companies, obviously. But money is finite. What if we upgrade all these ambulances, only to find that there’s no significant cost savings on rehab and recovery when TPA is used in the field? Then the money comes out of doctors’ and nurses’ salaries, higher premiums for everyone, and a cutback in treatment for some other disorder. I’m pretty sure it won’t be taken out of an insurance executive’s year-end bonus.

And just try explaining that to the family of a stroke victim.

It’s not practical to put a CT scanner in every ambulance, so where do we put those so equipped? Again, there’s no easy answer. In areas with large retirement communities? Seems like a safe bet, but young people have strokes, too. Only in cities? More people live in cities, but those in rural areas may be too far from a hospital to receive TPA early. Shouldn’t they have one, too?

Who’s going to make the decision to send the TPA ambulance vs. the regular ambulance? That’s another tough question. The layman who calls in usually isn’t sure what’s going on, only that an ambulance is needed. The dispatcher often can’t tell over the phone if the patient has had a stroke, seizure, or psychogenic event. Should a neurologist or emergency medicine physician make the decision? Maybe, but how much extra time will it take to get one on the line? And, even then, they’ll be making a critical decision with sparse, secondhand information. What if the special ambulance is mistakenly sent to deal with a conversion disorder, only to have a legitimate stroke occur elsewhere when it’s no longer immediately available? That, inevitably, will lead to a lawsuit because the wrong ambulance was sent.

I’m not against the stroke ambulance – far from it – but there are still a lot questions to be answered. Putting a CT scanner and TPA in an ambulance is, comparatively, the easiest part.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Plasma for transfusion

Photo by Cristina Granados

The US Food and Drug Administration (FDA) has approved a revised label for the pooled plasma product Octaplas, increasing the product’s shelf life.

The new label says Octaplas can now be stored frozen, at or below -18°C (-0.4°F), for 3 years from the date of manufacture.

And thawed Octaplas should be used within 24 hours if refrigerated (between 1°C and 6°C/33.8°F to 42.8°F) or within 8 hours if stored at room temperature (between 20°C and 25°C/68°F to 77°F)

The previous product label said frozen Octaplas could be stored for 2 years, and thawed Octaplas should be used within 12 hours if stored between 2°C and 4°C (35.6°F to 39.2°F) or within 3 hours if stored between 20°C and 25°C (68°F to 77°F).

About Octaplas

Octaplas is a sterile, frozen solution of human plasma from several donors that has been treated with a solvent detergent process to minimize the risk of serious virus transmission. The plasma is collected from US donors who have been screened and tested for diseases transmitted by blood.

Octaplas gained FDA approval in January 2013. The product is indicated for the replacement of multiple coagulation factors in patients with acquired deficiencies due to liver disease or undergoing cardiac surgery or liver transplant. Octaplas can also be used for plasma exchange in patients with thrombotic thrombocytopenic purpura.

Octaplas is contraindicated in patients with immunoglobulin A deficiency, severe deficiency of protein S, history of hypersensitivity to fresh-frozen plasma or to plasma-derived products including any plasma protein, or a history of hypersensitivity reaction to Octaplas.

Serious adverse events observed in clinical trials of Octaplas were anaphylactic shock, citrate toxicity, and severe hypotension. The most common adverse events observed in 1% of patients or more included pruritus, urticaria, nausea, headache, and paresthesia.

Transfusion reactions can occur with ABO blood group mismatches. High infusion rates can induce hypervolemia with consequent pulmonary edema or cardiac failure. Excessive bleeding due to hyperfibrinolysis can occur due to low levels of alpha2-antiplasmin.

Thrombosis can occur due to low levels of protein S. Citrate toxicity can occur with transfusion rates exceeding 1 mL/kg/min of Octaplas. As Octaplas is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, the variant Creutzfeldt-Jakob disease agent, and, theoretically, the Creutzfeldt-Jakob disease agent.

For more details on Octaplas, see the complete prescribing information.

Plasma for transfusion

Photo by Cristina Granados

The US Food and Drug Administration (FDA) has approved a revised label for the pooled plasma product Octaplas, increasing the product’s shelf life.

The new label says Octaplas can now be stored frozen, at or below -18°C (-0.4°F), for 3 years from the date of manufacture.

And thawed Octaplas should be used within 24 hours if refrigerated (between 1°C and 6°C/33.8°F to 42.8°F) or within 8 hours if stored at room temperature (between 20°C and 25°C/68°F to 77°F)

The previous product label said frozen Octaplas could be stored for 2 years, and thawed Octaplas should be used within 12 hours if stored between 2°C and 4°C (35.6°F to 39.2°F) or within 3 hours if stored between 20°C and 25°C (68°F to 77°F).

About Octaplas

Octaplas is a sterile, frozen solution of human plasma from several donors that has been treated with a solvent detergent process to minimize the risk of serious virus transmission. The plasma is collected from US donors who have been screened and tested for diseases transmitted by blood.

Octaplas gained FDA approval in January 2013. The product is indicated for the replacement of multiple coagulation factors in patients with acquired deficiencies due to liver disease or undergoing cardiac surgery or liver transplant. Octaplas can also be used for plasma exchange in patients with thrombotic thrombocytopenic purpura.

Octaplas is contraindicated in patients with immunoglobulin A deficiency, severe deficiency of protein S, history of hypersensitivity to fresh-frozen plasma or to plasma-derived products including any plasma protein, or a history of hypersensitivity reaction to Octaplas.

Serious adverse events observed in clinical trials of Octaplas were anaphylactic shock, citrate toxicity, and severe hypotension. The most common adverse events observed in 1% of patients or more included pruritus, urticaria, nausea, headache, and paresthesia.

Transfusion reactions can occur with ABO blood group mismatches. High infusion rates can induce hypervolemia with consequent pulmonary edema or cardiac failure. Excessive bleeding due to hyperfibrinolysis can occur due to low levels of alpha2-antiplasmin.

Thrombosis can occur due to low levels of protein S. Citrate toxicity can occur with transfusion rates exceeding 1 mL/kg/min of Octaplas. As Octaplas is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, the variant Creutzfeldt-Jakob disease agent, and, theoretically, the Creutzfeldt-Jakob disease agent.

For more details on Octaplas, see the complete prescribing information.

Plasma for transfusion

Photo by Cristina Granados

The US Food and Drug Administration (FDA) has approved a revised label for the pooled plasma product Octaplas, increasing the product’s shelf life.

The new label says Octaplas can now be stored frozen, at or below -18°C (-0.4°F), for 3 years from the date of manufacture.

And thawed Octaplas should be used within 24 hours if refrigerated (between 1°C and 6°C/33.8°F to 42.8°F) or within 8 hours if stored at room temperature (between 20°C and 25°C/68°F to 77°F)

The previous product label said frozen Octaplas could be stored for 2 years, and thawed Octaplas should be used within 12 hours if stored between 2°C and 4°C (35.6°F to 39.2°F) or within 3 hours if stored between 20°C and 25°C (68°F to 77°F).

About Octaplas

Octaplas is a sterile, frozen solution of human plasma from several donors that has been treated with a solvent detergent process to minimize the risk of serious virus transmission. The plasma is collected from US donors who have been screened and tested for diseases transmitted by blood.

Octaplas gained FDA approval in January 2013. The product is indicated for the replacement of multiple coagulation factors in patients with acquired deficiencies due to liver disease or undergoing cardiac surgery or liver transplant. Octaplas can also be used for plasma exchange in patients with thrombotic thrombocytopenic purpura.

Octaplas is contraindicated in patients with immunoglobulin A deficiency, severe deficiency of protein S, history of hypersensitivity to fresh-frozen plasma or to plasma-derived products including any plasma protein, or a history of hypersensitivity reaction to Octaplas.

Serious adverse events observed in clinical trials of Octaplas were anaphylactic shock, citrate toxicity, and severe hypotension. The most common adverse events observed in 1% of patients or more included pruritus, urticaria, nausea, headache, and paresthesia.

Transfusion reactions can occur with ABO blood group mismatches. High infusion rates can induce hypervolemia with consequent pulmonary edema or cardiac failure. Excessive bleeding due to hyperfibrinolysis can occur due to low levels of alpha2-antiplasmin.

Thrombosis can occur due to low levels of protein S. Citrate toxicity can occur with transfusion rates exceeding 1 mL/kg/min of Octaplas. As Octaplas is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, the variant Creutzfeldt-Jakob disease agent, and, theoretically, the Creutzfeldt-Jakob disease agent.

For more details on Octaplas, see the complete prescribing information.

Rendering of fibrin forming

a blood clot, with PolySTAT

(blue) binding strands together

Image by William Walker–

University of Washington

Preclinical research suggests an injectable polymer known as PolySTAT may one day be able to halt life-threatening bleeding in soldiers and trauma patients.

Once injected, this hemostatic polymer circulates in the blood, homes to sites of vascular injury, and promotes the formation of blood clots.

In experiments with rats, 100% of animals injected with PolySTAT survived a typically lethal injury to the femoral artery. In comparison, 0% to 40% of controls survived.

“Most of the patients who die from bleeding die quickly,” said Nathan White, MD, of the University of Washington in Seattle.

“[PolySTAT] is something you could potentially put in a syringe inside a backpack and give right away to reduce blood loss and keep people alive long enough to make it to medical care.”

Dr White and his colleagues described their work with PolySTAT in Science Translational Medicine. A related Focus article addressed the promises and challenges of advancing PolySTAT and other clotting approaches from proof-of-principle to clinical development.

PolySTAT induces hemostasis by cross-linking the fibrin matrix within blood clots, just as factor XIII does. But the researchers said PolySTAT offers greater protection against natural enzymes that dissolve blood clots.

That’s because PolySTAT binds to fibrin monomers and is uniformly integrated into fibrin fibers during polymerization. This produces a fortified, hybrid polymer network that can resist enzymatic degradation.

In vitro experiments showed that PolySTAT accelerated clotting kinetics, increased the strength of blood clots, and delayed clot breakdown.

The researchers also assessed how PolySTAT affected rats following a femoral artery injury, comparing results with PolySTAT to those with volume control (0.9% saline), a nonbinding scrambled control polymer (PolySCRAM), rat albumin, and human FXIIIa.

The team found that PolySTAT conferred superior survival by reducing blood loss and fluid resuscitation requirements.

All of the rats treated with PolySTAT (5/5) survived to the end of the experiment, compared to none of the rats that received albumin, 20% that received PolySCRAM or FXIIIa, and 40% that received volume control.

The researchers said PolySTAT’s initial safety profile looks promising, but they are still planning to test the polymer on larger animals and conduct additional screening to find out if PolySTAT binds to any other unintended substances.

The team also plans to investigate PolySTAT’s potential for treating hemophilia and for integration into bandages.

Rendering of fibrin forming

a blood clot, with PolySTAT

(blue) binding strands together

Image by William Walker–

University of Washington

Preclinical research suggests an injectable polymer known as PolySTAT may one day be able to halt life-threatening bleeding in soldiers and trauma patients.

Once injected, this hemostatic polymer circulates in the blood, homes to sites of vascular injury, and promotes the formation of blood clots.

In experiments with rats, 100% of animals injected with PolySTAT survived a typically lethal injury to the femoral artery. In comparison, 0% to 40% of controls survived.

“Most of the patients who die from bleeding die quickly,” said Nathan White, MD, of the University of Washington in Seattle.

“[PolySTAT] is something you could potentially put in a syringe inside a backpack and give right away to reduce blood loss and keep people alive long enough to make it to medical care.”

Dr White and his colleagues described their work with PolySTAT in Science Translational Medicine. A related Focus article addressed the promises and challenges of advancing PolySTAT and other clotting approaches from proof-of-principle to clinical development.

PolySTAT induces hemostasis by cross-linking the fibrin matrix within blood clots, just as factor XIII does. But the researchers said PolySTAT offers greater protection against natural enzymes that dissolve blood clots.

That’s because PolySTAT binds to fibrin monomers and is uniformly integrated into fibrin fibers during polymerization. This produces a fortified, hybrid polymer network that can resist enzymatic degradation.

In vitro experiments showed that PolySTAT accelerated clotting kinetics, increased the strength of blood clots, and delayed clot breakdown.

The researchers also assessed how PolySTAT affected rats following a femoral artery injury, comparing results with PolySTAT to those with volume control (0.9% saline), a nonbinding scrambled control polymer (PolySCRAM), rat albumin, and human FXIIIa.

The team found that PolySTAT conferred superior survival by reducing blood loss and fluid resuscitation requirements.

All of the rats treated with PolySTAT (5/5) survived to the end of the experiment, compared to none of the rats that received albumin, 20% that received PolySCRAM or FXIIIa, and 40% that received volume control.

The researchers said PolySTAT’s initial safety profile looks promising, but they are still planning to test the polymer on larger animals and conduct additional screening to find out if PolySTAT binds to any other unintended substances.

The team also plans to investigate PolySTAT’s potential for treating hemophilia and for integration into bandages.

