Psoriasis

GRAND CAYMAN – When considering the use of biologic therapy for psoriasis patients who are at greater risk of cancer or of serious infection, Dr. Kenneth B. Gordon advises clinicians to “look at the patient in front of you” and the impact the disease is having on them.

In an interview at the annual Caribbean Dermatology Symposium, Dr. Gordon, professor of dermatology at Northwestern University, Chicago, discusses the use of biologics to treat psoriasis in patients with a history of cancer, patients at an increased risk for serious infections (such as those with chronic renal disease or diabetes), as well as patients with HIV, who can have significant psoriasis.

He also provides some recommendations on counseling patients and discusses the use of biologics in children with psoriasis.

The meeting is provided by Global Academy for Medical Education. Global Academy and this news organization are owned by the same parent company.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

This article was updated 1/31/2016.

GRAND CAYMAN – When considering the use of biologic therapy for psoriasis patients who are at greater risk of cancer or of serious infection, Dr. Kenneth B. Gordon advises clinicians to “look at the patient in front of you” and the impact the disease is having on them.

In an interview at the annual Caribbean Dermatology Symposium, Dr. Gordon, professor of dermatology at Northwestern University, Chicago, discusses the use of biologics to treat psoriasis in patients with a history of cancer, patients at an increased risk for serious infections (such as those with chronic renal disease or diabetes), as well as patients with HIV, who can have significant psoriasis.

He also provides some recommendations on counseling patients and discusses the use of biologics in children with psoriasis.

The meeting is provided by Global Academy for Medical Education. Global Academy and this news organization are owned by the same parent company.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

This article was updated 1/31/2016.

GRAND CAYMAN – When considering the use of biologic therapy for psoriasis patients who are at greater risk of cancer or of serious infection, Dr. Kenneth B. Gordon advises clinicians to “look at the patient in front of you” and the impact the disease is having on them.

In an interview at the annual Caribbean Dermatology Symposium, Dr. Gordon, professor of dermatology at Northwestern University, Chicago, discusses the use of biologics to treat psoriasis in patients with a history of cancer, patients at an increased risk for serious infections (such as those with chronic renal disease or diabetes), as well as patients with HIV, who can have significant psoriasis.

He also provides some recommendations on counseling patients and discusses the use of biologics in children with psoriasis.

The meeting is provided by Global Academy for Medical Education. Global Academy and this news organization are owned by the same parent company.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

This article was updated 1/31/2016.

Laws recently passed or under consideration in state legislatures may offer some relief to physicians and patients dogged by the “step” or “fail-first” therapy protocols mandated by insurers, but until better clinical evidence is available to support treatment decisions and biosimilars reduce costs, clinicians must strategize to get patients through the step pathways as fast as possible.

Rheumatologists, gastroenterologists, and dermatologists all confront fail-first policies in their practices, particularly when prescribing the biologic agents that have been game changers in treating rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, among other diseases.

In RA, for example, a patient might be required to fail a series of disease-modifying antirheumatic drugs (DMARDs), including methotrexate, before starting a biologic. In Crohn’s disease, patients might have to first fail on steroids and immunosuppressants.

Most clinicians consider cost concerns fair as a basis for insurance decisions. But they can also have strong rationales for making exceptions. This may mean starting patients on a biologic early, particularly those they deem unlikely to respond to first- or second-line treatments – which may be cheaper but are not necessarily safer.

In egregious cases, a patient already stable on a biologic who has changed insurance plans may be forced to go backwards in the treatment pathway, and fail first- and second-line therapies all over again before resuming – a process unlikely to be cost-effective in the long term, and also rife with ethical concerns, say clinicians.

“Making a patient fail to get a less toxic drug sort of violates our ‘do no harm’ principle,” Dr. Stephen B. Hanauer, medical director of the Digestive Health Center at Northwestern University, Chicago, said in an interview.

“I always say that if biologics cost a dollar, we’d be using them for everybody. If you take away the steroids and the immunosuppressants, these are very safe drugs for IBD, far safer than steroids – but steroids are cheap,” Dr. Hanauer said.

And with some debilitating disease presentations, such as severe Crohn’s, “being told that we have to try conventional therapies and the patient has to fail them can mean putting the patient through progression of their disease, and suffering,” Dr. David T. Rubin, codirector of the Digestive Diseases Center at the University of Chicago, said in an interview. “We really struggle with this.”

Dr. Joseph S. Eastern, a dermatologist practicing in Belleville, N.J., said his specialty faces similar challenges with step therapy. “Dermatologists as a group are pretty risk averse. When given the opportunity, we do an excellent job of prescribing conventional medications, ultraviolet therapy, and biologics in the most cost-efficient possible way,” he said in an email.

Yet “third-party payers tell us, for example, that a patient must fail methotrexate before we can use a biologic, when the whole advantage of biologic therapy for many of these patients is the avoidance of organotoxicity and other serious risks.”

As a result, Dr. Eastern said, “I write a lot more vehement letters to payers about the biologics these days.”

Choice vs. cost

Rheumatologists are among the clinicians most affected by fail-first and step therapy mandates, as the diseases they treat – particularly RA – are the most established indications for biologic therapies, and for which the largest number of these are approved.

Courtesy Dr. Norman Gaylis

Though Medicare and Medicaid allow physicians considerable leeway, private insurers often tightly circumscribe the timing and choice of biologics in RA. As insurers’ first-choice biologic drug changes frequently, and varies from plan to plan, a patient who is stable on one agent might be asked to switch to another, a phenomenon known as nonmedical switching.

Insurers are seldom transparent about their reasons for establishing certain biologic drugs as their go-to agents, clinicians say, while making it difficult for physicians to prescribe others. “There’s a tremendous amount of discounting going on that we are oblivious to as physicians. I’ve seen situations where drug A is the first one you have to use this month and the next month, drug C,” said Dr. Norman Gaylis, a rheumatologist practicing in Aventura, Fla.

Attempting to start a patient on a nonpreferential biologic will generate paperwork and delays, Dr. Gaylis said, which can cost patients valuable time. “There’s a window of opportunity to treat these diseases, and by creating a step therapy pathway we’re closing the window at least partially.”

“As an example, rituximab in most payer plans is not tiered as a first-line biologic treatment option despite the fact that there are frequent scenarios where the clinical and serological presentation of a patient would suggest it to be preferable as a first-line treatment choice over an anti-TNF [tumor necrosis factor],” Dr. Gaylis said.

“There is no room for clinical decision making based upon the unique presentation of each different patient when choosing the best treatment option,” he said.

Rheumatologists often become overwhelmed with authorization paperwork, “and still in many instances end up with a denial of their request.”

Dr. Karen Kolba, a rheumatologist in private practice in Santa Maria, Calif., said that she agreed in principle with the way step therapy protocols have been established, and that some of the frustration with step therapy amounts to a tendency among specialist clinicians to bristle at being told what to do.

“Physicians hate protocol,” Dr. Kolba said. “But comparing one protocol to another is the only way we are going to make advances.” It took the rheumatology community about 30 years to come to terms with the use of methotrexate in RA, she noted, and the stepped approach grew naturally from the treatment of methotrexate failures with biologic agents when these first emerged in the late 1990s.

A majority of RA patients started on a stepped approach using DMARDs will respond, Dr. Kolba said, and for those who must move into the biologic realm, the vast majority will succeed on the first anti-TNF agent prescribed. And there is little science to establish that one TNF inhibitor is superior – only that patients can sometimes succeed with one and fail another.

“As far as which biologic to initiate, my personal opinion is I don’t care, and I tell the patients that I don’t mind if the insurer picks out of this category because I’m flipping a coin as well,” she said.

Step mandates become objectionable, Dr. Kolba said, when they are purportedly based in science that doesn’t exist, or when they seem to exist only to wear down the provider.

“With private insurance not only do they have the drug of the year, they’re going to make me battle for every single prescription. When I say I have tried this patient on maximal tolerable doses of all these DMARDs, they ought to believe me. Yet I get six-page forms back saying, ‘Give me the start and stop dates of all the drugs you’ve used.’”

States constrain fail first

For many specialists treating patients with biologics, some of these hurdles are already getting lowered.

Concerns about physician choice, a lack of transparency in insurer decision making, and the ethics of forcing patients to fail have led advocacy groups to press hard in recent years for legislation limiting step therapy – with successes in a dozen states.

While the state legislation is not disease or drug specific, it has important implications for clinicians treating with biologics. “Step therapy in its genesis was a good idea – it’s OK to try to reduce costs in the health care system,” said Patrick Stone, state government relations manager at the National Psoriasis Foundation in Annapolis, Md., a group that works extensively on step therapy issues. “But when these protocols were first crafted, medications like biologics weren’t in use.”

Jeff Okazaki, associate director of the Coalition of State Rheumatology Organizations, a group based in Schaumberg, Ill., said lawmakers are starting to accept that in terms of cost of care, “somebody not being treated appropriately and down the line has organ damage or comorbidity because of incorrect treatment decisions due to step therapy is a higher burden.”

Moreover, he said, “we’d seen protocols requiring five or more steps, and for each step you have to try it at least 90 days.” For a patient with rheumatic or autoimmune disease, “getting through something like that can just be devastating.”