Rendering of fibrin forming

a blood clot, with PolySTAT

(blue) binding strands together

Image by William Walker–

University of Washington

Preclinical research suggests an injectable polymer known as PolySTAT may one day be able to halt life-threatening bleeding in soldiers and trauma patients.

Once injected, this hemostatic polymer circulates in the blood, homes to sites of vascular injury, and promotes the formation of blood clots.

In experiments with rats, 100% of animals injected with PolySTAT survived a typically lethal injury to the femoral artery. In comparison, 0% to 40% of controls survived.

“Most of the patients who die from bleeding die quickly,” said Nathan White, MD, of the University of Washington in Seattle.

“[PolySTAT] is something you could potentially put in a syringe inside a backpack and give right away to reduce blood loss and keep people alive long enough to make it to medical care.”

Dr White and his colleagues described their work with PolySTAT in Science Translational Medicine. A related Focus article addressed the promises and challenges of advancing PolySTAT and other clotting approaches from proof-of-principle to clinical development.

PolySTAT induces hemostasis by cross-linking the fibrin matrix within blood clots, just as factor XIII does. But the researchers said PolySTAT offers greater protection against natural enzymes that dissolve blood clots.

That’s because PolySTAT binds to fibrin monomers and is uniformly integrated into fibrin fibers during polymerization. This produces a fortified, hybrid polymer network that can resist enzymatic degradation.

In vitro experiments showed that PolySTAT accelerated clotting kinetics, increased the strength of blood clots, and delayed clot breakdown.

The researchers also assessed how PolySTAT affected rats following a femoral artery injury, comparing results with PolySTAT to those with volume control (0.9% saline), a nonbinding scrambled control polymer (PolySCRAM), rat albumin, and human FXIIIa.

The team found that PolySTAT conferred superior survival by reducing blood loss and fluid resuscitation requirements.

All of the rats treated with PolySTAT (5/5) survived to the end of the experiment, compared to none of the rats that received albumin, 20% that received PolySCRAM or FXIIIa, and 40% that received volume control.

The researchers said PolySTAT’s initial safety profile looks promising, but they are still planning to test the polymer on larger animals and conduct additional screening to find out if PolySTAT binds to any other unintended substances.

The team also plans to investigate PolySTAT’s potential for treating hemophilia and for integration into bandages.

Red blood cells

A new analysis indicates that patients hospitalized for severe sepsis are often readmitted within 90 days, and many of these readmissions may be preventable.

About 43% of the patients studied were readmitted to the hospital within 90 days of their sepsis hospitalization.

And 42% of these hospitalizations were due to conditions that could potentially be prevented or treated early to avoid hospitalization, according to researchers.

Hallie C. Prescott, MD, of the University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA.

The researchers analyzed participants in the nationally representative US Health and Retirement Study, a sample of households with adults 50 years of age or older that is linked to Medicare claims (1998-2010).

The team examined the most common readmission diagnoses among patients who were hospitalized for severe sepsis, the extent to which readmissions might have been preventable, and whether the pattern of readmission diagnoses differed compared with that of other acute medical conditions.

To gauge what proportion of rehospitalizations might have been preventable, the researchers looked at ambulatory-care-sensitive conditions (ACSCs) identified by the Agency for Healthcare Research and Quality. They also expanded the definition of ACSCs to include conditions that aren’t common among the general population but arise more often in sepsis survivors.

So their potentially preventable readmission diagnoses included pneumonia, hypertension, dehydration, asthma, urinary tract infection, chronic obstructive pulmonary disease exacerbation, perforated appendix, diabetes, angina, congestive heart failure, sepsis, acute renal failure, skin or soft tissue infection, and aspiration pneumonitis.

Dr Prescott and her colleagues identified 2617 hospitalizations for severe sepsis that could be matched to hospitalizations for other acute medical conditions. And they found that 1115 of the severe sepsis survivors (42.6%) were rehospitalized within 90 days.

The 10 most common readmission diagnoses following severe sepsis were sepsis (6.4%), congestive heart failure (5.5%), pneumonia (3.5%), acute renal failure (3.3%), rehabilitation (2.8%), respiratory failure (2.5%), complication related to a device, implant, or graft (2%), exacerbation of chronic obstructive pulmonary disorder (1.9%), aspiration pneumonitis (1.8%), and urinary tract infection (1.7%).

Readmissions for a primary diagnosis of infection (sepsis, pneumonia, urinary tract, and skin or soft tissue infection) occurred in 11.9% of severe sepsis survivors and 8.0% of patients with acute medical conditions (P<0.001).

Likewise, readmissions for ACSCs were more common after severe sepsis than for patients with acute conditions—21.6% and 19.1%, respectively (P=0.02)—and accounted for a greater proportion of all 90-day readmissions—41.6% and 37%.1, respectively (P=0.009).

“Many of these conditions can be managed if the patient can get in to see a doctor at the start of the illness, meaning that we potentially avoid hospitalization,” Dr Prescott said. “We need to assess their vulnerability and design a better landing pad for patients when they leave the hospital, and avoid the second hit that derails recovery.”

Red blood cells

A new analysis indicates that patients hospitalized for severe sepsis are often readmitted within 90 days, and many of these readmissions may be preventable.

About 43% of the patients studied were readmitted to the hospital within 90 days of their sepsis hospitalization.

And 42% of these hospitalizations were due to conditions that could potentially be prevented or treated early to avoid hospitalization, according to researchers.

Hallie C. Prescott, MD, of the University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA.

The researchers analyzed participants in the nationally representative US Health and Retirement Study, a sample of households with adults 50 years of age or older that is linked to Medicare claims (1998-2010).

The team examined the most common readmission diagnoses among patients who were hospitalized for severe sepsis, the extent to which readmissions might have been preventable, and whether the pattern of readmission diagnoses differed compared with that of other acute medical conditions.

To gauge what proportion of rehospitalizations might have been preventable, the researchers looked at ambulatory-care-sensitive conditions (ACSCs) identified by the Agency for Healthcare Research and Quality. They also expanded the definition of ACSCs to include conditions that aren’t common among the general population but arise more often in sepsis survivors.

So their potentially preventable readmission diagnoses included pneumonia, hypertension, dehydration, asthma, urinary tract infection, chronic obstructive pulmonary disease exacerbation, perforated appendix, diabetes, angina, congestive heart failure, sepsis, acute renal failure, skin or soft tissue infection, and aspiration pneumonitis.

Dr Prescott and her colleagues identified 2617 hospitalizations for severe sepsis that could be matched to hospitalizations for other acute medical conditions. And they found that 1115 of the severe sepsis survivors (42.6%) were rehospitalized within 90 days.

The 10 most common readmission diagnoses following severe sepsis were sepsis (6.4%), congestive heart failure (5.5%), pneumonia (3.5%), acute renal failure (3.3%), rehabilitation (2.8%), respiratory failure (2.5%), complication related to a device, implant, or graft (2%), exacerbation of chronic obstructive pulmonary disorder (1.9%), aspiration pneumonitis (1.8%), and urinary tract infection (1.7%).

Readmissions for a primary diagnosis of infection (sepsis, pneumonia, urinary tract, and skin or soft tissue infection) occurred in 11.9% of severe sepsis survivors and 8.0% of patients with acute medical conditions (P<0.001).

Likewise, readmissions for ACSCs were more common after severe sepsis than for patients with acute conditions—21.6% and 19.1%, respectively (P=0.02)—and accounted for a greater proportion of all 90-day readmissions—41.6% and 37%.1, respectively (P=0.009).

“Many of these conditions can be managed if the patient can get in to see a doctor at the start of the illness, meaning that we potentially avoid hospitalization,” Dr Prescott said. “We need to assess their vulnerability and design a better landing pad for patients when they leave the hospital, and avoid the second hit that derails recovery.”

Red blood cells

A new analysis indicates that patients hospitalized for severe sepsis are often readmitted within 90 days, and many of these readmissions may be preventable.

About 43% of the patients studied were readmitted to the hospital within 90 days of their sepsis hospitalization.

And 42% of these hospitalizations were due to conditions that could potentially be prevented or treated early to avoid hospitalization, according to researchers.

Hallie C. Prescott, MD, of the University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA.

The researchers analyzed participants in the nationally representative US Health and Retirement Study, a sample of households with adults 50 years of age or older that is linked to Medicare claims (1998-2010).

The team examined the most common readmission diagnoses among patients who were hospitalized for severe sepsis, the extent to which readmissions might have been preventable, and whether the pattern of readmission diagnoses differed compared with that of other acute medical conditions.

To gauge what proportion of rehospitalizations might have been preventable, the researchers looked at ambulatory-care-sensitive conditions (ACSCs) identified by the Agency for Healthcare Research and Quality. They also expanded the definition of ACSCs to include conditions that aren’t common among the general population but arise more often in sepsis survivors.

So their potentially preventable readmission diagnoses included pneumonia, hypertension, dehydration, asthma, urinary tract infection, chronic obstructive pulmonary disease exacerbation, perforated appendix, diabetes, angina, congestive heart failure, sepsis, acute renal failure, skin or soft tissue infection, and aspiration pneumonitis.

Dr Prescott and her colleagues identified 2617 hospitalizations for severe sepsis that could be matched to hospitalizations for other acute medical conditions. And they found that 1115 of the severe sepsis survivors (42.6%) were rehospitalized within 90 days.

The 10 most common readmission diagnoses following severe sepsis were sepsis (6.4%), congestive heart failure (5.5%), pneumonia (3.5%), acute renal failure (3.3%), rehabilitation (2.8%), respiratory failure (2.5%), complication related to a device, implant, or graft (2%), exacerbation of chronic obstructive pulmonary disorder (1.9%), aspiration pneumonitis (1.8%), and urinary tract infection (1.7%).

Readmissions for a primary diagnosis of infection (sepsis, pneumonia, urinary tract, and skin or soft tissue infection) occurred in 11.9% of severe sepsis survivors and 8.0% of patients with acute medical conditions (P<0.001).

Likewise, readmissions for ACSCs were more common after severe sepsis than for patients with acute conditions—21.6% and 19.1%, respectively (P=0.02)—and accounted for a greater proportion of all 90-day readmissions—41.6% and 37%.1, respectively (P=0.009).

“Many of these conditions can be managed if the patient can get in to see a doctor at the start of the illness, meaning that we potentially avoid hospitalization,” Dr Prescott said. “We need to assess their vulnerability and design a better landing pad for patients when they leave the hospital, and avoid the second hit that derails recovery.”

RBCs grown from edited iPSCs

Image by Ying Wang–

Johns Hopkins Medicine

Researchers say they have devised a technique for generating normal, mature red blood cells (RBCs) from patients with sickle cell disease (SCD).

The team hopes that, ultimately, the RBCs could be transfused back into the patients from which they are derived and eliminate the need for donor transfusion in SCD.

Linzhao Cheng, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues described the technique in Stem Cells.

Dr Cheng noted that SCD patients often require RBC transfusions, but over time, their bodies may begin to mount an immune response against the foreign blood.

“Their bodies quickly kill off the blood cells,” Dr Cheng said. “So they have to get transfusions more and more frequently.”

A solution, Dr Cheng and his colleagues thought, would be to generate RBCs for transfusion using a patient’s own cells.

To do this, the researchers first took hematopoietic cells from an SCD patient and generated induced pluripotent stem cells (iPSCs).

Then, the team used the gene-editing technique CRISPR/Cas9 to target the homozygous SCD mutation (nt. 69A>T) in the HBB gene and ensure the RBCs they generated would not be sickled.

Finally, they coaxed the iPSCs into mature RBCs that expressed the corrected HBB gene. The edited iPSCs generated RBCs just as efficiently as iPSCs that hadn’t been subjected to CRISPR/Cas9.

And the level of HBB protein expression in the RBCs derived from edited iPSCs was similar to that of RBCs generated from unedited iPSCs.

Dr Cheng noted that, to become medically useful, this method will have to be made more efficient and scaled up significantly. And the cells would need to be tested for safety.

“[Nevertheless,] this study shows it may be possible in the not-too-distant future to provide patients with sickle cell disease with an exciting new treatment option,” Dr Cheng said.

He and his colleagues believe this method of RBC generation may also be applicable for other blood disorders. And they think it might be possible to edit cells from healthy individuals so they can resist malaria and other infectious agents.

Another research group has reported the ability to correct the SCD mutation using zinc-finger nucleases.

RBCs grown from edited iPSCs

Image by Ying Wang–

Johns Hopkins Medicine

Researchers say they have devised a technique for generating normal, mature red blood cells (RBCs) from patients with sickle cell disease (SCD).

The team hopes that, ultimately, the RBCs could be transfused back into the patients from which they are derived and eliminate the need for donor transfusion in SCD.

Linzhao Cheng, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues described the technique in Stem Cells.

Dr Cheng noted that SCD patients often require RBC transfusions, but over time, their bodies may begin to mount an immune response against the foreign blood.

“Their bodies quickly kill off the blood cells,” Dr Cheng said. “So they have to get transfusions more and more frequently.”

A solution, Dr Cheng and his colleagues thought, would be to generate RBCs for transfusion using a patient’s own cells.

To do this, the researchers first took hematopoietic cells from an SCD patient and generated induced pluripotent stem cells (iPSCs).

Then, the team used the gene-editing technique CRISPR/Cas9 to target the homozygous SCD mutation (nt. 69A>T) in the HBB gene and ensure the RBCs they generated would not be sickled.

Finally, they coaxed the iPSCs into mature RBCs that expressed the corrected HBB gene. The edited iPSCs generated RBCs just as efficiently as iPSCs that hadn’t been subjected to CRISPR/Cas9.

And the level of HBB protein expression in the RBCs derived from edited iPSCs was similar to that of RBCs generated from unedited iPSCs.

Dr Cheng noted that, to become medically useful, this method will have to be made more efficient and scaled up significantly. And the cells would need to be tested for safety.

“[Nevertheless,] this study shows it may be possible in the not-too-distant future to provide patients with sickle cell disease with an exciting new treatment option,” Dr Cheng said.

He and his colleagues believe this method of RBC generation may also be applicable for other blood disorders. And they think it might be possible to edit cells from healthy individuals so they can resist malaria and other infectious agents.

Another research group has reported the ability to correct the SCD mutation using zinc-finger nucleases.

RBCs grown from edited iPSCs

Image by Ying Wang–

Johns Hopkins Medicine

Researchers say they have devised a technique for generating normal, mature red blood cells (RBCs) from patients with sickle cell disease (SCD).

The team hopes that, ultimately, the RBCs could be transfused back into the patients from which they are derived and eliminate the need for donor transfusion in SCD.

Linzhao Cheng, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues described the technique in Stem Cells.

Dr Cheng noted that SCD patients often require RBC transfusions, but over time, their bodies may begin to mount an immune response against the foreign blood.

“Their bodies quickly kill off the blood cells,” Dr Cheng said. “So they have to get transfusions more and more frequently.”

A solution, Dr Cheng and his colleagues thought, would be to generate RBCs for transfusion using a patient’s own cells.

To do this, the researchers first took hematopoietic cells from an SCD patient and generated induced pluripotent stem cells (iPSCs).

Then, the team used the gene-editing technique CRISPR/Cas9 to target the homozygous SCD mutation (nt. 69A>T) in the HBB gene and ensure the RBCs they generated would not be sickled.

Finally, they coaxed the iPSCs into mature RBCs that expressed the corrected HBB gene. The edited iPSCs generated RBCs just as efficiently as iPSCs that hadn’t been subjected to CRISPR/Cas9.

And the level of HBB protein expression in the RBCs derived from edited iPSCs was similar to that of RBCs generated from unedited iPSCs.

Dr Cheng noted that, to become medically useful, this method will have to be made more efficient and scaled up significantly. And the cells would need to be tested for safety.

“[Nevertheless,] this study shows it may be possible in the not-too-distant future to provide patients with sickle cell disease with an exciting new treatment option,” Dr Cheng said.

He and his colleagues believe this method of RBC generation may also be applicable for other blood disorders. And they think it might be possible to edit cells from healthy individuals so they can resist malaria and other infectious agents.

Another research group has reported the ability to correct the SCD mutation using zinc-finger nucleases.

BALTIMORE – If all Americans eligible for statins under new American College of Cardiology/American Heart Association guidelines actually took them, thousands of deaths per year from cardiovascular disease might be prevented but at a cost of increased incidence of diabetes and myopathy.

The 2013 ACC/AHA guidelines expand criteria for the use of statins for primary prevention of CVD to more Americans (Circulation 2015;131:A05). Compliance with those guidelines would save 7,930 lives per year that would have been lost to CVD, according to Quanhe Yang, Ph.D., of the Centers for Disease Control and Prevention’s Division for Heart Disease and Stroke Prevention, and colleagues from the CDC and Emory University, Atlanta. Dr. Yang presented the findings at the American Heart Association Epidemiology and Prevention, Lifestyle and Cardiometabolic Health 2015 Scientific Sessions.

Statins are now indicated for primary prevention of CVD for anyone with an LDL cholesterol level greater than or equal to 190 mg/dL, for individuals aged 40-75 years with diabetes, and for those aged 40-75 years with LDL cholesterol greater than or equal to 70 mg/dL but less than 190 mg/dL who have at least a 7.5% estimated 10-year risk of developing atherosclerotic CVD. This means that an additional 24.2 million Americans are now eligible for statins but are not taking one, according to Dr. Yang and coinvestigators. However, “no study has assessed the potential impact of statin therapy under the new guidelines,” said Dr. Yang.

In order to obtain treatment group-specific atherosclerotic CVD, investigators first estimated hazard ratios for each treatment group by sex from the National Health and Nutrition Examination Survey III (NHANES III)–linked Mortality files. These hazard ratios were then applied to data from NHANES 2005-2010, the 2010 Multiple Cause of Death file, and the 2010 U.S. census to obtain age/race/sex-specific atherosclerotic CVD for each treatment group.

Applying the per-group hazard ratios, Dr. Yang and colleagues calculated that an annual 7,930 atherosclerotic CVD deaths would be prevented with full statin compliance, a reduction of 12.6%. However, modeling predicted an additional 16,400 additional cases of diabetes caused by statin use, he cautioned. More cases of myopathy would also occur, though the estimated number depends on whether the rate is derived from randomized, controlled trials (RCTs) or from population-based reports of myopathy. If the RCT data are used, just 1,510 excess cases of myopathy would be seen, in contrast to the 36,100 cases predicted by population-based data.

The study could model deaths caused by CVD only and not the reduction in disease burden of CVD that would result if all of the additional 24.2 million Americans took a statin, Dr Yang noted. Other limitations of the study included the lack of agreement in incidence of myopathy between RCTs and population-based studies, as well as the likelihood that the risk of diabetes increases with age and higher statin dose – effects not accounted for in the study.

Questioning after the talk focused on sex-specific differences in statin takers. For example, statin-associated diabetes is more common in women than men, another effect not accounted for in the study’s modeling, noted an audience member. Additionally, given that women have been underrepresented in clinical trials in general and in those for CVD in particular, some modeling assumptions in the present study may also lack full generalizability to women at risk for CVD.

BALTIMORE – If all Americans eligible for statins under new American College of Cardiology/American Heart Association guidelines actually took them, thousands of deaths per year from cardiovascular disease might be prevented but at a cost of increased incidence of diabetes and myopathy.

The 2013 ACC/AHA guidelines expand criteria for the use of statins for primary prevention of CVD to more Americans (Circulation 2015;131:A05). Compliance with those guidelines would save 7,930 lives per year that would have been lost to CVD, according to Quanhe Yang, Ph.D., of the Centers for Disease Control and Prevention’s Division for Heart Disease and Stroke Prevention, and colleagues from the CDC and Emory University, Atlanta. Dr. Yang presented the findings at the American Heart Association Epidemiology and Prevention, Lifestyle and Cardiometabolic Health 2015 Scientific Sessions.

Statins are now indicated for primary prevention of CVD for anyone with an LDL cholesterol level greater than or equal to 190 mg/dL, for individuals aged 40-75 years with diabetes, and for those aged 40-75 years with LDL cholesterol greater than or equal to 70 mg/dL but less than 190 mg/dL who have at least a 7.5% estimated 10-year risk of developing atherosclerotic CVD. This means that an additional 24.2 million Americans are now eligible for statins but are not taking one, according to Dr. Yang and coinvestigators. However, “no study has assessed the potential impact of statin therapy under the new guidelines,” said Dr. Yang.

In order to obtain treatment group-specific atherosclerotic CVD, investigators first estimated hazard ratios for each treatment group by sex from the National Health and Nutrition Examination Survey III (NHANES III)–linked Mortality files. These hazard ratios were then applied to data from NHANES 2005-2010, the 2010 Multiple Cause of Death file, and the 2010 U.S. census to obtain age/race/sex-specific atherosclerotic CVD for each treatment group.

Applying the per-group hazard ratios, Dr. Yang and colleagues calculated that an annual 7,930 atherosclerotic CVD deaths would be prevented with full statin compliance, a reduction of 12.6%. However, modeling predicted an additional 16,400 additional cases of diabetes caused by statin use, he cautioned. More cases of myopathy would also occur, though the estimated number depends on whether the rate is derived from randomized, controlled trials (RCTs) or from population-based reports of myopathy. If the RCT data are used, just 1,510 excess cases of myopathy would be seen, in contrast to the 36,100 cases predicted by population-based data.

The study could model deaths caused by CVD only and not the reduction in disease burden of CVD that would result if all of the additional 24.2 million Americans took a statin, Dr Yang noted. Other limitations of the study included the lack of agreement in incidence of myopathy between RCTs and population-based studies, as well as the likelihood that the risk of diabetes increases with age and higher statin dose – effects not accounted for in the study.

Questioning after the talk focused on sex-specific differences in statin takers. For example, statin-associated diabetes is more common in women than men, another effect not accounted for in the study’s modeling, noted an audience member. Additionally, given that women have been underrepresented in clinical trials in general and in those for CVD in particular, some modeling assumptions in the present study may also lack full generalizability to women at risk for CVD.

BALTIMORE – If all Americans eligible for statins under new American College of Cardiology/American Heart Association guidelines actually took them, thousands of deaths per year from cardiovascular disease might be prevented but at a cost of increased incidence of diabetes and myopathy.

The 2013 ACC/AHA guidelines expand criteria for the use of statins for primary prevention of CVD to more Americans (Circulation 2015;131:A05). Compliance with those guidelines would save 7,930 lives per year that would have been lost to CVD, according to Quanhe Yang, Ph.D., of the Centers for Disease Control and Prevention’s Division for Heart Disease and Stroke Prevention, and colleagues from the CDC and Emory University, Atlanta. Dr. Yang presented the findings at the American Heart Association Epidemiology and Prevention, Lifestyle and Cardiometabolic Health 2015 Scientific Sessions.

Statins are now indicated for primary prevention of CVD for anyone with an LDL cholesterol level greater than or equal to 190 mg/dL, for individuals aged 40-75 years with diabetes, and for those aged 40-75 years with LDL cholesterol greater than or equal to 70 mg/dL but less than 190 mg/dL who have at least a 7.5% estimated 10-year risk of developing atherosclerotic CVD. This means that an additional 24.2 million Americans are now eligible for statins but are not taking one, according to Dr. Yang and coinvestigators. However, “no study has assessed the potential impact of statin therapy under the new guidelines,” said Dr. Yang.

In order to obtain treatment group-specific atherosclerotic CVD, investigators first estimated hazard ratios for each treatment group by sex from the National Health and Nutrition Examination Survey III (NHANES III)–linked Mortality files. These hazard ratios were then applied to data from NHANES 2005-2010, the 2010 Multiple Cause of Death file, and the 2010 U.S. census to obtain age/race/sex-specific atherosclerotic CVD for each treatment group.

Applying the per-group hazard ratios, Dr. Yang and colleagues calculated that an annual 7,930 atherosclerotic CVD deaths would be prevented with full statin compliance, a reduction of 12.6%. However, modeling predicted an additional 16,400 additional cases of diabetes caused by statin use, he cautioned. More cases of myopathy would also occur, though the estimated number depends on whether the rate is derived from randomized, controlled trials (RCTs) or from population-based reports of myopathy. If the RCT data are used, just 1,510 excess cases of myopathy would be seen, in contrast to the 36,100 cases predicted by population-based data.

The study could model deaths caused by CVD only and not the reduction in disease burden of CVD that would result if all of the additional 24.2 million Americans took a statin, Dr Yang noted. Other limitations of the study included the lack of agreement in incidence of myopathy between RCTs and population-based studies, as well as the likelihood that the risk of diabetes increases with age and higher statin dose – effects not accounted for in the study.

Questioning after the talk focused on sex-specific differences in statin takers. For example, statin-associated diabetes is more common in women than men, another effect not accounted for in the study’s modeling, noted an audience member. Additionally, given that women have been underrepresented in clinical trials in general and in those for CVD in particular, some modeling assumptions in the present study may also lack full generalizability to women at risk for CVD.

Psoriasis affects 2% to 4% of the US population, with approximately one-third of cases beginning in childhood. The understanding of pediatric psoriasis has developed at a far slower pace than adult disease, with limitations in care including few medications that are approved by the US Food and Drug Administration for pediatric and adolescent use. Recently, a stable fixed-combination dose of calcipo-triene 0.005%–betamethasone dipropionate 0.064% topical suspension was approved for treatment of plaque psoriasis of the scalp in patients aged 12 to 17 years, which hopefully will lead a trend in psoriasis medication approval for children and teenagers.¹ Based on a PubMed search of articles indexed for MEDLINE using the search terms pediatric psoriasis, psoriasis, and strep that were published from April 2012 to April 2014, this article reviews newer data to address the issues that surround pediatric psoriasis and to provide an update on prior review articles on pediatric psoriasis.^2-5 This article reviews some of the newer literature on clinical presentation and comorbidities in pediatric psoriasis.⁵ Based on these recent findings, additional screenings including review of obesity parameters are recommended for pediatric patients with psoriasis (Table 1).