In 2011, Connecticut, Mississippi, and Arkansas became the first states to pass legislation limiting some aspect of step therapy. Since then, nine additional states have passed legislation varying in focus and scope.

In Kentucky, for example, patients cannot be forced by their insurer to remain on an ineffective therapy for more than 30 days, and insurers must respond to physician requests for an override within 2 days. Mississippi allows physicians to override insurer decisions with proof of clinical evidence. In California, legislation passed last year aims to reduce bureaucracy and speed up response to physician requests for overrides.

Mr. Stone and Mr. Okazaki are working in a coalition with other dermatology, rheumatology, and GI groups to push bills in seven more states, including New York, North Carolina, and Ohio.

While all the bills differ in what they attempt to limit, the model legislation has three basic objectives, Mr. Okazaki said. “We want a clear set of clinical guidelines, a quick review process, and overrides that allow for exceptions in cases where patients shouldn’t have to go through step therapy.”

Clinical strategies and research gaps

New legislation undoubtedly will help providers and patients get access to their choice of treatment agents. But so long as biologics are expensive – and it will be a while before the first biosimilar drugs, which will have efficacy and safety similar to their reference biologics, reduce prices in any meaningful way – step therapy will likely remain the norm.

One of the key difficulties providers face when pushing back on an insurer in favor of a biologic drug is insufficient clinical evidence.

With IBD, Dr. Rubin said, “we need a need more longitudinal understanding” and better prognostic indicators “in order to justify spending the extra money or going to one of these therapies.”

Dr. Hanauer said one of the limitations he faces in practice is insufficient clinical evidence for biologics early in the treatment pathway for IBD.

RA “is much more common than Crohn’s disease is. In trials, it’s much easier to recruit hundreds of patients [for an RA trial], while with Crohn’s it’s very hard to enroll more than a couple a year at most sites,” he said. “And as you move earlier in the treatment pathway that becomes somewhat more difficult as well.”

His solution for now, he said, is to follow established step pathways in an accelerated way, for “a rapid transition toward highly effective therapies” without having to face extensive pushback from insurers.

“The idea is to initiate immunosuppressants for any patients with sufficient disease activity to justify steroids,” Dr. Hanauer said. “Their steroids are then tapered, and while on immunosuppressants, patients are in a perfect setup to get combination therapy with an immunosuppressive and a biologic – and that’s a 2- to 3-month transition, not 2-3 years.”

Dr. Kolba said that despite the wide array of options for treating RA, the specialty suffers from a dearth of understanding as to why some patients fail drugs while others succeed, even within the same drug class.

Rheumatologists’ prescribing choices would be highly influenced by better biomarkers, were they to become available, she said. And they’d have far better arguments when confronted with payer pushback.

“We’re all looking for that magic biologic marker to tell me which drug to use,” Dr. Kolba said, “because God knows if I had a blood test that said ‘this is the drug,’ I would go to the mat with the insurer.”

Laws recently passed or under consideration in state legislatures may offer some relief to physicians and patients dogged by the “step” or “fail-first” therapy protocols mandated by insurers, but until better clinical evidence is available to support treatment decisions and biosimilars reduce costs, clinicians must strategize to get patients through the step pathways as fast as possible.

Rheumatologists, gastroenterologists, and dermatologists all confront fail-first policies in their practices, particularly when prescribing the biologic agents that have been game changers in treating rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, among other diseases.

In RA, for example, a patient might be required to fail a series of disease-modifying antirheumatic drugs (DMARDs), including methotrexate, before starting a biologic. In Crohn’s disease, patients might have to first fail on steroids and immunosuppressants.

Most clinicians consider cost concerns fair as a basis for insurance decisions. But they can also have strong rationales for making exceptions. This may mean starting patients on a biologic early, particularly those they deem unlikely to respond to first- or second-line treatments – which may be cheaper but are not necessarily safer.

In egregious cases, a patient already stable on a biologic who has changed insurance plans may be forced to go backwards in the treatment pathway, and fail first- and second-line therapies all over again before resuming – a process unlikely to be cost-effective in the long term, and also rife with ethical concerns, say clinicians.

“Making a patient fail to get a less toxic drug sort of violates our ‘do no harm’ principle,” Dr. Stephen B. Hanauer, medical director of the Digestive Health Center at Northwestern University, Chicago, said in an interview.

“I always say that if biologics cost a dollar, we’d be using them for everybody. If you take away the steroids and the immunosuppressants, these are very safe drugs for IBD, far safer than steroids – but steroids are cheap,” Dr. Hanauer said.

And with some debilitating disease presentations, such as severe Crohn’s, “being told that we have to try conventional therapies and the patient has to fail them can mean putting the patient through progression of their disease, and suffering,” Dr. David T. Rubin, codirector of the Digestive Diseases Center at the University of Chicago, said in an interview. “We really struggle with this.”

Dr. Joseph S. Eastern, a dermatologist practicing in Belleville, N.J., said his specialty faces similar challenges with step therapy. “Dermatologists as a group are pretty risk averse. When given the opportunity, we do an excellent job of prescribing conventional medications, ultraviolet therapy, and biologics in the most cost-efficient possible way,” he said in an email.

Yet “third-party payers tell us, for example, that a patient must fail methotrexate before we can use a biologic, when the whole advantage of biologic therapy for many of these patients is the avoidance of organotoxicity and other serious risks.”

As a result, Dr. Eastern said, “I write a lot more vehement letters to payers about the biologics these days.”

Choice vs. cost

Rheumatologists are among the clinicians most affected by fail-first and step therapy mandates, as the diseases they treat – particularly RA – are the most established indications for biologic therapies, and for which the largest number of these are approved.

Courtesy Dr. Norman Gaylis

Though Medicare and Medicaid allow physicians considerable leeway, private insurers often tightly circumscribe the timing and choice of biologics in RA. As insurers’ first-choice biologic drug changes frequently, and varies from plan to plan, a patient who is stable on one agent might be asked to switch to another, a phenomenon known as nonmedical switching.

Insurers are seldom transparent about their reasons for establishing certain biologic drugs as their go-to agents, clinicians say, while making it difficult for physicians to prescribe others. “There’s a tremendous amount of discounting going on that we are oblivious to as physicians. I’ve seen situations where drug A is the first one you have to use this month and the next month, drug C,” said Dr. Norman Gaylis, a rheumatologist practicing in Aventura, Fla.

Attempting to start a patient on a nonpreferential biologic will generate paperwork and delays, Dr. Gaylis said, which can cost patients valuable time. “There’s a window of opportunity to treat these diseases, and by creating a step therapy pathway we’re closing the window at least partially.”

“As an example, rituximab in most payer plans is not tiered as a first-line biologic treatment option despite the fact that there are frequent scenarios where the clinical and serological presentation of a patient would suggest it to be preferable as a first-line treatment choice over an anti-TNF [tumor necrosis factor],” Dr. Gaylis said.

“There is no room for clinical decision making based upon the unique presentation of each different patient when choosing the best treatment option,” he said.

Rheumatologists often become overwhelmed with authorization paperwork, “and still in many instances end up with a denial of their request.”

Dr. Karen Kolba, a rheumatologist in private practice in Santa Maria, Calif., said that she agreed in principle with the way step therapy protocols have been established, and that some of the frustration with step therapy amounts to a tendency among specialist clinicians to bristle at being told what to do.

“Physicians hate protocol,” Dr. Kolba said. “But comparing one protocol to another is the only way we are going to make advances.” It took the rheumatology community about 30 years to come to terms with the use of methotrexate in RA, she noted, and the stepped approach grew naturally from the treatment of methotrexate failures with biologic agents when these first emerged in the late 1990s.

A majority of RA patients started on a stepped approach using DMARDs will respond, Dr. Kolba said, and for those who must move into the biologic realm, the vast majority will succeed on the first anti-TNF agent prescribed. And there is little science to establish that one TNF inhibitor is superior – only that patients can sometimes succeed with one and fail another.

“As far as which biologic to initiate, my personal opinion is I don’t care, and I tell the patients that I don’t mind if the insurer picks out of this category because I’m flipping a coin as well,” she said.

Step mandates become objectionable, Dr. Kolba said, when they are purportedly based in science that doesn’t exist, or when they seem to exist only to wear down the provider.

“With private insurance not only do they have the drug of the year, they’re going to make me battle for every single prescription. When I say I have tried this patient on maximal tolerable doses of all these DMARDs, they ought to believe me. Yet I get six-page forms back saying, ‘Give me the start and stop dates of all the drugs you’ve used.’”

States constrain fail first

For many specialists treating patients with biologics, some of these hurdles are already getting lowered.

Concerns about physician choice, a lack of transparency in insurer decision making, and the ethics of forcing patients to fail have led advocacy groups to press hard in recent years for legislation limiting step therapy – with successes in a dozen states.

While the state legislation is not disease or drug specific, it has important implications for clinicians treating with biologics. “Step therapy in its genesis was a good idea – it’s OK to try to reduce costs in the health care system,” said Patrick Stone, state government relations manager at the National Psoriasis Foundation in Annapolis, Md., a group that works extensively on step therapy issues. “But when these protocols were first crafted, medications like biologics weren’t in use.”