Update on Disease Manifestations, Associations, and Comorbidities

Disease Manifestations

A 2013 multicenter study delineated the clinical features of pediatric psoriasis.⁶ The study was conducted at 8 geographically diverse dermatology clinics in the United States to delineate the clinical manifestations of pediatric psoriasis. In an assessment of 181 participants aged 5 to 17 years, the investigators sought to determine the frequency of disease sites, severity, and guttate disease. Over a period of approximately 2 years, 43.1% of participants were determined to have mild disease and 56.9% had severe disease. Family history of psoriasis was present in 51.4% of participants, with first-degree relatives affected in 59.8% of cases. Scalp involvement at some time was noted in 79.0% of participants, and nail disease was noted in 55% of boys and 29% of girls. Guttate psoriasis was noted in 30% of participants, with more cases in the severe range (35.9%) versus the mild range (21.8%). Additionally, 22.1% of participants had a precipitating streptococcal infection, with the association being more common in pediatric patients with guttate psoriasis than plaque psoriasis.⁶ This study highlighted that pediatric psoriasis has a genetic basis, is frequently guttate in nature, commonly affects the nails, shows a trend toward being classified as severe, and may be triggered by streptococcal infections.

Streptococcal Infection

Pediatric psoriasis may be triggered or flared by Streptococcus pyogenes (group A β-hemolytic streptococci) infections, specifically β-hemolytic streptococci groups A, C, and G that have streptococcal M protein,^2,3,7 and this tendency can be associated with HLA-Cw6 or guttate psoriasis. Newer data have elucidated the role of streptococcal throat infections in psoriasis. Given that streptococcal throat infections are most common in school-aged children, these studies suggest a putative mechanism in pediatric psoriasis for triggering streptococcal infections, which would need to be confirmed in future studies, specifically in pediatric psoriasis patients.

It has been shown that T cells in psoriasis patients recognize common streptococcal M proteins and keratin determinants.⁷ Ferran et al⁸ recently demonstrated activation of circulating cutaneous lymphocyte–associated antigen (CLA)⁺ T cells but not CLA^- memory T cells in 27 psoriasis patients (ages not specified) when mixed with streptococcal throat extracts, causing production of IL-17, IP-10, IL-22, and IFN-γ; activation was not found in 6 healthy control patients. Antistreptolysin O levels were correlated with the messenger RNA up- regulation for IL-17, IP-10, IL-22, and IFN-γ, and also correlated with psoriasis area and severity index score in psoriasis patients. In this same study, injection of the activated culture supernatant into mouse skin caused epidermal hyperkeratosis and activation of nonlesional epidermal cells from psoriatic patients. This study thereby delineated some of the potential pathways of the streptococcal induction of psoriasis and psoriatic flares in childhood⁸; however, confirmation is needed through further study of pediatric psoriatic lymphocyte activity.

Differential Diagnosis

Additions to the extensive differential list have been cited in the recent literature. The differential diagnosis of pediatric psoriasis now includes sodium valproate–induced psoriasiform drug eruption⁹ and allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone, which are present in many sanitizing hand and diaper wipes and has been reported to cause psoriasiform dermatitis in a periorificial or perineal distribution.¹⁰ Clinicians should inquire about the use of these wipes, as caregivers rarely suspect this agent to be causative of the eruption.

Psoriatic Arthritis

Previously, psoriasis and psoriatic arthritis have been linked to autoimmune thyroid disease in adults.¹¹ A study of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry showed that family history of psoriasis, autoimmune thyroiditis, Crohn disease, and ankylosing spondylitis in a first-degree relative has been linked to juvenile idiopathic arthritis, highlighting that pediatric psoriasis can be genetically linked or associated with multiple autoimmune conditions and vice versa.¹²

Obesity, Metabolic Syndrome, and Cardiovascular Risks

Obesity is associated with pediatric psoriasis as highlighted in a growing body of recent literature.¹³ Excess adiposity as manifested by body mass index in the 85th percentile or greater (37.9% of 155 pediatric psoriasis patients vs 20.5% of 42 controls) and excess central adiposity as manifested by excess waist circumference and increased waist-to-height ratios are more common in pediatric patients with psoriasis than in controls.¹⁴

Obesity may be a trigger or associated with increased disease activity in pediatric psoriasis patients. Excess overall adiposity correlates with more severe disease. Obesity parameters may correlate with the onset of psoriasis and with disease severity. In fact, the odds of obesity may be higher in childhood than in adults.^14,15 A 2011 report of pediatric psoriasis patients aged 10 to 17 years (n=12) and wart controls (n=6)(mean age, 13.2 and 13.5 years, respectively) demonstrated that 4 of 12 patients with psoriasis and 0 of 6 patients with warts met criteria for metabolic syndrome as defined by 3 of the following: (1) triglycerides greater than or equal to 100 mg/dL; (2) high-density lipoprotein cholesterol less than 50 mg/dL in females and less than 5 mg/dL in males; (3) fasting blood glucose levels greater than or equal to 110 mg/dL, (4) waist circumference greater than the 75th percentile for age and sex; and (5) systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height.¹⁶ These studies highlight that obesity and metabolic syndrome are of concern in pediatric psoriasis patients; however, the best management approach using diet and weight interventions has yet to be identified.

Adiposity may precede the onset of psoriasis. A recent cohort of 27 pediatric psoriasis patients reported that the average age at onset of psoriasis was 8.7 years and the average age at onset of obesity was 4.1 years.¹⁵ In this study, 93% (25/27) of patients had adiposity preceding their psoriasis by 2 or more years. It is unclear if this is nature or nurture, as 48% (13/27) of patients had a family history of obesity, 41% (11/27) had a family history of psoriasis, and 48% (13/27) had a family history of hyperlipidemia.¹⁵ Therefore, obesity may be cultivated in some psoriatic families. The issue of household influences on diet and obesity needs to be addressed if successful weight management is to be achieved in future studies of pediatric psoriasis.

Cardiovascular risks in the pediatric psoriasis population are the subject of ongoing assessment but will likely mimic studies of adult psoriasis patients when reviewed longitudinally.¹⁶ Weight loss and healthy lifestyle interventions likely are beneficial to long-term health, but there is a lack of published data addressing dietary modification as a disease modifier for long-term care of pediatric psoriasis.

Anxiety and Depression

Anxiety and depression have been noted in adults with chronic skin diseases. A recent study assessed 118 patients and caregivers of pediatric patients with atopic dermatitis (n=50), psoriasis (n=25), or vitiligo (n=43) using the Children’s Dermatology Life Quality Index, the Hamilton Anxiety Scale, and the Beck Depression Inventory.¹⁷ Anxiety and depression were found in 36% of caregivers of pediatric psoriasis patients and depression was found in 36% of pediatric psoriasis patients, highlighting the need for interventions on a personal and family level to improve quality of life. As a comparator, anxiety was more prevalent in vitiligo caregivers (42%), but depression was only found in 26% of caregivers in the same group. Extent of disease (25%–75% body surface area affected) correlated with both depression and anxiety in the caregivers of pediatric patients with psoriasis as well as with anxiety in caregivers of pediatric patients with increased visible surface area of vitiligo.¹⁷ Parental anxiety has been reported at times to be linked to corticosteroid phobia, or corticophobia, which may interfere with disease therapy, as topical corticosteroids are considered the mainstay of therapy in childhood disease.¹⁸ Coordinating care with caregivers and addressing their concerns about the safety of medications should be integral to the pediatric psoriasis visit.

Pustular Psoriasis

Pustular psoriasis can be seen in any age group. Researchers recently have attempted to delineate the features and successful management of this severe subset of pediatric psoriasis patients. Twenty-four pediatric pustular psoriasis cases reviewed by Posso-De Los Rios et al¹⁹ revealed that 92% (22/24) had generalized and 8% (2/24) had limited acral disease. The mean (standard deviation) age at onset of pediatric pustular psoriasis was 6.3 (4.9) years. Half of the reported cases required more than one intervention. Treatment with acitretin, cyclosporine, and methotrexate was effective, but the investigators identified that there is a true dearth of evidence-based therapeutics in pediatric pustular psoriasis and much rebound with discontinuation.¹⁹ Although the subset of pediatric pustular psoriasis is rare, study of evidence-based intervention is needed.

Therapy

Recent reviews of pediatric and adolescent psoriasis highlight the paucity of therapeutic information for these patient populations. Investigators typically focus on topical therapies as the basis of treatment,²⁰ as well as the addition of phototherapy in mild to moderate plaque or guttate psoriasis and biologic or systemic agents in moderate to severe flares of plaque, erythrodermic, or pustular psoriasis.²¹ Further studies are needed to identify evidence-based therapeutic paradigms for pediatric psoriasis and to pinpoint therapies associated with the best quality of life in patients and their caregivers.

Tumor Necrosis Factor α Inhibitors

Safety and efficacy of etanercept for juvenile idiopathic arthritis including oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis recently was reviewed by Windschall et al²² using data from the German pediatric Biologika in der Kinderrheumatologie registry. Juvenile Arthritis Disease Activity Score 10 improved from baseline for 127 pediatric patients with psoriatic arthritis in 3 to 24 months (mean [standard deviation], 14.7 [6.4], 5.0 [4.6], 5.3 [6.4] at baseline, 3 months, and 24 months, respectively). Overall side effects were relatively higher in the psoriatic arthritis group; the rate of serious (relative risk, 1.39 [0.95-2.03; P=.08]) and nonserious (relative risk, 1.18 [1.02-1.35; P=.03]) adverse events also was elevated. Uveitis risk was greatest in the psoriatic arthritis group and the number of associated cases of inflammatory bowel disease outnumbered those seen in other forms of arthritis. The investigators concluded that monitoring for extra-articular immunopathies should be conducted in pediatric patients with psoriatic arthritis who are undergoing etanercept therapy.²²

Tumor necrosis factor α (TNF-α) inhibitors have been associated with triggering psoriasiform dermatitis in pediatric patients treated for inflammatory bowel disease. A Finnish study of infliximab side effects in pediatric patients with inflammatory bowel disease (n=84; Crohn disease: n=64) demonstrated that almost half (47.6% [40/84]) of the participants presented with chronic skin reactions, 23% of which were severe in nature.²³ Psoriasiform lesions of the scalp and ears were most common, followed by the periorificial area, genitals, trunk, and extremities. Rare association with HLA-Cw*0602 genotype was noted. Skin manifestations did not correlate with gut inflammation (as determined by fecal calprotectin levels). Discontinuation of therapy rarely was required.²³ Other studies also have highlighted this side effect, suggesting an incidence of 2.7% in adults with colitis treated with TNF-α inhibitors²⁴ and 10.5% in pediatric patients with Crohn disease.²⁵ In a study by Sherlock et al,²⁵  pediatric patients with Crohn disease developing psoriasis following infliximab therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151).

Methotrexate

For pediatric patients who are being treated with methotrexate, the polyglutamate assay recently has been reported to be helpful in identifying patients needing a dose escalation.²⁶ Higher numbers on the polyglutamate assay are associated with superior response to methotrexate therapy. Doses can be increased after 12 weeks in patients with low assays.²⁶

IL-23

The safety of IL-23 blockade in pediatric psoriasis patients has not yet been established, but data from adult cases have implicated the IL-17 and IL-23 pathways in psoriasis/psoriatic arthritis, including an association with IL-23R polymorphisms²⁷ and increases in soluble IL-20 and IL-22 associated with disease severity and an association of IL-17 levels with activity on the psoriasis area and severity index scores.²⁸ The data are more limited for pediatric cases. Pediatric patients with inflammatory bowel disease who have an IL-23R polymorphism appear to be susceptible to psoriatic flares while on TNF-α inhibitor therapy,²⁵ which suggests that the IL-23 blockade may be of benefit for some pediatric patients with psoriasis or psoriatic arthritis.

Conclusion

Pediatric psoriasis and psoriatic arthritis have now been identified as being part of the autoimmune spectrum and are associated with metabolic syndrome, including obesity and excess central adiposity, similar to their adult variants. An overview of potential unmet needs in pediatric psoriasis is included in Table 2. These unmet needs include further delineation of diet and weight modification in the care and prevention of psoriasis; expansion of therapeutic trials and US Food and Drug Administration–approved medications for children with psoriasis, especially severe variants such as extensive plaque and pustular disease; and development of guidelines for ongoing monitoring of children with psoriasis. The role of therapeutic interventions and weight management on long-term disease course remains to be shown in extended clinical trials. Despite the great advancements in psoriatic care, knowledge gaps remain in pediatric psoriasis that will need to be addressed in the future.

Psoriasis affects 2% to 4% of the US population, with approximately one-third of cases beginning in childhood. The understanding of pediatric psoriasis has developed at a far slower pace than adult disease, with limitations in care including few medications that are approved by the US Food and Drug Administration for pediatric and adolescent use. Recently, a stable fixed-combination dose of calcipo-triene 0.005%–betamethasone dipropionate 0.064% topical suspension was approved for treatment of plaque psoriasis of the scalp in patients aged 12 to 17 years, which hopefully will lead a trend in psoriasis medication approval for children and teenagers.¹ Based on a PubMed search of articles indexed for MEDLINE using the search terms pediatric psoriasis, psoriasis, and strep that were published from April 2012 to April 2014, this article reviews newer data to address the issues that surround pediatric psoriasis and to provide an update on prior review articles on pediatric psoriasis.^2-5 This article reviews some of the newer literature on clinical presentation and comorbidities in pediatric psoriasis.⁵ Based on these recent findings, additional screenings including review of obesity parameters are recommended for pediatric patients with psoriasis (Table 1).

Update on Disease Manifestations, Associations, and Comorbidities

Disease Manifestations

A 2013 multicenter study delineated the clinical features of pediatric psoriasis.⁶ The study was conducted at 8 geographically diverse dermatology clinics in the United States to delineate the clinical manifestations of pediatric psoriasis. In an assessment of 181 participants aged 5 to 17 years, the investigators sought to determine the frequency of disease sites, severity, and guttate disease. Over a period of approximately 2 years, 43.1% of participants were determined to have mild disease and 56.9% had severe disease. Family history of psoriasis was present in 51.4% of participants, with first-degree relatives affected in 59.8% of cases. Scalp involvement at some time was noted in 79.0% of participants, and nail disease was noted in 55% of boys and 29% of girls. Guttate psoriasis was noted in 30% of participants, with more cases in the severe range (35.9%) versus the mild range (21.8%). Additionally, 22.1% of participants had a precipitating streptococcal infection, with the association being more common in pediatric patients with guttate psoriasis than plaque psoriasis.⁶ This study highlighted that pediatric psoriasis has a genetic basis, is frequently guttate in nature, commonly affects the nails, shows a trend toward being classified as severe, and may be triggered by streptococcal infections.

Streptococcal Infection

Pediatric psoriasis may be triggered or flared by Streptococcus pyogenes (group A β-hemolytic streptococci) infections, specifically β-hemolytic streptococci groups A, C, and G that have streptococcal M protein,^2,3,7 and this tendency can be associated with HLA-Cw6 or guttate psoriasis. Newer data have elucidated the role of streptococcal throat infections in psoriasis. Given that streptococcal throat infections are most common in school-aged children, these studies suggest a putative mechanism in pediatric psoriasis for triggering streptococcal infections, which would need to be confirmed in future studies, specifically in pediatric psoriasis patients.

It has been shown that T cells in psoriasis patients recognize common streptococcal M proteins and keratin determinants.⁷ Ferran et al⁸ recently demonstrated activation of circulating cutaneous lymphocyte–associated antigen (CLA)⁺ T cells but not CLA^- memory T cells in 27 psoriasis patients (ages not specified) when mixed with streptococcal throat extracts, causing production of IL-17, IP-10, IL-22, and IFN-γ; activation was not found in 6 healthy control patients. Antistreptolysin O levels were correlated with the messenger RNA up- regulation for IL-17, IP-10, IL-22, and IFN-γ, and also correlated with psoriasis area and severity index score in psoriasis patients. In this same study, injection of the activated culture supernatant into mouse skin caused epidermal hyperkeratosis and activation of nonlesional epidermal cells from psoriatic patients. This study thereby delineated some of the potential pathways of the streptococcal induction of psoriasis and psoriatic flares in childhood⁸; however, confirmation is needed through further study of pediatric psoriatic lymphocyte activity.

Differential Diagnosis

Additions to the extensive differential list have been cited in the recent literature. The differential diagnosis of pediatric psoriasis now includes sodium valproate–induced psoriasiform drug eruption⁹ and allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone, which are present in many sanitizing hand and diaper wipes and has been reported to cause psoriasiform dermatitis in a periorificial or perineal distribution.¹⁰ Clinicians should inquire about the use of these wipes, as caregivers rarely suspect this agent to be causative of the eruption.

Psoriatic Arthritis

Previously, psoriasis and psoriatic arthritis have been linked to autoimmune thyroid disease in adults.¹¹ A study of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry showed that family history of psoriasis, autoimmune thyroiditis, Crohn disease, and ankylosing spondylitis in a first-degree relative has been linked to juvenile idiopathic arthritis, highlighting that pediatric psoriasis can be genetically linked or associated with multiple autoimmune conditions and vice versa.¹²

Obesity, Metabolic Syndrome, and Cardiovascular Risks

Obesity is associated with pediatric psoriasis as highlighted in a growing body of recent literature.¹³ Excess adiposity as manifested by body mass index in the 85th percentile or greater (37.9% of 155 pediatric psoriasis patients vs 20.5% of 42 controls) and excess central adiposity as manifested by excess waist circumference and increased waist-to-height ratios are more common in pediatric patients with psoriasis than in controls.¹⁴

Obesity may be a trigger or associated with increased disease activity in pediatric psoriasis patients. Excess overall adiposity correlates with more severe disease. Obesity parameters may correlate with the onset of psoriasis and with disease severity. In fact, the odds of obesity may be higher in childhood than in adults.^14,15 A 2011 report of pediatric psoriasis patients aged 10 to 17 years (n=12) and wart controls (n=6)(mean age, 13.2 and 13.5 years, respectively) demonstrated that 4 of 12 patients with psoriasis and 0 of 6 patients with warts met criteria for metabolic syndrome as defined by 3 of the following: (1) triglycerides greater than or equal to 100 mg/dL; (2) high-density lipoprotein cholesterol less than 50 mg/dL in females and less than 5 mg/dL in males; (3) fasting blood glucose levels greater than or equal to 110 mg/dL, (4) waist circumference greater than the 75th percentile for age and sex; and (5) systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height.¹⁶ These studies highlight that obesity and metabolic syndrome are of concern in pediatric psoriasis patients; however, the best management approach using diet and weight interventions has yet to be identified.

Adiposity may precede the onset of psoriasis. A recent cohort of 27 pediatric psoriasis patients reported that the average age at onset of psoriasis was 8.7 years and the average age at onset of obesity was 4.1 years.¹⁵ In this study, 93% (25/27) of patients had adiposity preceding their psoriasis by 2 or more years. It is unclear if this is nature or nurture, as 48% (13/27) of patients had a family history of obesity, 41% (11/27) had a family history of psoriasis, and 48% (13/27) had a family history of hyperlipidemia.¹⁵ Therefore, obesity may be cultivated in some psoriatic families. The issue of household influences on diet and obesity needs to be addressed if successful weight management is to be achieved in future studies of pediatric psoriasis.

Cardiovascular risks in the pediatric psoriasis population are the subject of ongoing assessment but will likely mimic studies of adult psoriasis patients when reviewed longitudinally.¹⁶ Weight loss and healthy lifestyle interventions likely are beneficial to long-term health, but there is a lack of published data addressing dietary modification as a disease modifier for long-term care of pediatric psoriasis.

Anxiety and Depression

Anxiety and depression have been noted in adults with chronic skin diseases. A recent study assessed 118 patients and caregivers of pediatric patients with atopic dermatitis (n=50), psoriasis (n=25), or vitiligo (n=43) using the Children’s Dermatology Life Quality Index, the Hamilton Anxiety Scale, and the Beck Depression Inventory.¹⁷ Anxiety and depression were found in 36% of caregivers of pediatric psoriasis patients and depression was found in 36% of pediatric psoriasis patients, highlighting the need for interventions on a personal and family level to improve quality of life. As a comparator, anxiety was more prevalent in vitiligo caregivers (42%), but depression was only found in 26% of caregivers in the same group. Extent of disease (25%–75% body surface area affected) correlated with both depression and anxiety in the caregivers of pediatric patients with psoriasis as well as with anxiety in caregivers of pediatric patients with increased visible surface area of vitiligo.¹⁷ Parental anxiety has been reported at times to be linked to corticosteroid phobia, or corticophobia, which may interfere with disease therapy, as topical corticosteroids are considered the mainstay of therapy in childhood disease.¹⁸ Coordinating care with caregivers and addressing their concerns about the safety of medications should be integral to the pediatric psoriasis visit.

Pustular Psoriasis

Pustular psoriasis can be seen in any age group. Researchers recently have attempted to delineate the features and successful management of this severe subset of pediatric psoriasis patients. Twenty-four pediatric pustular psoriasis cases reviewed by Posso-De Los Rios et al¹⁹ revealed that 92% (22/24) had generalized and 8% (2/24) had limited acral disease. The mean (standard deviation) age at onset of pediatric pustular psoriasis was 6.3 (4.9) years. Half of the reported cases required more than one intervention. Treatment with acitretin, cyclosporine, and methotrexate was effective, but the investigators identified that there is a true dearth of evidence-based therapeutics in pediatric pustular psoriasis and much rebound with discontinuation.¹⁹ Although the subset of pediatric pustular psoriasis is rare, study of evidence-based intervention is needed.

Therapy

Recent reviews of pediatric and adolescent psoriasis highlight the paucity of therapeutic information for these patient populations. Investigators typically focus on topical therapies as the basis of treatment,²⁰ as well as the addition of phototherapy in mild to moderate plaque or guttate psoriasis and biologic or systemic agents in moderate to severe flares of plaque, erythrodermic, or pustular psoriasis.²¹ Further studies are needed to identify evidence-based therapeutic paradigms for pediatric psoriasis and to pinpoint therapies associated with the best quality of life in patients and their caregivers.

Tumor Necrosis Factor α Inhibitors

Safety and efficacy of etanercept for juvenile idiopathic arthritis including oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis recently was reviewed by Windschall et al²² using data from the German pediatric Biologika in der Kinderrheumatologie registry. Juvenile Arthritis Disease Activity Score 10 improved from baseline for 127 pediatric patients with psoriatic arthritis in 3 to 24 months (mean [standard deviation], 14.7 [6.4], 5.0 [4.6], 5.3 [6.4] at baseline, 3 months, and 24 months, respectively). Overall side effects were relatively higher in the psoriatic arthritis group; the rate of serious (relative risk, 1.39 [0.95-2.03; P=.08]) and nonserious (relative risk, 1.18 [1.02-1.35; P=.03]) adverse events also was elevated. Uveitis risk was greatest in the psoriatic arthritis group and the number of associated cases of inflammatory bowel disease outnumbered those seen in other forms of arthritis. The investigators concluded that monitoring for extra-articular immunopathies should be conducted in pediatric patients with psoriatic arthritis who are undergoing etanercept therapy.²²

Tumor necrosis factor α (TNF-α) inhibitors have been associated with triggering psoriasiform dermatitis in pediatric patients treated for inflammatory bowel disease. A Finnish study of infliximab side effects in pediatric patients with inflammatory bowel disease (n=84; Crohn disease: n=64) demonstrated that almost half (47.6% [40/84]) of the participants presented with chronic skin reactions, 23% of which were severe in nature.²³ Psoriasiform lesions of the scalp and ears were most common, followed by the periorificial area, genitals, trunk, and extremities. Rare association with HLA-Cw*0602 genotype was noted. Skin manifestations did not correlate with gut inflammation (as determined by fecal calprotectin levels). Discontinuation of therapy rarely was required.²³ Other studies also have highlighted this side effect, suggesting an incidence of 2.7% in adults with colitis treated with TNF-α inhibitors²⁴ and 10.5% in pediatric patients with Crohn disease.²⁵ In a study by Sherlock et al,²⁵  pediatric patients with Crohn disease developing psoriasis following infliximab therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151).

Methotrexate

For pediatric patients who are being treated with methotrexate, the polyglutamate assay recently has been reported to be helpful in identifying patients needing a dose escalation.²⁶ Higher numbers on the polyglutamate assay are associated with superior response to methotrexate therapy. Doses can be increased after 12 weeks in patients with low assays.²⁶

IL-23

The safety of IL-23 blockade in pediatric psoriasis patients has not yet been established, but data from adult cases have implicated the IL-17 and IL-23 pathways in psoriasis/psoriatic arthritis, including an association with IL-23R polymorphisms²⁷ and increases in soluble IL-20 and IL-22 associated with disease severity and an association of IL-17 levels with activity on the psoriasis area and severity index scores.²⁸ The data are more limited for pediatric cases. Pediatric patients with inflammatory bowel disease who have an IL-23R polymorphism appear to be susceptible to psoriatic flares while on TNF-α inhibitor therapy,²⁵ which suggests that the IL-23 blockade may be of benefit for some pediatric patients with psoriasis or psoriatic arthritis.