Jeff Okazaki, associate director of the Coalition of State Rheumatology Organizations, a group based in Schaumberg, Ill., said lawmakers are starting to accept that in terms of cost of care, “somebody not being treated appropriately and down the line has organ damage or comorbidity because of incorrect treatment decisions due to step therapy is a higher burden.”

Moreover, he said, “we’d seen protocols requiring five or more steps, and for each step you have to try it at least 90 days.” For a patient with rheumatic or autoimmune disease, “getting through something like that can just be devastating.”

In 2011, Connecticut, Mississippi, and Arkansas became the first states to pass legislation limiting some aspect of step therapy. Since then, nine additional states have passed legislation varying in focus and scope.

In Kentucky, for example, patients cannot be forced by their insurer to remain on an ineffective therapy for more than 30 days, and insurers must respond to physician requests for an override within 2 days. Mississippi allows physicians to override insurer decisions with proof of clinical evidence. In California, legislation passed last year aims to reduce bureaucracy and speed up response to physician requests for overrides.

Mr. Stone and Mr. Okazaki are working in a coalition with other dermatology, rheumatology, and GI groups to push bills in seven more states, including New York, North Carolina, and Ohio.

While all the bills differ in what they attempt to limit, the model legislation has three basic objectives, Mr. Okazaki said. “We want a clear set of clinical guidelines, a quick review process, and overrides that allow for exceptions in cases where patients shouldn’t have to go through step therapy.”

Clinical strategies and research gaps

New legislation undoubtedly will help providers and patients get access to their choice of treatment agents. But so long as biologics are expensive – and it will be a while before the first biosimilar drugs, which will have efficacy and safety similar to their reference biologics, reduce prices in any meaningful way – step therapy will likely remain the norm.

One of the key difficulties providers face when pushing back on an insurer in favor of a biologic drug is insufficient clinical evidence.

With IBD, Dr. Rubin said, “we need a need more longitudinal understanding” and better prognostic indicators “in order to justify spending the extra money or going to one of these therapies.”

Dr. Hanauer said one of the limitations he faces in practice is insufficient clinical evidence for biologics early in the treatment pathway for IBD.

RA “is much more common than Crohn’s disease is. In trials, it’s much easier to recruit hundreds of patients [for an RA trial], while with Crohn’s it’s very hard to enroll more than a couple a year at most sites,” he said. “And as you move earlier in the treatment pathway that becomes somewhat more difficult as well.”

His solution for now, he said, is to follow established step pathways in an accelerated way, for “a rapid transition toward highly effective therapies” without having to face extensive pushback from insurers.

“The idea is to initiate immunosuppressants for any patients with sufficient disease activity to justify steroids,” Dr. Hanauer said. “Their steroids are then tapered, and while on immunosuppressants, patients are in a perfect setup to get combination therapy with an immunosuppressive and a biologic – and that’s a 2- to 3-month transition, not 2-3 years.”

Dr. Kolba said that despite the wide array of options for treating RA, the specialty suffers from a dearth of understanding as to why some patients fail drugs while others succeed, even within the same drug class.

Rheumatologists’ prescribing choices would be highly influenced by better biomarkers, were they to become available, she said. And they’d have far better arguments when confronted with payer pushback.

“We’re all looking for that magic biologic marker to tell me which drug to use,” Dr. Kolba said, “because God knows if I had a blood test that said ‘this is the drug,’ I would go to the mat with the insurer.”

Laws recently passed or under consideration in state legislatures may offer some relief to physicians and patients dogged by the “step” or “fail-first” therapy protocols mandated by insurers, but until better clinical evidence is available to support treatment decisions and biosimilars reduce costs, clinicians must strategize to get patients through the step pathways as fast as possible.

Rheumatologists, gastroenterologists, and dermatologists all confront fail-first policies in their practices, particularly when prescribing the biologic agents that have been game changers in treating rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, among other diseases.

In RA, for example, a patient might be required to fail a series of disease-modifying antirheumatic drugs (DMARDs), including methotrexate, before starting a biologic. In Crohn’s disease, patients might have to first fail on steroids and immunosuppressants.

Most clinicians consider cost concerns fair as a basis for insurance decisions. But they can also have strong rationales for making exceptions. This may mean starting patients on a biologic early, particularly those they deem unlikely to respond to first- or second-line treatments – which may be cheaper but are not necessarily safer.

In egregious cases, a patient already stable on a biologic who has changed insurance plans may be forced to go backwards in the treatment pathway, and fail first- and second-line therapies all over again before resuming – a process unlikely to be cost-effective in the long term, and also rife with ethical concerns, say clinicians.

“Making a patient fail to get a less toxic drug sort of violates our ‘do no harm’ principle,” Dr. Stephen B. Hanauer, medical director of the Digestive Health Center at Northwestern University, Chicago, said in an interview.

“I always say that if biologics cost a dollar, we’d be using them for everybody. If you take away the steroids and the immunosuppressants, these are very safe drugs for IBD, far safer than steroids – but steroids are cheap,” Dr. Hanauer said.

And with some debilitating disease presentations, such as severe Crohn’s, “being told that we have to try conventional therapies and the patient has to fail them can mean putting the patient through progression of their disease, and suffering,” Dr. David T. Rubin, codirector of the Digestive Diseases Center at the University of Chicago, said in an interview. “We really struggle with this.”

Dr. Joseph S. Eastern, a dermatologist practicing in Belleville, N.J., said his specialty faces similar challenges with step therapy. “Dermatologists as a group are pretty risk averse. When given the opportunity, we do an excellent job of prescribing conventional medications, ultraviolet therapy, and biologics in the most cost-efficient possible way,” he said in an email.

Yet “third-party payers tell us, for example, that a patient must fail methotrexate before we can use a biologic, when the whole advantage of biologic therapy for many of these patients is the avoidance of organotoxicity and other serious risks.”

As a result, Dr. Eastern said, “I write a lot more vehement letters to payers about the biologics these days.”

Choice vs. cost

Rheumatologists are among the clinicians most affected by fail-first and step therapy mandates, as the diseases they treat – particularly RA – are the most established indications for biologic therapies, and for which the largest number of these are approved.

Courtesy Dr. Norman Gaylis

Though Medicare and Medicaid allow physicians considerable leeway, private insurers often tightly circumscribe the timing and choice of biologics in RA. As insurers’ first-choice biologic drug changes frequently, and varies from plan to plan, a patient who is stable on one agent might be asked to switch to another, a phenomenon known as nonmedical switching.

Insurers are seldom transparent about their reasons for establishing certain biologic drugs as their go-to agents, clinicians say, while making it difficult for physicians to prescribe others. “There’s a tremendous amount of discounting going on that we are oblivious to as physicians. I’ve seen situations where drug A is the first one you have to use this month and the next month, drug C,” said Dr. Norman Gaylis, a rheumatologist practicing in Aventura, Fla.

Attempting to start a patient on a nonpreferential biologic will generate paperwork and delays, Dr. Gaylis said, which can cost patients valuable time. “There’s a window of opportunity to treat these diseases, and by creating a step therapy pathway we’re closing the window at least partially.”

“As an example, rituximab in most payer plans is not tiered as a first-line biologic treatment option despite the fact that there are frequent scenarios where the clinical and serological presentation of a patient would suggest it to be preferable as a first-line treatment choice over an anti-TNF [tumor necrosis factor],” Dr. Gaylis said.

“There is no room for clinical decision making based upon the unique presentation of each different patient when choosing the best treatment option,” he said.

Rheumatologists often become overwhelmed with authorization paperwork, “and still in many instances end up with a denial of their request.”

Dr. Karen Kolba, a rheumatologist in private practice in Santa Maria, Calif., said that she agreed in principle with the way step therapy protocols have been established, and that some of the frustration with step therapy amounts to a tendency among specialist clinicians to bristle at being told what to do.

“Physicians hate protocol,” Dr. Kolba said. “But comparing one protocol to another is the only way we are going to make advances.” It took the rheumatology community about 30 years to come to terms with the use of methotrexate in RA, she noted, and the stepped approach grew naturally from the treatment of methotrexate failures with biologic agents when these first emerged in the late 1990s.

A majority of RA patients started on a stepped approach using DMARDs will respond, Dr. Kolba said, and for those who must move into the biologic realm, the vast majority will succeed on the first anti-TNF agent prescribed. And there is little science to establish that one TNF inhibitor is superior – only that patients can sometimes succeed with one and fail another.

“As far as which biologic to initiate, my personal opinion is I don’t care, and I tell the patients that I don’t mind if the insurer picks out of this category because I’m flipping a coin as well,” she said.

Step mandates become objectionable, Dr. Kolba said, when they are purportedly based in science that doesn’t exist, or when they seem to exist only to wear down the provider.

“With private insurance not only do they have the drug of the year, they’re going to make me battle for every single prescription. When I say I have tried this patient on maximal tolerable doses of all these DMARDs, they ought to believe me. Yet I get six-page forms back saying, ‘Give me the start and stop dates of all the drugs you’ve used.’”

States constrain fail first

For many specialists treating patients with biologics, some of these hurdles are already getting lowered.

Concerns about physician choice, a lack of transparency in insurer decision making, and the ethics of forcing patients to fail have led advocacy groups to press hard in recent years for legislation limiting step therapy – with successes in a dozen states.

While the state legislation is not disease or drug specific, it has important implications for clinicians treating with biologics. “Step therapy in its genesis was a good idea – it’s OK to try to reduce costs in the health care system,” said Patrick Stone, state government relations manager at the National Psoriasis Foundation in Annapolis, Md., a group that works extensively on step therapy issues. “But when these protocols were first crafted, medications like biologics weren’t in use.”

Jeff Okazaki, associate director of the Coalition of State Rheumatology Organizations, a group based in Schaumberg, Ill., said lawmakers are starting to accept that in terms of cost of care, “somebody not being treated appropriately and down the line has organ damage or comorbidity because of incorrect treatment decisions due to step therapy is a higher burden.”

Moreover, he said, “we’d seen protocols requiring five or more steps, and for each step you have to try it at least 90 days.” For a patient with rheumatic or autoimmune disease, “getting through something like that can just be devastating.”

In 2011, Connecticut, Mississippi, and Arkansas became the first states to pass legislation limiting some aspect of step therapy. Since then, nine additional states have passed legislation varying in focus and scope.

In Kentucky, for example, patients cannot be forced by their insurer to remain on an ineffective therapy for more than 30 days, and insurers must respond to physician requests for an override within 2 days. Mississippi allows physicians to override insurer decisions with proof of clinical evidence. In California, legislation passed last year aims to reduce bureaucracy and speed up response to physician requests for overrides.

Mr. Stone and Mr. Okazaki are working in a coalition with other dermatology, rheumatology, and GI groups to push bills in seven more states, including New York, North Carolina, and Ohio.

While all the bills differ in what they attempt to limit, the model legislation has three basic objectives, Mr. Okazaki said. “We want a clear set of clinical guidelines, a quick review process, and overrides that allow for exceptions in cases where patients shouldn’t have to go through step therapy.”

Clinical strategies and research gaps

New legislation undoubtedly will help providers and patients get access to their choice of treatment agents. But so long as biologics are expensive – and it will be a while before the first biosimilar drugs, which will have efficacy and safety similar to their reference biologics, reduce prices in any meaningful way – step therapy will likely remain the norm.

One of the key difficulties providers face when pushing back on an insurer in favor of a biologic drug is insufficient clinical evidence.

With IBD, Dr. Rubin said, “we need a need more longitudinal understanding” and better prognostic indicators “in order to justify spending the extra money or going to one of these therapies.”

Dr. Hanauer said one of the limitations he faces in practice is insufficient clinical evidence for biologics early in the treatment pathway for IBD.

RA “is much more common than Crohn’s disease is. In trials, it’s much easier to recruit hundreds of patients [for an RA trial], while with Crohn’s it’s very hard to enroll more than a couple a year at most sites,” he said. “And as you move earlier in the treatment pathway that becomes somewhat more difficult as well.”

His solution for now, he said, is to follow established step pathways in an accelerated way, for “a rapid transition toward highly effective therapies” without having to face extensive pushback from insurers.

“The idea is to initiate immunosuppressants for any patients with sufficient disease activity to justify steroids,” Dr. Hanauer said. “Their steroids are then tapered, and while on immunosuppressants, patients are in a perfect setup to get combination therapy with an immunosuppressive and a biologic – and that’s a 2- to 3-month transition, not 2-3 years.”

Dr. Kolba said that despite the wide array of options for treating RA, the specialty suffers from a dearth of understanding as to why some patients fail drugs while others succeed, even within the same drug class.

Rheumatologists’ prescribing choices would be highly influenced by better biomarkers, were they to become available, she said. And they’d have far better arguments when confronted with payer pushback.

“We’re all looking for that magic biologic marker to tell me which drug to use,” Dr. Kolba said, “because God knows if I had a blood test that said ‘this is the drug,’ I would go to the mat with the insurer.”

COPENHAGEN – The increased risk of MI and stroke in patients who develop psoriasis as young adults is essentially confined to those having a positive family history of cardiovascular disease, according to a Danish national study presented at the annual congress of the European Academy of Dermatology and Venereology.

“We found a significantly increased risk of MACE [major adverse cardiovascular events] in patients with psoriasis only when a family history of cardiovascular disease was present. This just highlights why it’s important that future studies of cardiovascular risk in psoriasis should include family history. Also, an increased focus on cardiovascular disease in relatives may be appropriate in the cardiovascular risk assessment of patients with psoriasis,” said Dr. Alexander Egeberg of the University of Copenhagen.

He presented a population-based study involving 15 years of follow-up of 30,278 Danes diagnosed with psoriasis in their 20s and a control group consisting of nearly 2.7 million of their Danish contemporaries who were not. None had personal history of acute MI or stroke at baseline. Family medical history, including whether cardiovascular disease occurred in first-degree relatives, was available for all subjects.

Dr. Egeberg and coinvestigators mapped the incidence of acute MI, ischemic stroke, or cardiovascular death in psoriasis patients and the general population controls during follow-up.

“When you look at the patients who developed psoriasis and didn’t have a positive family history of cardiovascular disease, there are almost no cardiovascular events for the entire country,” Dr. Egeberg observed.

In contrast, in a multivariate analysis adjusted for age, gender, socioeconomic status, comorbid cardiovascular disease, smoking, and the use of cardiovascular medications, patients with mild psoriasis and a positive family history for cardiovascular disease had a 28% greater risk of a premature cardiovascular event than the general population during follow-up out to roughly age 40. Those with a positive family history and severe psoriasis as defined by the use of systemic therapies had a 62% increase in risk. Both of these elevated risks were statistically significant.

Among young adult Danes with a positive family history for cardiovascular disease, there were 222 MACE events during 62,225 person-years of follow-up in the mild psoriasis group and 31 events during 6,848 person-years in the 4,504 subjects with severe psoriasis. The resultant incidence rates in both groups were significantly higher than in the control group, who experienced 28,846 MACE events during 16.1 million person-years of follow-up.

In contrast, fewer than 10 MACE events occurred in Danish psoriasis patients without a family history of cardiovascular disease.

A positive family history was also associated with increased MACE in the nonpsoriatic general population, although it didn’t confer as great a risk as in the Danes with psoriasis.

A point worthy of consideration, Dr. Egeberg noted, is that the epidemiology of psoriasis in Denmark apparently differs in several important ways from psoriasis in the United States and some other countries. For one, the prevalence is higher in Scandinavian countries – 7.1% in a Danish national cross-sectional study (Int J Dermatol. 2013 Jun;52[6]:681-3) and 8% in neighboring Norway – as compared with 2%-3% in much of the rest of the world.

Moreover, according to the same cross-sectional study, the prevalence of traditional cardiovascular risk factors, such as smoking and the components of the metabolic syndrome, isn’t higher in Danish psoriasis patients than in the country’s general population. That’s in contrast to the situation in the United Kingdom, where Dr. Joel M. Gelfand of the University of Pennsylvania and associates reported a decade ago in a landmark study that the prevalence of hypertension, obesity, hyperlipidemia, diabetes, and smoking were all higher in persons with psoriasis than in the general population (J Am Acad Dermatol. 2006 Nov;55[5]:829-35). Similar findings were subsequently reported in U.S. psoriasis patients.

Despite their absence of elevated levels of the standard cardiovascular risk factors, Danish psoriasis patients as a group do face a clinically significant increase in cardiovascular risk, compared with the general population, as shown in yet another Danish national cohort study in which the rate ratios for cardiovascular death for mild and severe psoriasis were 1.14 and 1.57, respectively, compared with controls (J Intern Med. 2011 Aug;270[2]:147-57).

In an even more recent Danish nationwide study, the overall death rate was found to be 25.4 per 1,000 person-years in patients with severe psoriasis, 17.0 in those with mild psoriasis, and 13.8 per 1,000 person-years in the general population (J Eur Acad Dermatol Venereol. 2015 May;29[5]:1002-5).

Dr. Egeberg said his new Danish findings suggest that even in psoriasis patients with a greater burden of systemic inflammation as expressed in severe disease, that burden alone doesn’t translate into increased cardiovascular risk. Rather, elevated cardiovascular risk appears to be a consequence of heritable factors, Dr. Egeberg said.

An important caveat regarding this study, he continued, is that the mean age at which participants were diagnosed with psoriasis was 26.6 years. It’s unclear whether the study findings extend to individuals who develop the dermatologic disease later in life.

Dr. Egeberg reported having no financial conflicts regarding this study, supported by Danish national research funding.

bjancin@frontlinemedcom.com

COPENHAGEN – The increased risk of MI and stroke in patients who develop psoriasis as young adults is essentially confined to those having a positive family history of cardiovascular disease, according to a Danish national study presented at the annual congress of the European Academy of Dermatology and Venereology.

“We found a significantly increased risk of MACE [major adverse cardiovascular events] in patients with psoriasis only when a family history of cardiovascular disease was present. This just highlights why it’s important that future studies of cardiovascular risk in psoriasis should include family history. Also, an increased focus on cardiovascular disease in relatives may be appropriate in the cardiovascular risk assessment of patients with psoriasis,” said Dr. Alexander Egeberg of the University of Copenhagen.

He presented a population-based study involving 15 years of follow-up of 30,278 Danes diagnosed with psoriasis in their 20s and a control group consisting of nearly 2.7 million of their Danish contemporaries who were not. None had personal history of acute MI or stroke at baseline. Family medical history, including whether cardiovascular disease occurred in first-degree relatives, was available for all subjects.