Conclusion

Pediatric psoriasis and psoriatic arthritis have now been identified as being part of the autoimmune spectrum and are associated with metabolic syndrome, including obesity and excess central adiposity, similar to their adult variants. An overview of potential unmet needs in pediatric psoriasis is included in Table 2. These unmet needs include further delineation of diet and weight modification in the care and prevention of psoriasis; expansion of therapeutic trials and US Food and Drug Administration–approved medications for children with psoriasis, especially severe variants such as extensive plaque and pustular disease; and development of guidelines for ongoing monitoring of children with psoriasis. The role of therapeutic interventions and weight management on long-term disease course remains to be shown in extended clinical trials. Despite the great advancements in psoriatic care, knowledge gaps remain in pediatric psoriasis that will need to be addressed in the future.

Psoriasis affects 2% to 4% of the US population, with approximately one-third of cases beginning in childhood. The understanding of pediatric psoriasis has developed at a far slower pace than adult disease, with limitations in care including few medications that are approved by the US Food and Drug Administration for pediatric and adolescent use. Recently, a stable fixed-combination dose of calcipo-triene 0.005%–betamethasone dipropionate 0.064% topical suspension was approved for treatment of plaque psoriasis of the scalp in patients aged 12 to 17 years, which hopefully will lead a trend in psoriasis medication approval for children and teenagers.¹ Based on a PubMed search of articles indexed for MEDLINE using the search terms pediatric psoriasis, psoriasis, and strep that were published from April 2012 to April 2014, this article reviews newer data to address the issues that surround pediatric psoriasis and to provide an update on prior review articles on pediatric psoriasis.^2-5 This article reviews some of the newer literature on clinical presentation and comorbidities in pediatric psoriasis.⁵ Based on these recent findings, additional screenings including review of obesity parameters are recommended for pediatric patients with psoriasis (Table 1).

Update on Disease Manifestations, Associations, and Comorbidities

Disease Manifestations

A 2013 multicenter study delineated the clinical features of pediatric psoriasis.⁶ The study was conducted at 8 geographically diverse dermatology clinics in the United States to delineate the clinical manifestations of pediatric psoriasis. In an assessment of 181 participants aged 5 to 17 years, the investigators sought to determine the frequency of disease sites, severity, and guttate disease. Over a period of approximately 2 years, 43.1% of participants were determined to have mild disease and 56.9% had severe disease. Family history of psoriasis was present in 51.4% of participants, with first-degree relatives affected in 59.8% of cases. Scalp involvement at some time was noted in 79.0% of participants, and nail disease was noted in 55% of boys and 29% of girls. Guttate psoriasis was noted in 30% of participants, with more cases in the severe range (35.9%) versus the mild range (21.8%). Additionally, 22.1% of participants had a precipitating streptococcal infection, with the association being more common in pediatric patients with guttate psoriasis than plaque psoriasis.⁶ This study highlighted that pediatric psoriasis has a genetic basis, is frequently guttate in nature, commonly affects the nails, shows a trend toward being classified as severe, and may be triggered by streptococcal infections.

Streptococcal Infection

Pediatric psoriasis may be triggered or flared by Streptococcus pyogenes (group A β-hemolytic streptococci) infections, specifically β-hemolytic streptococci groups A, C, and G that have streptococcal M protein,^2,3,7 and this tendency can be associated with HLA-Cw6 or guttate psoriasis. Newer data have elucidated the role of streptococcal throat infections in psoriasis. Given that streptococcal throat infections are most common in school-aged children, these studies suggest a putative mechanism in pediatric psoriasis for triggering streptococcal infections, which would need to be confirmed in future studies, specifically in pediatric psoriasis patients.

It has been shown that T cells in psoriasis patients recognize common streptococcal M proteins and keratin determinants.⁷ Ferran et al⁸ recently demonstrated activation of circulating cutaneous lymphocyte–associated antigen (CLA)⁺ T cells but not CLA^- memory T cells in 27 psoriasis patients (ages not specified) when mixed with streptococcal throat extracts, causing production of IL-17, IP-10, IL-22, and IFN-γ; activation was not found in 6 healthy control patients. Antistreptolysin O levels were correlated with the messenger RNA up- regulation for IL-17, IP-10, IL-22, and IFN-γ, and also correlated with psoriasis area and severity index score in psoriasis patients. In this same study, injection of the activated culture supernatant into mouse skin caused epidermal hyperkeratosis and activation of nonlesional epidermal cells from psoriatic patients. This study thereby delineated some of the potential pathways of the streptococcal induction of psoriasis and psoriatic flares in childhood⁸; however, confirmation is needed through further study of pediatric psoriatic lymphocyte activity.

Differential Diagnosis

Additions to the extensive differential list have been cited in the recent literature. The differential diagnosis of pediatric psoriasis now includes sodium valproate–induced psoriasiform drug eruption⁹ and allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone, which are present in many sanitizing hand and diaper wipes and has been reported to cause psoriasiform dermatitis in a periorificial or perineal distribution.¹⁰ Clinicians should inquire about the use of these wipes, as caregivers rarely suspect this agent to be causative of the eruption.

Psoriatic Arthritis

Previously, psoriasis and psoriatic arthritis have been linked to autoimmune thyroid disease in adults.¹¹ A study of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry showed that family history of psoriasis, autoimmune thyroiditis, Crohn disease, and ankylosing spondylitis in a first-degree relative has been linked to juvenile idiopathic arthritis, highlighting that pediatric psoriasis can be genetically linked or associated with multiple autoimmune conditions and vice versa.¹²

Obesity, Metabolic Syndrome, and Cardiovascular Risks

Obesity is associated with pediatric psoriasis as highlighted in a growing body of recent literature.¹³ Excess adiposity as manifested by body mass index in the 85th percentile or greater (37.9% of 155 pediatric psoriasis patients vs 20.5% of 42 controls) and excess central adiposity as manifested by excess waist circumference and increased waist-to-height ratios are more common in pediatric patients with psoriasis than in controls.¹⁴

Obesity may be a trigger or associated with increased disease activity in pediatric psoriasis patients. Excess overall adiposity correlates with more severe disease. Obesity parameters may correlate with the onset of psoriasis and with disease severity. In fact, the odds of obesity may be higher in childhood than in adults.^14,15 A 2011 report of pediatric psoriasis patients aged 10 to 17 years (n=12) and wart controls (n=6)(mean age, 13.2 and 13.5 years, respectively) demonstrated that 4 of 12 patients with psoriasis and 0 of 6 patients with warts met criteria for metabolic syndrome as defined by 3 of the following: (1) triglycerides greater than or equal to 100 mg/dL; (2) high-density lipoprotein cholesterol less than 50 mg/dL in females and less than 5 mg/dL in males; (3) fasting blood glucose levels greater than or equal to 110 mg/dL, (4) waist circumference greater than the 75th percentile for age and sex; and (5) systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height.¹⁶ These studies highlight that obesity and metabolic syndrome are of concern in pediatric psoriasis patients; however, the best management approach using diet and weight interventions has yet to be identified.

Adiposity may precede the onset of psoriasis. A recent cohort of 27 pediatric psoriasis patients reported that the average age at onset of psoriasis was 8.7 years and the average age at onset of obesity was 4.1 years.¹⁵ In this study, 93% (25/27) of patients had adiposity preceding their psoriasis by 2 or more years. It is unclear if this is nature or nurture, as 48% (13/27) of patients had a family history of obesity, 41% (11/27) had a family history of psoriasis, and 48% (13/27) had a family history of hyperlipidemia.¹⁵ Therefore, obesity may be cultivated in some psoriatic families. The issue of household influences on diet and obesity needs to be addressed if successful weight management is to be achieved in future studies of pediatric psoriasis.

Cardiovascular risks in the pediatric psoriasis population are the subject of ongoing assessment but will likely mimic studies of adult psoriasis patients when reviewed longitudinally.¹⁶ Weight loss and healthy lifestyle interventions likely are beneficial to long-term health, but there is a lack of published data addressing dietary modification as a disease modifier for long-term care of pediatric psoriasis.

Anxiety and Depression

Anxiety and depression have been noted in adults with chronic skin diseases. A recent study assessed 118 patients and caregivers of pediatric patients with atopic dermatitis (n=50), psoriasis (n=25), or vitiligo (n=43) using the Children’s Dermatology Life Quality Index, the Hamilton Anxiety Scale, and the Beck Depression Inventory.¹⁷ Anxiety and depression were found in 36% of caregivers of pediatric psoriasis patients and depression was found in 36% of pediatric psoriasis patients, highlighting the need for interventions on a personal and family level to improve quality of life. As a comparator, anxiety was more prevalent in vitiligo caregivers (42%), but depression was only found in 26% of caregivers in the same group. Extent of disease (25%–75% body surface area affected) correlated with both depression and anxiety in the caregivers of pediatric patients with psoriasis as well as with anxiety in caregivers of pediatric patients with increased visible surface area of vitiligo.¹⁷ Parental anxiety has been reported at times to be linked to corticosteroid phobia, or corticophobia, which may interfere with disease therapy, as topical corticosteroids are considered the mainstay of therapy in childhood disease.¹⁸ Coordinating care with caregivers and addressing their concerns about the safety of medications should be integral to the pediatric psoriasis visit.

Pustular Psoriasis

Pustular psoriasis can be seen in any age group. Researchers recently have attempted to delineate the features and successful management of this severe subset of pediatric psoriasis patients. Twenty-four pediatric pustular psoriasis cases reviewed by Posso-De Los Rios et al¹⁹ revealed that 92% (22/24) had generalized and 8% (2/24) had limited acral disease. The mean (standard deviation) age at onset of pediatric pustular psoriasis was 6.3 (4.9) years. Half of the reported cases required more than one intervention. Treatment with acitretin, cyclosporine, and methotrexate was effective, but the investigators identified that there is a true dearth of evidence-based therapeutics in pediatric pustular psoriasis and much rebound with discontinuation.¹⁹ Although the subset of pediatric pustular psoriasis is rare, study of evidence-based intervention is needed.

Therapy

Recent reviews of pediatric and adolescent psoriasis highlight the paucity of therapeutic information for these patient populations. Investigators typically focus on topical therapies as the basis of treatment,²⁰ as well as the addition of phototherapy in mild to moderate plaque or guttate psoriasis and biologic or systemic agents in moderate to severe flares of plaque, erythrodermic, or pustular psoriasis.²¹ Further studies are needed to identify evidence-based therapeutic paradigms for pediatric psoriasis and to pinpoint therapies associated with the best quality of life in patients and their caregivers.

Tumor Necrosis Factor α Inhibitors

Safety and efficacy of etanercept for juvenile idiopathic arthritis including oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis recently was reviewed by Windschall et al²² using data from the German pediatric Biologika in der Kinderrheumatologie registry. Juvenile Arthritis Disease Activity Score 10 improved from baseline for 127 pediatric patients with psoriatic arthritis in 3 to 24 months (mean [standard deviation], 14.7 [6.4], 5.0 [4.6], 5.3 [6.4] at baseline, 3 months, and 24 months, respectively). Overall side effects were relatively higher in the psoriatic arthritis group; the rate of serious (relative risk, 1.39 [0.95-2.03; P=.08]) and nonserious (relative risk, 1.18 [1.02-1.35; P=.03]) adverse events also was elevated. Uveitis risk was greatest in the psoriatic arthritis group and the number of associated cases of inflammatory bowel disease outnumbered those seen in other forms of arthritis. The investigators concluded that monitoring for extra-articular immunopathies should be conducted in pediatric patients with psoriatic arthritis who are undergoing etanercept therapy.²²

Tumor necrosis factor α (TNF-α) inhibitors have been associated with triggering psoriasiform dermatitis in pediatric patients treated for inflammatory bowel disease. A Finnish study of infliximab side effects in pediatric patients with inflammatory bowel disease (n=84; Crohn disease: n=64) demonstrated that almost half (47.6% [40/84]) of the participants presented with chronic skin reactions, 23% of which were severe in nature.²³ Psoriasiform lesions of the scalp and ears were most common, followed by the periorificial area, genitals, trunk, and extremities. Rare association with HLA-Cw*0602 genotype was noted. Skin manifestations did not correlate with gut inflammation (as determined by fecal calprotectin levels). Discontinuation of therapy rarely was required.²³ Other studies also have highlighted this side effect, suggesting an incidence of 2.7% in adults with colitis treated with TNF-α inhibitors²⁴ and 10.5% in pediatric patients with Crohn disease.²⁵ In a study by Sherlock et al,²⁵  pediatric patients with Crohn disease developing psoriasis following infliximab therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151).