Dr. Egeberg and coinvestigators mapped the incidence of acute MI, ischemic stroke, or cardiovascular death in psoriasis patients and the general population controls during follow-up.

“When you look at the patients who developed psoriasis and didn’t have a positive family history of cardiovascular disease, there are almost no cardiovascular events for the entire country,” Dr. Egeberg observed.

In contrast, in a multivariate analysis adjusted for age, gender, socioeconomic status, comorbid cardiovascular disease, smoking, and the use of cardiovascular medications, patients with mild psoriasis and a positive family history for cardiovascular disease had a 28% greater risk of a premature cardiovascular event than the general population during follow-up out to roughly age 40. Those with a positive family history and severe psoriasis as defined by the use of systemic therapies had a 62% increase in risk. Both of these elevated risks were statistically significant.

Among young adult Danes with a positive family history for cardiovascular disease, there were 222 MACE events during 62,225 person-years of follow-up in the mild psoriasis group and 31 events during 6,848 person-years in the 4,504 subjects with severe psoriasis. The resultant incidence rates in both groups were significantly higher than in the control group, who experienced 28,846 MACE events during 16.1 million person-years of follow-up.

In contrast, fewer than 10 MACE events occurred in Danish psoriasis patients without a family history of cardiovascular disease.

A positive family history was also associated with increased MACE in the nonpsoriatic general population, although it didn’t confer as great a risk as in the Danes with psoriasis.

A point worthy of consideration, Dr. Egeberg noted, is that the epidemiology of psoriasis in Denmark apparently differs in several important ways from psoriasis in the United States and some other countries. For one, the prevalence is higher in Scandinavian countries – 7.1% in a Danish national cross-sectional study (Int J Dermatol. 2013 Jun;52[6]:681-3) and 8% in neighboring Norway – as compared with 2%-3% in much of the rest of the world.

Moreover, according to the same cross-sectional study, the prevalence of traditional cardiovascular risk factors, such as smoking and the components of the metabolic syndrome, isn’t higher in Danish psoriasis patients than in the country’s general population. That’s in contrast to the situation in the United Kingdom, where Dr. Joel M. Gelfand of the University of Pennsylvania and associates reported a decade ago in a landmark study that the prevalence of hypertension, obesity, hyperlipidemia, diabetes, and smoking were all higher in persons with psoriasis than in the general population (J Am Acad Dermatol. 2006 Nov;55[5]:829-35). Similar findings were subsequently reported in U.S. psoriasis patients.

Despite their absence of elevated levels of the standard cardiovascular risk factors, Danish psoriasis patients as a group do face a clinically significant increase in cardiovascular risk, compared with the general population, as shown in yet another Danish national cohort study in which the rate ratios for cardiovascular death for mild and severe psoriasis were 1.14 and 1.57, respectively, compared with controls (J Intern Med. 2011 Aug;270[2]:147-57).

In an even more recent Danish nationwide study, the overall death rate was found to be 25.4 per 1,000 person-years in patients with severe psoriasis, 17.0 in those with mild psoriasis, and 13.8 per 1,000 person-years in the general population (J Eur Acad Dermatol Venereol. 2015 May;29[5]:1002-5).

Dr. Egeberg said his new Danish findings suggest that even in psoriasis patients with a greater burden of systemic inflammation as expressed in severe disease, that burden alone doesn’t translate into increased cardiovascular risk. Rather, elevated cardiovascular risk appears to be a consequence of heritable factors, Dr. Egeberg said.

An important caveat regarding this study, he continued, is that the mean age at which participants were diagnosed with psoriasis was 26.6 years. It’s unclear whether the study findings extend to individuals who develop the dermatologic disease later in life.

Dr. Egeberg reported having no financial conflicts regarding this study, supported by Danish national research funding.

bjancin@frontlinemedcom.com

COPENHAGEN – The increased risk of MI and stroke in patients who develop psoriasis as young adults is essentially confined to those having a positive family history of cardiovascular disease, according to a Danish national study presented at the annual congress of the European Academy of Dermatology and Venereology.

“We found a significantly increased risk of MACE [major adverse cardiovascular events] in patients with psoriasis only when a family history of cardiovascular disease was present. This just highlights why it’s important that future studies of cardiovascular risk in psoriasis should include family history. Also, an increased focus on cardiovascular disease in relatives may be appropriate in the cardiovascular risk assessment of patients with psoriasis,” said Dr. Alexander Egeberg of the University of Copenhagen.

He presented a population-based study involving 15 years of follow-up of 30,278 Danes diagnosed with psoriasis in their 20s and a control group consisting of nearly 2.7 million of their Danish contemporaries who were not. None had personal history of acute MI or stroke at baseline. Family medical history, including whether cardiovascular disease occurred in first-degree relatives, was available for all subjects.

Dr. Egeberg and coinvestigators mapped the incidence of acute MI, ischemic stroke, or cardiovascular death in psoriasis patients and the general population controls during follow-up.

“When you look at the patients who developed psoriasis and didn’t have a positive family history of cardiovascular disease, there are almost no cardiovascular events for the entire country,” Dr. Egeberg observed.

In contrast, in a multivariate analysis adjusted for age, gender, socioeconomic status, comorbid cardiovascular disease, smoking, and the use of cardiovascular medications, patients with mild psoriasis and a positive family history for cardiovascular disease had a 28% greater risk of a premature cardiovascular event than the general population during follow-up out to roughly age 40. Those with a positive family history and severe psoriasis as defined by the use of systemic therapies had a 62% increase in risk. Both of these elevated risks were statistically significant.

Among young adult Danes with a positive family history for cardiovascular disease, there were 222 MACE events during 62,225 person-years of follow-up in the mild psoriasis group and 31 events during 6,848 person-years in the 4,504 subjects with severe psoriasis. The resultant incidence rates in both groups were significantly higher than in the control group, who experienced 28,846 MACE events during 16.1 million person-years of follow-up.

In contrast, fewer than 10 MACE events occurred in Danish psoriasis patients without a family history of cardiovascular disease.

A positive family history was also associated with increased MACE in the nonpsoriatic general population, although it didn’t confer as great a risk as in the Danes with psoriasis.

A point worthy of consideration, Dr. Egeberg noted, is that the epidemiology of psoriasis in Denmark apparently differs in several important ways from psoriasis in the United States and some other countries. For one, the prevalence is higher in Scandinavian countries – 7.1% in a Danish national cross-sectional study (Int J Dermatol. 2013 Jun;52[6]:681-3) and 8% in neighboring Norway – as compared with 2%-3% in much of the rest of the world.

Moreover, according to the same cross-sectional study, the prevalence of traditional cardiovascular risk factors, such as smoking and the components of the metabolic syndrome, isn’t higher in Danish psoriasis patients than in the country’s general population. That’s in contrast to the situation in the United Kingdom, where Dr. Joel M. Gelfand of the University of Pennsylvania and associates reported a decade ago in a landmark study that the prevalence of hypertension, obesity, hyperlipidemia, diabetes, and smoking were all higher in persons with psoriasis than in the general population (J Am Acad Dermatol. 2006 Nov;55[5]:829-35). Similar findings were subsequently reported in U.S. psoriasis patients.

Despite their absence of elevated levels of the standard cardiovascular risk factors, Danish psoriasis patients as a group do face a clinically significant increase in cardiovascular risk, compared with the general population, as shown in yet another Danish national cohort study in which the rate ratios for cardiovascular death for mild and severe psoriasis were 1.14 and 1.57, respectively, compared with controls (J Intern Med. 2011 Aug;270[2]:147-57).

In an even more recent Danish nationwide study, the overall death rate was found to be 25.4 per 1,000 person-years in patients with severe psoriasis, 17.0 in those with mild psoriasis, and 13.8 per 1,000 person-years in the general population (J Eur Acad Dermatol Venereol. 2015 May;29[5]:1002-5).

Dr. Egeberg said his new Danish findings suggest that even in psoriasis patients with a greater burden of systemic inflammation as expressed in severe disease, that burden alone doesn’t translate into increased cardiovascular risk. Rather, elevated cardiovascular risk appears to be a consequence of heritable factors, Dr. Egeberg said.

An important caveat regarding this study, he continued, is that the mean age at which participants were diagnosed with psoriasis was 26.6 years. It’s unclear whether the study findings extend to individuals who develop the dermatologic disease later in life.

Dr. Egeberg reported having no financial conflicts regarding this study, supported by Danish national research funding.

bjancin@frontlinemedcom.com

COPENHAGEN – An oral small molecule with a novel mechanism of action for treatment of moderate to severe plaque psoriasis is being developed as a potential first-line systemic treatment in view of its highly favorable safety profile.

The investigational drug, known for now as CF101, is a first-in-class agonist of the A3 adenosine receptor. This cell surface receptor is upregulated in the pathologic cells of certain inflammatory diseases, but has little or no expression in normal cells. This high degree of specificity accounts for its safety, which in a recent phase II/III trial was essentially indistinguishable from placebo, making it an attractive potential alternative to methotrexate or biologics as a starting point in systemic therapy, Pnina Fishman, Ph.D., said at the annual congress of the European Academy of Dermatology and Venereology.

Planning is underway for a pivotal phase III trial of CF101 in psoriasis, which is also being organized for CF101 in rheumatoid arthritis on the strength of favorable phase II findings, according to Dr. Fishman, CEO of Can-Fite BioPharma, an Israeli biotech company that is developing the drug.

The phase II/III psoriasis trial was a 326-patient, double-blind, placebo-controlled study. It showed efficacy comparable to and in some respects better than that reported in the phase III ESTEEM-1 study of the oral phosphodiesterase 4 inhibitor apremilast (J Am Acad Dermatol. 2015 Jul;73:37-49).

Moreover, it appears that the twice-daily 2-mg dosing of CF101 studied in the phase II/III trial was suboptimal in light of the observed linear increase in Psoriasis Area and Severity Index (PASI)-75, -90, and -100 response rates over time. Those response rates rose steadily until the study’s end at week 32 with no evidence of a plateau. In contrast, in ESTEEM-1, the improvement with apremilast (Otezla) leveled off starting at about week 20, she observed.

In the recent phase II/III trial, the PASI-75 rate for CF101 at week 12 – the prespecified primary endpoint – was not significantly better than placebo was. However, the PASI-75 response rate continued to climb such that by week 32, it was 35.3%, similar to the 33.1% PASI-75 response seen at 16 weeks in ESTEEM-1. PASI improved by an average of 57% from baseline to week 32 with CF101 with no plateau in sight, and by 55% with apremilast at week 16, with a leveling off at week 20. This is why the upcoming phase III trial will employ a higher dose of CF101 than twice-daily 2-mg dose used in the phase II/III study and will run longer. The goal is to achieve higher PASI response rates faster than obtainable with 2 mg BID, Dr. Fishman explained.

She added that the PASI-90 response data in the phase II/III trial bode particularly well for the future of CF101 as a first-line systemic agent. At week 32, this stringent outcome measure was achieved by 26.9% of participants who hadn’t previously been on methotrexate or a biologic and by 13.7% of those who had. And as was the case for the PASI-75 results, the PASI-90 response increased in linear fashion out to 32 weeks with no plateau. In ESTEEM-1, the PASI-90 rate was 9.8% at week 16.

No treatment-related adverse events were seen in the phase II/III CF101 study, Dr. Fishman reported.

The study was sponsored by Can-Fite BioPharma and presented by Dr. Fishman, who is the company’s CEO.

bjancin@frontlinemedcom.com

COPENHAGEN – An oral small molecule with a novel mechanism of action for treatment of moderate to severe plaque psoriasis is being developed as a potential first-line systemic treatment in view of its highly favorable safety profile.

The investigational drug, known for now as CF101, is a first-in-class agonist of the A3 adenosine receptor. This cell surface receptor is upregulated in the pathologic cells of certain inflammatory diseases, but has little or no expression in normal cells. This high degree of specificity accounts for its safety, which in a recent phase II/III trial was essentially indistinguishable from placebo, making it an attractive potential alternative to methotrexate or biologics as a starting point in systemic therapy, Pnina Fishman, Ph.D., said at the annual congress of the European Academy of Dermatology and Venereology.

Planning is underway for a pivotal phase III trial of CF101 in psoriasis, which is also being organized for CF101 in rheumatoid arthritis on the strength of favorable phase II findings, according to Dr. Fishman, CEO of Can-Fite BioPharma, an Israeli biotech company that is developing the drug.

The phase II/III psoriasis trial was a 326-patient, double-blind, placebo-controlled study. It showed efficacy comparable to and in some respects better than that reported in the phase III ESTEEM-1 study of the oral phosphodiesterase 4 inhibitor apremilast (J Am Acad Dermatol. 2015 Jul;73:37-49).

Moreover, it appears that the twice-daily 2-mg dosing of CF101 studied in the phase II/III trial was suboptimal in light of the observed linear increase in Psoriasis Area and Severity Index (PASI)-75, -90, and -100 response rates over time. Those response rates rose steadily until the study’s end at week 32 with no evidence of a plateau. In contrast, in ESTEEM-1, the improvement with apremilast (Otezla) leveled off starting at about week 20, she observed.

In the recent phase II/III trial, the PASI-75 rate for CF101 at week 12 – the prespecified primary endpoint – was not significantly better than placebo was. However, the PASI-75 response rate continued to climb such that by week 32, it was 35.3%, similar to the 33.1% PASI-75 response seen at 16 weeks in ESTEEM-1. PASI improved by an average of 57% from baseline to week 32 with CF101 with no plateau in sight, and by 55% with apremilast at week 16, with a leveling off at week 20. This is why the upcoming phase III trial will employ a higher dose of CF101 than twice-daily 2-mg dose used in the phase II/III study and will run longer. The goal is to achieve higher PASI response rates faster than obtainable with 2 mg BID, Dr. Fishman explained.

She added that the PASI-90 response data in the phase II/III trial bode particularly well for the future of CF101 as a first-line systemic agent. At week 32, this stringent outcome measure was achieved by 26.9% of participants who hadn’t previously been on methotrexate or a biologic and by 13.7% of those who had. And as was the case for the PASI-75 results, the PASI-90 response increased in linear fashion out to 32 weeks with no plateau. In ESTEEM-1, the PASI-90 rate was 9.8% at week 16.

No treatment-related adverse events were seen in the phase II/III CF101 study, Dr. Fishman reported.

The study was sponsored by Can-Fite BioPharma and presented by Dr. Fishman, who is the company’s CEO.

bjancin@frontlinemedcom.com

COPENHAGEN – An oral small molecule with a novel mechanism of action for treatment of moderate to severe plaque psoriasis is being developed as a potential first-line systemic treatment in view of its highly favorable safety profile.

The investigational drug, known for now as CF101, is a first-in-class agonist of the A3 adenosine receptor. This cell surface receptor is upregulated in the pathologic cells of certain inflammatory diseases, but has little or no expression in normal cells. This high degree of specificity accounts for its safety, which in a recent phase II/III trial was essentially indistinguishable from placebo, making it an attractive potential alternative to methotrexate or biologics as a starting point in systemic therapy, Pnina Fishman, Ph.D., said at the annual congress of the European Academy of Dermatology and Venereology.

Planning is underway for a pivotal phase III trial of CF101 in psoriasis, which is also being organized for CF101 in rheumatoid arthritis on the strength of favorable phase II findings, according to Dr. Fishman, CEO of Can-Fite BioPharma, an Israeli biotech company that is developing the drug.

The phase II/III psoriasis trial was a 326-patient, double-blind, placebo-controlled study. It showed efficacy comparable to and in some respects better than that reported in the phase III ESTEEM-1 study of the oral phosphodiesterase 4 inhibitor apremilast (J Am Acad Dermatol. 2015 Jul;73:37-49).

Moreover, it appears that the twice-daily 2-mg dosing of CF101 studied in the phase II/III trial was suboptimal in light of the observed linear increase in Psoriasis Area and Severity Index (PASI)-75, -90, and -100 response rates over time. Those response rates rose steadily until the study’s end at week 32 with no evidence of a plateau. In contrast, in ESTEEM-1, the improvement with apremilast (Otezla) leveled off starting at about week 20, she observed.

In the recent phase II/III trial, the PASI-75 rate for CF101 at week 12 – the prespecified primary endpoint – was not significantly better than placebo was. However, the PASI-75 response rate continued to climb such that by week 32, it was 35.3%, similar to the 33.1% PASI-75 response seen at 16 weeks in ESTEEM-1. PASI improved by an average of 57% from baseline to week 32 with CF101 with no plateau in sight, and by 55% with apremilast at week 16, with a leveling off at week 20. This is why the upcoming phase III trial will employ a higher dose of CF101 than twice-daily 2-mg dose used in the phase II/III study and will run longer. The goal is to achieve higher PASI response rates faster than obtainable with 2 mg BID, Dr. Fishman explained.

She added that the PASI-90 response data in the phase II/III trial bode particularly well for the future of CF101 as a first-line systemic agent. At week 32, this stringent outcome measure was achieved by 26.9% of participants who hadn’t previously been on methotrexate or a biologic and by 13.7% of those who had. And as was the case for the PASI-75 results, the PASI-90 response increased in linear fashion out to 32 weeks with no plateau. In ESTEEM-1, the PASI-90 rate was 9.8% at week 16.

No treatment-related adverse events were seen in the phase II/III CF101 study, Dr. Fishman reported.

The study was sponsored by Can-Fite BioPharma and presented by Dr. Fishman, who is the company’s CEO.

bjancin@frontlinemedcom.com

Although a wide variety of treatment modalities exist for the management of psoriasis, nontreatment, undertreatment, and treatment dissatisfaction represent key clinical challenges. Careful tailoring of therapeutic regimens to meet individual patient needs and priorities may therefore be critical to improving treatment adherence and clinical outcomes. Importantly, systemic therapies such as methotrexate (MTX) may be particularly useful for individualizing patient treatment regimens and appear to be underutilized components of treatment optimization.