Methotrexate

For pediatric patients who are being treated with methotrexate, the polyglutamate assay recently has been reported to be helpful in identifying patients needing a dose escalation.²⁶ Higher numbers on the polyglutamate assay are associated with superior response to methotrexate therapy. Doses can be increased after 12 weeks in patients with low assays.²⁶

IL-23

The safety of IL-23 blockade in pediatric psoriasis patients has not yet been established, but data from adult cases have implicated the IL-17 and IL-23 pathways in psoriasis/psoriatic arthritis, including an association with IL-23R polymorphisms²⁷ and increases in soluble IL-20 and IL-22 associated with disease severity and an association of IL-17 levels with activity on the psoriasis area and severity index scores.²⁸ The data are more limited for pediatric cases. Pediatric patients with inflammatory bowel disease who have an IL-23R polymorphism appear to be susceptible to psoriatic flares while on TNF-α inhibitor therapy,²⁵ which suggests that the IL-23 blockade may be of benefit for some pediatric patients with psoriasis or psoriatic arthritis.

Conclusion

Pediatric psoriasis and psoriatic arthritis have now been identified as being part of the autoimmune spectrum and are associated with metabolic syndrome, including obesity and excess central adiposity, similar to their adult variants. An overview of potential unmet needs in pediatric psoriasis is included in Table 2. These unmet needs include further delineation of diet and weight modification in the care and prevention of psoriasis; expansion of therapeutic trials and US Food and Drug Administration–approved medications for children with psoriasis, especially severe variants such as extensive plaque and pustular disease; and development of guidelines for ongoing monitoring of children with psoriasis. The role of therapeutic interventions and weight management on long-term disease course remains to be shown in extended clinical trials. Despite the great advancements in psoriatic care, knowledge gaps remain in pediatric psoriasis that will need to be addressed in the future.

Kinetin (N6-furfuryladenine or 6-furfurylaminopurine) is a plant cytokinin or phytohormone that promotes cell division, delays senescence in plants, and is reputed to aid in the restoration of skin barrier function and, possibly, in reducing the signs and symptoms of rosacea (Clin. Exp. Dermatol. 2007;32:693-5; Plant Sci. 1999;148:37-45).

Kinetin is believed to develop in cellular DNA as a product of the oxidative, secondary modification of DNA (Plant Sci. 1999;148:37-45). In 1955, it became the first cytokinin isolated from DNA (from herring sperm) as an artifactual rearrangement product of the autoclaving process (J. Cosmet. Dermatol. 2007;6:243-9; Int. J. Biol. Macromol. 2007;40:182-92).

It has since been found to be present in human urine as well as DNA freshly extracted from human cells (Int. J. Biol. Macromol. 2007;40:182-92). The preponderance of amassed experimental evidence suggests that endogenous kinetin acts in vitro and in vivo as a potent antioxidant (Plant Sci. 1999;148:37-45). Currently, it is used as an anti-aging agent in various cosmetic products (J. Cosmet. Dermatol. 2007;6:243-9; J. Cosmet. Dermatol. 2010;9:218-25). Synthetic kinetin is thought to have the capacity to neutralize free radicals as well as limit the damage to DNA and fibroblasts (Photochem. Photobiol. 2012;88:748-52).

In vitro results

Olsen et al. demonstrated in vitro in 1999 that kinetin dose-dependently protected DNA against oxidative damage mediated by the Fenton reaction, and noted that kinetin had previously been linked to anti-aging activity in plants, fruit flies, and human cells in culture (Biochem. Biophys. Res. Commun. 1999;265:499-502). The following year, Verbeke et al. showed in vitro that kinetin potently inhibited damage caused by oxidation and glycoxidation (Biochem. Biophys. Res. Commun. 2000;276:1265-70).

In 2006, Vicanova et al. analyzed the effects of active ingredients from topical and systemic skin care formulations in vitro, finding that kinetin affected the upper dermis by enhancing deposits of fibrillin-1 and elastin fibers as well as their organization perpendicular to the dermal-epidermal junction. In the epidermis, kinetin stimulated keratinocyte production. Further, the investigators noted that the combination of topically applied kinetin with Imedeen Time Perfection ingredients (i.e., BioMarine Complex, grape seed extract, tomato extract, and vitamin C) supplemented systemically into culture medium yielded complementary benefits to dermal and epidermal development (Ann. N.Y. Acad. Sci. 2006;1067:337-42).

It is worth noting that in a study by Tournas et al. published the same month, investigators found that the topical application of a combination of vitamins C and E and ferulic acid yielded photoprotection to pig skin at 5 times the minimal erythema dose (MED) while individual antioxidants to which it was compared (i.e., coenzyme Q10, idebenone, and kinetin) delivered no photoprotective effects (J. Invest. Dermatol. 2006;126:1185-7). Nevertheless, Barciszewski et al. have observed that kinetin is the first stable secondary DNA damage product characterized by well defined cytokinin and anti-aging activity, with data showing that it has delayed human cellular aging in culture (Int. J. Biol. Macromol. 2007;40:182-92).

Rosacea

In 2007, Wu et al. performed a 12-week open-label study in 15 women and 3 men (aged 30-67 years) to ascertain the tolerability and efficacy of kinetin 0.1% lotion in the treatment of mild to moderate facial rosacea. Patients (17 of whom completed the study) applied the lotion twice daily, also daily applying an SPF 30 sunscreen. By week 4, significant improvements were observed in the reduction of skin roughness and mottled hyperpigmentation. Subject assessments at each 4-week interval after baseline and after 12 weeks revealed that kinetin 0.1% was well tolerated and effective for mild to moderate inflammatory rosacea (Clin. Exp. Dermatol. 2007;32:693-5).

Anti-aging

A 2002 study by J.L. McCullough and G.D. Weinstein represented the first evidence of the efficacy of topical kinetin in human beings, with twice-daily application for 24 weeks found to ameliorate skin texture, color, and blotchiness while diminishing rhytides and transepidermal water loss (J. Cosmet. Dermatol. 2002;15:29-32).

Two years later, T. Kimura and K. Doi showed that topical administration of kinetin improved the texture, wrinkling, and pigmentation of aged skin of hairless descendants of Mexican hairless dogs, resulting in notable depigmentation and rejuvenation after 100 days of treatment (Rejuvenation Res. 2004;7:32-9).In 2007, Chiu et al. conducted a randomized, double-blind, placebo-controlled, split-face comparative study in 52 Taiwanese subjects aged 30-60 years (90% of whom were female, all of whom had Fitzpatrick skin types II, III, or IV) to evaluate the clinical anti-aging effects and efficacy differences between kinetin plus niacinamide (kinetin 0.03%, niacinamide 4%) and niacinamide 4% alone versus vehicle placebo.

In the combination group, significant and sustained decreases were observed in counts of spots, pores, wrinkles, and evenness as well as persistent reductions in erythema index at weeks 8 and 12. At week 12, stratum corneum hydration status also was significantly enhanced in this group. In the niacinamide-only group, pore and evenness counts were significantly decreased at week 8, with declines in wrinkle counts emerging at week 12. The investigators concluded that kinetin and niacinamide display synergistic and dynamic anti-aging effects, showing substantial potential as topical anti-aging cosmeceutical agents (J. Cosmet. Dermatol. 2007;6:243-9).

However, Levin et al. noted in 2010 that while the effects of kinetin have been established in plants and its antioxidant properties have been displayed in vitro, the anti-aging effects and clinical efficacy ascribed to kinetin have been based on limited evidence, with no studies extant on the percutaneous absorption of kinetin. They added that research elucidating the mechanisms through which kinetin appears to improve skin barrier function, texture, and pigmentation also are lacking (J. Clin. Aesthet. Dermatol. 2010;3:22-41).

In 2012, Campos et al. assessed the effects on hydration, viscoelastic characteristics, and photoprotection of cosmetic preparations containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid, and kinetin. They observed that the formulation protected hairless mouse skin barrier function against UV harm. After 4 weeks of application on human skin, the combination product was found to have improved moisturization of the stratum corneum, also delivering hydration effects to deeper skin layers. The researchers concluded that the cosmetic formulation containing kinetin shows promise as a cutaneous anti-aging product (Photochem. Photobiol. 2012;88:748-52).

Conclusion

While some experimental and clinical results appear to suggest an anti-aging effect exerted by topically applied kinetin, much more research – particularly randomized controlled and comparison studies – are needed to provide a clearer picture as to the mechanisms and appropriate role of kinetin in the dermatologic armamentarium.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.

Kinetin (N6-furfuryladenine or 6-furfurylaminopurine) is a plant cytokinin or phytohormone that promotes cell division, delays senescence in plants, and is reputed to aid in the restoration of skin barrier function and, possibly, in reducing the signs and symptoms of rosacea (Clin. Exp. Dermatol. 2007;32:693-5; Plant Sci. 1999;148:37-45).

Kinetin is believed to develop in cellular DNA as a product of the oxidative, secondary modification of DNA (Plant Sci. 1999;148:37-45). In 1955, it became the first cytokinin isolated from DNA (from herring sperm) as an artifactual rearrangement product of the autoclaving process (J. Cosmet. Dermatol. 2007;6:243-9; Int. J. Biol. Macromol. 2007;40:182-92).

It has since been found to be present in human urine as well as DNA freshly extracted from human cells (Int. J. Biol. Macromol. 2007;40:182-92). The preponderance of amassed experimental evidence suggests that endogenous kinetin acts in vitro and in vivo as a potent antioxidant (Plant Sci. 1999;148:37-45). Currently, it is used as an anti-aging agent in various cosmetic products (J. Cosmet. Dermatol. 2007;6:243-9; J. Cosmet. Dermatol. 2010;9:218-25). Synthetic kinetin is thought to have the capacity to neutralize free radicals as well as limit the damage to DNA and fibroblasts (Photochem. Photobiol. 2012;88:748-52).

In vitro results

Olsen et al. demonstrated in vitro in 1999 that kinetin dose-dependently protected DNA against oxidative damage mediated by the Fenton reaction, and noted that kinetin had previously been linked to anti-aging activity in plants, fruit flies, and human cells in culture (Biochem. Biophys. Res. Commun. 1999;265:499-502). The following year, Verbeke et al. showed in vitro that kinetin potently inhibited damage caused by oxidation and glycoxidation (Biochem. Biophys. Res. Commun. 2000;276:1265-70).

In 2006, Vicanova et al. analyzed the effects of active ingredients from topical and systemic skin care formulations in vitro, finding that kinetin affected the upper dermis by enhancing deposits of fibrillin-1 and elastin fibers as well as their organization perpendicular to the dermal-epidermal junction. In the epidermis, kinetin stimulated keratinocyte production. Further, the investigators noted that the combination of topically applied kinetin with Imedeen Time Perfection ingredients (i.e., BioMarine Complex, grape seed extract, tomato extract, and vitamin C) supplemented systemically into culture medium yielded complementary benefits to dermal and epidermal development (Ann. N.Y. Acad. Sci. 2006;1067:337-42).

It is worth noting that in a study by Tournas et al. published the same month, investigators found that the topical application of a combination of vitamins C and E and ferulic acid yielded photoprotection to pig skin at 5 times the minimal erythema dose (MED) while individual antioxidants to which it was compared (i.e., coenzyme Q10, idebenone, and kinetin) delivered no photoprotective effects (J. Invest. Dermatol. 2006;126:1185-7). Nevertheless, Barciszewski et al. have observed that kinetin is the first stable secondary DNA damage product characterized by well defined cytokinin and anti-aging activity, with data showing that it has delayed human cellular aging in culture (Int. J. Biol. Macromol. 2007;40:182-92).

Rosacea

In 2007, Wu et al. performed a 12-week open-label study in 15 women and 3 men (aged 30-67 years) to ascertain the tolerability and efficacy of kinetin 0.1% lotion in the treatment of mild to moderate facial rosacea. Patients (17 of whom completed the study) applied the lotion twice daily, also daily applying an SPF 30 sunscreen. By week 4, significant improvements were observed in the reduction of skin roughness and mottled hyperpigmentation. Subject assessments at each 4-week interval after baseline and after 12 weeks revealed that kinetin 0.1% was well tolerated and effective for mild to moderate inflammatory rosacea (Clin. Exp. Dermatol. 2007;32:693-5).

Anti-aging

A 2002 study by J.L. McCullough and G.D. Weinstein represented the first evidence of the efficacy of topical kinetin in human beings, with twice-daily application for 24 weeks found to ameliorate skin texture, color, and blotchiness while diminishing rhytides and transepidermal water loss (J. Cosmet. Dermatol. 2002;15:29-32).

Two years later, T. Kimura and K. Doi showed that topical administration of kinetin improved the texture, wrinkling, and pigmentation of aged skin of hairless descendants of Mexican hairless dogs, resulting in notable depigmentation and rejuvenation after 100 days of treatment (Rejuvenation Res. 2004;7:32-9).In 2007, Chiu et al. conducted a randomized, double-blind, placebo-controlled, split-face comparative study in 52 Taiwanese subjects aged 30-60 years (90% of whom were female, all of whom had Fitzpatrick skin types II, III, or IV) to evaluate the clinical anti-aging effects and efficacy differences between kinetin plus niacinamide (kinetin 0.03%, niacinamide 4%) and niacinamide 4% alone versus vehicle placebo.

In the combination group, significant and sustained decreases were observed in counts of spots, pores, wrinkles, and evenness as well as persistent reductions in erythema index at weeks 8 and 12. At week 12, stratum corneum hydration status also was significantly enhanced in this group. In the niacinamide-only group, pore and evenness counts were significantly decreased at week 8, with declines in wrinkle counts emerging at week 12. The investigators concluded that kinetin and niacinamide display synergistic and dynamic anti-aging effects, showing substantial potential as topical anti-aging cosmeceutical agents (J. Cosmet. Dermatol. 2007;6:243-9).

However, Levin et al. noted in 2010 that while the effects of kinetin have been established in plants and its antioxidant properties have been displayed in vitro, the anti-aging effects and clinical efficacy ascribed to kinetin have been based on limited evidence, with no studies extant on the percutaneous absorption of kinetin. They added that research elucidating the mechanisms through which kinetin appears to improve skin barrier function, texture, and pigmentation also are lacking (J. Clin. Aesthet. Dermatol. 2010;3:22-41).

In 2012, Campos et al. assessed the effects on hydration, viscoelastic characteristics, and photoprotection of cosmetic preparations containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid, and kinetin. They observed that the formulation protected hairless mouse skin barrier function against UV harm. After 4 weeks of application on human skin, the combination product was found to have improved moisturization of the stratum corneum, also delivering hydration effects to deeper skin layers. The researchers concluded that the cosmetic formulation containing kinetin shows promise as a cutaneous anti-aging product (Photochem. Photobiol. 2012;88:748-52).

Conclusion

While some experimental and clinical results appear to suggest an anti-aging effect exerted by topically applied kinetin, much more research – particularly randomized controlled and comparison studies – are needed to provide a clearer picture as to the mechanisms and appropriate role of kinetin in the dermatologic armamentarium.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.

Kinetin (N6-furfuryladenine or 6-furfurylaminopurine) is a plant cytokinin or phytohormone that promotes cell division, delays senescence in plants, and is reputed to aid in the restoration of skin barrier function and, possibly, in reducing the signs and symptoms of rosacea (Clin. Exp. Dermatol. 2007;32:693-5; Plant Sci. 1999;148:37-45).

Kinetin is believed to develop in cellular DNA as a product of the oxidative, secondary modification of DNA (Plant Sci. 1999;148:37-45). In 1955, it became the first cytokinin isolated from DNA (from herring sperm) as an artifactual rearrangement product of the autoclaving process (J. Cosmet. Dermatol. 2007;6:243-9; Int. J. Biol. Macromol. 2007;40:182-92).

It has since been found to be present in human urine as well as DNA freshly extracted from human cells (Int. J. Biol. Macromol. 2007;40:182-92). The preponderance of amassed experimental evidence suggests that endogenous kinetin acts in vitro and in vivo as a potent antioxidant (Plant Sci. 1999;148:37-45). Currently, it is used as an anti-aging agent in various cosmetic products (J. Cosmet. Dermatol. 2007;6:243-9; J. Cosmet. Dermatol. 2010;9:218-25). Synthetic kinetin is thought to have the capacity to neutralize free radicals as well as limit the damage to DNA and fibroblasts (Photochem. Photobiol. 2012;88:748-52).

In vitro results

Olsen et al. demonstrated in vitro in 1999 that kinetin dose-dependently protected DNA against oxidative damage mediated by the Fenton reaction, and noted that kinetin had previously been linked to anti-aging activity in plants, fruit flies, and human cells in culture (Biochem. Biophys. Res. Commun. 1999;265:499-502). The following year, Verbeke et al. showed in vitro that kinetin potently inhibited damage caused by oxidation and glycoxidation (Biochem. Biophys. Res. Commun. 2000;276:1265-70).

In 2006, Vicanova et al. analyzed the effects of active ingredients from topical and systemic skin care formulations in vitro, finding that kinetin affected the upper dermis by enhancing deposits of fibrillin-1 and elastin fibers as well as their organization perpendicular to the dermal-epidermal junction. In the epidermis, kinetin stimulated keratinocyte production. Further, the investigators noted that the combination of topically applied kinetin with Imedeen Time Perfection ingredients (i.e., BioMarine Complex, grape seed extract, tomato extract, and vitamin C) supplemented systemically into culture medium yielded complementary benefits to dermal and epidermal development (Ann. N.Y. Acad. Sci. 2006;1067:337-42).

It is worth noting that in a study by Tournas et al. published the same month, investigators found that the topical application of a combination of vitamins C and E and ferulic acid yielded photoprotection to pig skin at 5 times the minimal erythema dose (MED) while individual antioxidants to which it was compared (i.e., coenzyme Q10, idebenone, and kinetin) delivered no photoprotective effects (J. Invest. Dermatol. 2006;126:1185-7). Nevertheless, Barciszewski et al. have observed that kinetin is the first stable secondary DNA damage product characterized by well defined cytokinin and anti-aging activity, with data showing that it has delayed human cellular aging in culture (Int. J. Biol. Macromol. 2007;40:182-92).

Rosacea

In 2007, Wu et al. performed a 12-week open-label study in 15 women and 3 men (aged 30-67 years) to ascertain the tolerability and efficacy of kinetin 0.1% lotion in the treatment of mild to moderate facial rosacea. Patients (17 of whom completed the study) applied the lotion twice daily, also daily applying an SPF 30 sunscreen. By week 4, significant improvements were observed in the reduction of skin roughness and mottled hyperpigmentation. Subject assessments at each 4-week interval after baseline and after 12 weeks revealed that kinetin 0.1% was well tolerated and effective for mild to moderate inflammatory rosacea (Clin. Exp. Dermatol. 2007;32:693-5).

Anti-aging

A 2002 study by J.L. McCullough and G.D. Weinstein represented the first evidence of the efficacy of topical kinetin in human beings, with twice-daily application for 24 weeks found to ameliorate skin texture, color, and blotchiness while diminishing rhytides and transepidermal water loss (J. Cosmet. Dermatol. 2002;15:29-32).

Two years later, T. Kimura and K. Doi showed that topical administration of kinetin improved the texture, wrinkling, and pigmentation of aged skin of hairless descendants of Mexican hairless dogs, resulting in notable depigmentation and rejuvenation after 100 days of treatment (Rejuvenation Res. 2004;7:32-9).In 2007, Chiu et al. conducted a randomized, double-blind, placebo-controlled, split-face comparative study in 52 Taiwanese subjects aged 30-60 years (90% of whom were female, all of whom had Fitzpatrick skin types II, III, or IV) to evaluate the clinical anti-aging effects and efficacy differences between kinetin plus niacinamide (kinetin 0.03%, niacinamide 4%) and niacinamide 4% alone versus vehicle placebo.

In the combination group, significant and sustained decreases were observed in counts of spots, pores, wrinkles, and evenness as well as persistent reductions in erythema index at weeks 8 and 12. At week 12, stratum corneum hydration status also was significantly enhanced in this group. In the niacinamide-only group, pore and evenness counts were significantly decreased at week 8, with declines in wrinkle counts emerging at week 12. The investigators concluded that kinetin and niacinamide display synergistic and dynamic anti-aging effects, showing substantial potential as topical anti-aging cosmeceutical agents (J. Cosmet. Dermatol. 2007;6:243-9).

However, Levin et al. noted in 2010 that while the effects of kinetin have been established in plants and its antioxidant properties have been displayed in vitro, the anti-aging effects and clinical efficacy ascribed to kinetin have been based on limited evidence, with no studies extant on the percutaneous absorption of kinetin. They added that research elucidating the mechanisms through which kinetin appears to improve skin barrier function, texture, and pigmentation also are lacking (J. Clin. Aesthet. Dermatol. 2010;3:22-41).

In 2012, Campos et al. assessed the effects on hydration, viscoelastic characteristics, and photoprotection of cosmetic preparations containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid, and kinetin. They observed that the formulation protected hairless mouse skin barrier function against UV harm. After 4 weeks of application on human skin, the combination product was found to have improved moisturization of the stratum corneum, also delivering hydration effects to deeper skin layers. The researchers concluded that the cosmetic formulation containing kinetin shows promise as a cutaneous anti-aging product (Photochem. Photobiol. 2012;88:748-52).

Conclusion

While some experimental and clinical results appear to suggest an anti-aging effect exerted by topically applied kinetin, much more research – particularly randomized controlled and comparison studies – are needed to provide a clearer picture as to the mechanisms and appropriate role of kinetin in the dermatologic armamentarium.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.

Patients with coronary heart disease who have both depression and stress are at increased risk of myocardial infarction and death, according to findings from a large, prospective, cohort study.

Of 4,487 adults with CHD who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 1,337 experienced MI or death during a median of nearly 6 years of follow-up. Those with both high depressive symptoms and high stress at baseline – about 6% of the study population – were at significantly increased risk of such events (adjusted hazard ratio, 1.48) during the first 2.5 years of follow-up, compared with those with low stress and low depressive symptoms. However, the association was not significant beyond the initial 2.5 years (HR, 0.89), Carmela Alcántara, Ph.D., of Columbia University, New York, and her colleagues reported.

Those with low stress and high depressive symptoms, and those with high stress and low depressive symptoms, were not at increased risk (HR, 0.92 and 0.86, respectively) at any point during follow-up (Circ. Cardiovasc. Qual. Outcomes 2015 March 10 [doi:10.1161/IRCOUTCOMES.114.001180]).

The findings provide initial empirical evidence to support a “psychosocial perfect storm conceptual model” based on the idea that it takes an underlying chronic psychosocial vulnerability such as depression along with a more transient state such as psychological stress to precipitate a clinical event. The confluence of these factors may be particularly destructive in the short term, the investigators concluded, noting that the findings could have implications for the development of preventive treatments that focus on depression and stress during this vulnerable period in CHD patients.

The National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute supported the study. Dr. Alcantara reported having no disclosures, but two other authors received salary support from Amgen for research, and one served as a consultant for DiaDexus.

Patients with coronary heart disease who have both depression and stress are at increased risk of myocardial infarction and death, according to findings from a large, prospective, cohort study.

Of 4,487 adults with CHD who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 1,337 experienced MI or death during a median of nearly 6 years of follow-up. Those with both high depressive symptoms and high stress at baseline – about 6% of the study population – were at significantly increased risk of such events (adjusted hazard ratio, 1.48) during the first 2.5 years of follow-up, compared with those with low stress and low depressive symptoms. However, the association was not significant beyond the initial 2.5 years (HR, 0.89), Carmela Alcántara, Ph.D., of Columbia University, New York, and her colleagues reported.

Those with low stress and high depressive symptoms, and those with high stress and low depressive symptoms, were not at increased risk (HR, 0.92 and 0.86, respectively) at any point during follow-up (Circ. Cardiovasc. Qual. Outcomes 2015 March 10 [doi:10.1161/IRCOUTCOMES.114.001180]).

The findings provide initial empirical evidence to support a “psychosocial perfect storm conceptual model” based on the idea that it takes an underlying chronic psychosocial vulnerability such as depression along with a more transient state such as psychological stress to precipitate a clinical event. The confluence of these factors may be particularly destructive in the short term, the investigators concluded, noting that the findings could have implications for the development of preventive treatments that focus on depression and stress during this vulnerable period in CHD patients.

The National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute supported the study. Dr. Alcantara reported having no disclosures, but two other authors received salary support from Amgen for research, and one served as a consultant for DiaDexus.

Patients with coronary heart disease who have both depression and stress are at increased risk of myocardial infarction and death, according to findings from a large, prospective, cohort study.

Of 4,487 adults with CHD who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 1,337 experienced MI or death during a median of nearly 6 years of follow-up. Those with both high depressive symptoms and high stress at baseline – about 6% of the study population – were at significantly increased risk of such events (adjusted hazard ratio, 1.48) during the first 2.5 years of follow-up, compared with those with low stress and low depressive symptoms. However, the association was not significant beyond the initial 2.5 years (HR, 0.89), Carmela Alcántara, Ph.D., of Columbia University, New York, and her colleagues reported.

Those with low stress and high depressive symptoms, and those with high stress and low depressive symptoms, were not at increased risk (HR, 0.92 and 0.86, respectively) at any point during follow-up (Circ. Cardiovasc. Qual. Outcomes 2015 March 10 [doi:10.1161/IRCOUTCOMES.114.001180]).

The findings provide initial empirical evidence to support a “psychosocial perfect storm conceptual model” based on the idea that it takes an underlying chronic psychosocial vulnerability such as depression along with a more transient state such as psychological stress to precipitate a clinical event. The confluence of these factors may be particularly destructive in the short term, the investigators concluded, noting that the findings could have implications for the development of preventive treatments that focus on depression and stress during this vulnerable period in CHD patients.

The National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute supported the study. Dr. Alcantara reported having no disclosures, but two other authors received salary support from Amgen for research, and one served as a consultant for DiaDexus.