A majority of psoriasis patients have mild to moderate disease and many are treated primarily with topical medications. Although these treatments generally are safe and effective, practical limitations (eg, formulation, ease of application) may affect patients’ treatment adherence and satisfaction even in the context of high efficacy. Systemic therapies, although associated with a distinct set of risks and treatment challenges, may enable patients to overcome many of these limitations, particularly in patients with moderate to severe disease or impaired quality of life as well as those with an inadequate response to or dissatisfaction with topical treatments.

Systemic Treatment Options

Among the systemic treatment options for psoriasis, biologic therapies often are most highly regarded due to their strong efficacy, although traditional systemic therapies such as MTX, cyclosporine, and acitretin remain important treatment options and have an extensive history in the treatment of psoriasis. In addition to typically being required by insurance companies prior to the initiation of biologic therapies, traditional systemic therapies also may be preferred by patients because of the options for oral and subcutaneous administration and their relatively low costs. Furthermore, systemic therapies may be critical in patients for whom biologic therapies are relatively contraindicated, such as those with an increased risk of infection, history of malignancy, or hypersensitivity to any of the product’s ingredients.

Among traditional systemic therapies, MTX is one of the most frequently used psoriasis treatment worldwide and can be highly effective for even severe cases. Importantly, MTX is a valuable component of combination treatments for psoriasis and is frequently coadministered with topical and biologic agents and phototherapy, suggesting that MTX may be a particularly useful option to consider when adjusting a patient’s treatment regimen.

Benefits of Subcutaneous Methotrexate Administration

Methotrexate can be delivered either orally or parenterally, contributing to its compatibility with a wide variety of psoriasis treatment regimens and patient preferences. Administration is predominantly oral in the United States, but parenteral MTX (most commonly delivered subcutaneously) can confer important benefits and is used regularly in countries outside of the United States.

An important advantage of subcutaneous versus oral MTX is greater bioavailability, particularly at higher doses. In studies of healthy volunteers or patients with rheumatoid arthritis, the bioavailability of MTX following oral administration appears to plateau at doses of 15 mg or higher,¹ whereas that of subcutaneous MTX appears to increase linearly at a wide range of doses and exceeds that of oral MTX at each dose examined.^1,2 A switch from oral to subcutaneous MTX may therefore benefit patients experiencing suboptimal disease control.

Another important benefit of subcutanoues versus oral MTX is the potential for reduced intensity of gastrointestinal adverse events.^2,3 In a study of patients with rheumatoid arthritis, those who received subcutaneous MTX reported less severe nausea, vomiting, abdominal pain, and diarrhea than those who received oral MTX,³ which may improve treatment adherence and potentially enable patients to tolerate higher doses. Because gastrointestinal adverse events are a common cause of MTX treatment discontinuation, a switch from oral to subcutaneous MTX may be an important strategy to enable more patients to benefit from this treatment option.

Subcutaneous MTX presents some potential challenges, including patients’ fear of needles and difficulties with drawing and administering an accurate drug dose using a vial, needle, and syringe. However, recent developments in autoinjector technology have produced MTX injection devices that largely mitigate many of these challenges. Methotrexate autoinjectors allow for the accurate administration of prespecified doses, and patients generally find them easy to use.⁴ Furthermore, MTX autoinjectors have been associated with low levels of adminsitration-site pain (median pain score on a visual analog scale, 1.0/100 mm in one study⁴), and the concealment of a needle from view may potentially lessen needle phobia.

Role of Subcutaneous Methotrexate in Patient Care

The types of patients expected to benefit most from subcutaneous MTX include those with moderate to severe psoriasis and those who have experienced dissatisfaction with topical medications or phototherapy. The increased bioavailability of subcutaneous MTX as well as the reduced intensity of gastrointestinal adverse events compared with oral MTX may enable patients to achieve a greater clinical response, and the systemic route of administration may improve treatment adherence and patient satisfaction among those who are dissatisfied with topical treatment regimens. Notably, an additional benefit of optimizing MTX treatment may be the potential to prevent or delay progression to biologic therapies, which may be an important goal of both patients and physicians to prevent higher health care costs.

Another principal role of subcutaneous MTX is as a component of combination therapy with topicals or other systemic therapies for either long-term care or periodic treatment of disease flares. Methotrexate is a frequent component of combination therapies, and subcutaneous administration may be preferable for many patients, particularly those who are already accustomed to injectable therapies (eg, biologic agents) and those who regularly visit a physician who can perform the injections (eg, for regular phototherapy treatments). Interestingly, the coadministration of MTX may be especially valuable in the context of biologic therapies, as concomitant MTX is associated with a reduced incidence of antidrug antibodies and may therefore enhance or prolong responses to biologic agents.

Final Thoughts

Because subcutaneous MTX is infrequently used for the treatment of psoriasis in the United States, increased awareness of its unique advantages may provide new opportunities for patients to tailor treatment regimens to meet individual needs and preferences. Treatment optimization across a broad range of patient characteristics may be critical to improving adherence and satisfaction in psoriasis patients and may be considered a major therapeutic goal.

Acknowledgment

Medical writing assistance was provided by Anna Abt, PhD, of ETHOS Health Communications in Newtown, Pennsylvania, with financial support from LEO Pharma.

Although a wide variety of treatment modalities exist for the management of psoriasis, nontreatment, undertreatment, and treatment dissatisfaction represent key clinical challenges. Careful tailoring of therapeutic regimens to meet individual patient needs and priorities may therefore be critical to improving treatment adherence and clinical outcomes. Importantly, systemic therapies such as methotrexate (MTX) may be particularly useful for individualizing patient treatment regimens and appear to be underutilized components of treatment optimization.

A majority of psoriasis patients have mild to moderate disease and many are treated primarily with topical medications. Although these treatments generally are safe and effective, practical limitations (eg, formulation, ease of application) may affect patients’ treatment adherence and satisfaction even in the context of high efficacy. Systemic therapies, although associated with a distinct set of risks and treatment challenges, may enable patients to overcome many of these limitations, particularly in patients with moderate to severe disease or impaired quality of life as well as those with an inadequate response to or dissatisfaction with topical treatments.

Systemic Treatment Options

Among the systemic treatment options for psoriasis, biologic therapies often are most highly regarded due to their strong efficacy, although traditional systemic therapies such as MTX, cyclosporine, and acitretin remain important treatment options and have an extensive history in the treatment of psoriasis. In addition to typically being required by insurance companies prior to the initiation of biologic therapies, traditional systemic therapies also may be preferred by patients because of the options for oral and subcutaneous administration and their relatively low costs. Furthermore, systemic therapies may be critical in patients for whom biologic therapies are relatively contraindicated, such as those with an increased risk of infection, history of malignancy, or hypersensitivity to any of the product’s ingredients.

Among traditional systemic therapies, MTX is one of the most frequently used psoriasis treatment worldwide and can be highly effective for even severe cases. Importantly, MTX is a valuable component of combination treatments for psoriasis and is frequently coadministered with topical and biologic agents and phototherapy, suggesting that MTX may be a particularly useful option to consider when adjusting a patient’s treatment regimen.

Benefits of Subcutaneous Methotrexate Administration

Methotrexate can be delivered either orally or parenterally, contributing to its compatibility with a wide variety of psoriasis treatment regimens and patient preferences. Administration is predominantly oral in the United States, but parenteral MTX (most commonly delivered subcutaneously) can confer important benefits and is used regularly in countries outside of the United States.

An important advantage of subcutaneous versus oral MTX is greater bioavailability, particularly at higher doses. In studies of healthy volunteers or patients with rheumatoid arthritis, the bioavailability of MTX following oral administration appears to plateau at doses of 15 mg or higher,¹ whereas that of subcutaneous MTX appears to increase linearly at a wide range of doses and exceeds that of oral MTX at each dose examined.^1,2 A switch from oral to subcutaneous MTX may therefore benefit patients experiencing suboptimal disease control.

Another important benefit of subcutanoues versus oral MTX is the potential for reduced intensity of gastrointestinal adverse events.^2,3 In a study of patients with rheumatoid arthritis, those who received subcutaneous MTX reported less severe nausea, vomiting, abdominal pain, and diarrhea than those who received oral MTX,³ which may improve treatment adherence and potentially enable patients to tolerate higher doses. Because gastrointestinal adverse events are a common cause of MTX treatment discontinuation, a switch from oral to subcutaneous MTX may be an important strategy to enable more patients to benefit from this treatment option.

Subcutaneous MTX presents some potential challenges, including patients’ fear of needles and difficulties with drawing and administering an accurate drug dose using a vial, needle, and syringe. However, recent developments in autoinjector technology have produced MTX injection devices that largely mitigate many of these challenges. Methotrexate autoinjectors allow for the accurate administration of prespecified doses, and patients generally find them easy to use.⁴ Furthermore, MTX autoinjectors have been associated with low levels of adminsitration-site pain (median pain score on a visual analog scale, 1.0/100 mm in one study⁴), and the concealment of a needle from view may potentially lessen needle phobia.

Role of Subcutaneous Methotrexate in Patient Care

The types of patients expected to benefit most from subcutaneous MTX include those with moderate to severe psoriasis and those who have experienced dissatisfaction with topical medications or phototherapy. The increased bioavailability of subcutaneous MTX as well as the reduced intensity of gastrointestinal adverse events compared with oral MTX may enable patients to achieve a greater clinical response, and the systemic route of administration may improve treatment adherence and patient satisfaction among those who are dissatisfied with topical treatment regimens. Notably, an additional benefit of optimizing MTX treatment may be the potential to prevent or delay progression to biologic therapies, which may be an important goal of both patients and physicians to prevent higher health care costs.

Another principal role of subcutaneous MTX is as a component of combination therapy with topicals or other systemic therapies for either long-term care or periodic treatment of disease flares. Methotrexate is a frequent component of combination therapies, and subcutaneous administration may be preferable for many patients, particularly those who are already accustomed to injectable therapies (eg, biologic agents) and those who regularly visit a physician who can perform the injections (eg, for regular phototherapy treatments). Interestingly, the coadministration of MTX may be especially valuable in the context of biologic therapies, as concomitant MTX is associated with a reduced incidence of antidrug antibodies and may therefore enhance or prolong responses to biologic agents.

Final Thoughts

Because subcutaneous MTX is infrequently used for the treatment of psoriasis in the United States, increased awareness of its unique advantages may provide new opportunities for patients to tailor treatment regimens to meet individual needs and preferences. Treatment optimization across a broad range of patient characteristics may be critical to improving adherence and satisfaction in psoriasis patients and may be considered a major therapeutic goal.

Acknowledgment

Medical writing assistance was provided by Anna Abt, PhD, of ETHOS Health Communications in Newtown, Pennsylvania, with financial support from LEO Pharma.

Although a wide variety of treatment modalities exist for the management of psoriasis, nontreatment, undertreatment, and treatment dissatisfaction represent key clinical challenges. Careful tailoring of therapeutic regimens to meet individual patient needs and priorities may therefore be critical to improving treatment adherence and clinical outcomes. Importantly, systemic therapies such as methotrexate (MTX) may be particularly useful for individualizing patient treatment regimens and appear to be underutilized components of treatment optimization.

A majority of psoriasis patients have mild to moderate disease and many are treated primarily with topical medications. Although these treatments generally are safe and effective, practical limitations (eg, formulation, ease of application) may affect patients’ treatment adherence and satisfaction even in the context of high efficacy. Systemic therapies, although associated with a distinct set of risks and treatment challenges, may enable patients to overcome many of these limitations, particularly in patients with moderate to severe disease or impaired quality of life as well as those with an inadequate response to or dissatisfaction with topical treatments.

Systemic Treatment Options

Among the systemic treatment options for psoriasis, biologic therapies often are most highly regarded due to their strong efficacy, although traditional systemic therapies such as MTX, cyclosporine, and acitretin remain important treatment options and have an extensive history in the treatment of psoriasis. In addition to typically being required by insurance companies prior to the initiation of biologic therapies, traditional systemic therapies also may be preferred by patients because of the options for oral and subcutaneous administration and their relatively low costs. Furthermore, systemic therapies may be critical in patients for whom biologic therapies are relatively contraindicated, such as those with an increased risk of infection, history of malignancy, or hypersensitivity to any of the product’s ingredients.

Among traditional systemic therapies, MTX is one of the most frequently used psoriasis treatment worldwide and can be highly effective for even severe cases. Importantly, MTX is a valuable component of combination treatments for psoriasis and is frequently coadministered with topical and biologic agents and phototherapy, suggesting that MTX may be a particularly useful option to consider when adjusting a patient’s treatment regimen.

Benefits of Subcutaneous Methotrexate Administration

Methotrexate can be delivered either orally or parenterally, contributing to its compatibility with a wide variety of psoriasis treatment regimens and patient preferences. Administration is predominantly oral in the United States, but parenteral MTX (most commonly delivered subcutaneously) can confer important benefits and is used regularly in countries outside of the United States.

An important advantage of subcutaneous versus oral MTX is greater bioavailability, particularly at higher doses. In studies of healthy volunteers or patients with rheumatoid arthritis, the bioavailability of MTX following oral administration appears to plateau at doses of 15 mg or higher,¹ whereas that of subcutaneous MTX appears to increase linearly at a wide range of doses and exceeds that of oral MTX at each dose examined.^1,2 A switch from oral to subcutaneous MTX may therefore benefit patients experiencing suboptimal disease control.

Another important benefit of subcutanoues versus oral MTX is the potential for reduced intensity of gastrointestinal adverse events.^2,3 In a study of patients with rheumatoid arthritis, those who received subcutaneous MTX reported less severe nausea, vomiting, abdominal pain, and diarrhea than those who received oral MTX,³ which may improve treatment adherence and potentially enable patients to tolerate higher doses. Because gastrointestinal adverse events are a common cause of MTX treatment discontinuation, a switch from oral to subcutaneous MTX may be an important strategy to enable more patients to benefit from this treatment option.

Subcutaneous MTX presents some potential challenges, including patients’ fear of needles and difficulties with drawing and administering an accurate drug dose using a vial, needle, and syringe. However, recent developments in autoinjector technology have produced MTX injection devices that largely mitigate many of these challenges. Methotrexate autoinjectors allow for the accurate administration of prespecified doses, and patients generally find them easy to use.⁴ Furthermore, MTX autoinjectors have been associated with low levels of adminsitration-site pain (median pain score on a visual analog scale, 1.0/100 mm in one study⁴), and the concealment of a needle from view may potentially lessen needle phobia.

Role of Subcutaneous Methotrexate in Patient Care

The types of patients expected to benefit most from subcutaneous MTX include those with moderate to severe psoriasis and those who have experienced dissatisfaction with topical medications or phototherapy. The increased bioavailability of subcutaneous MTX as well as the reduced intensity of gastrointestinal adverse events compared with oral MTX may enable patients to achieve a greater clinical response, and the systemic route of administration may improve treatment adherence and patient satisfaction among those who are dissatisfied with topical treatment regimens. Notably, an additional benefit of optimizing MTX treatment may be the potential to prevent or delay progression to biologic therapies, which may be an important goal of both patients and physicians to prevent higher health care costs.

Another principal role of subcutaneous MTX is as a component of combination therapy with topicals or other systemic therapies for either long-term care or periodic treatment of disease flares. Methotrexate is a frequent component of combination therapies, and subcutaneous administration may be preferable for many patients, particularly those who are already accustomed to injectable therapies (eg, biologic agents) and those who regularly visit a physician who can perform the injections (eg, for regular phototherapy treatments). Interestingly, the coadministration of MTX may be especially valuable in the context of biologic therapies, as concomitant MTX is associated with a reduced incidence of antidrug antibodies and may therefore enhance or prolong responses to biologic agents.

Final Thoughts

Because subcutaneous MTX is infrequently used for the treatment of psoriasis in the United States, increased awareness of its unique advantages may provide new opportunities for patients to tailor treatment regimens to meet individual needs and preferences. Treatment optimization across a broad range of patient characteristics may be critical to improving adherence and satisfaction in psoriasis patients and may be considered a major therapeutic goal.

Acknowledgment

Medical writing assistance was provided by Anna Abt, PhD, of ETHOS Health Communications in Newtown, Pennsylvania, with financial support from LEO Pharma.

Patients with psoriatic arthritis taking methotrexate demonstrated an improvement in peripheral joint disease, skin disease, enthesitis, dactylitis, and nail disease over 12 weeks in a subanalysis of methotrexate users in the TICOPA (Tight Control of Psoriatic Arthritis) study.

Out of the original 206 patients in the open-label, randomized, controlled TICOPA study, the subanalysis involved 188 who received methotrexate in its first 12 weeks. Substudy authors Dr. Laura C. Coates and Dr. Philip S. Helliwell of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds (England) verified a maximum dose at 12 weeks of at least 15 mg/week in 175, 20 mg/week in 122, and 25 mg/week in 86 (J Rheumatol. Dec 15. doi: 10.3899/jrheum.150614).

©Thinkstock.com

The proportions of patients achieving American College of Rheumatology (ACR) outcomes at 12 weeks were 40.8% for ACR20, 18.8% for ACR50, and 8.6% for ACR70. A total of 22.4% achieved minimal disease activity, defined as meeting five of these seven criteria: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area and Severity Index (PASI) of 1 or less or body surface area involvement of 3 or less, patient pain visual analog score (VAS) of 15 or less, patient global disease activity VAS of 20 or less, health assessment questionnaire of 0.5 or less, and 0-1 tender entheseal points.

Other improvements that occurred at 12 weeks included 27.2% reaching a PASI75, a 62.7% drop in dactylitis incidence, a significant drop of –59.7 in Leeds dactylitis instrument median score, and a significant decrease in the proportion of patients with enthesitis (25.7%). However, the median change in enthesitis score was 0.

Response rates did not differ between patients receiving methotrexate 15 mg/week or higher doses, although there was generally a higher proportion who met various response criteria among those taking greater than 15 mg/week. However, the authors noted that there could be an underestimation of the dose effect because the design of the TICOPA study, which randomized patients to a protocol for tight control of psoriatic arthritis disease activity or standard care, introduced a bias by intentionally escalating treatment doses in patients who continue to have active disease.

The investigators advised that the study results be interpreted in the context of the open-label design of the study, and placed alongside the other observational studies that support its use in psoriatic arthritis.

No relevant conflicts of interest were disclosed.

Patients with psoriatic arthritis taking methotrexate demonstrated an improvement in peripheral joint disease, skin disease, enthesitis, dactylitis, and nail disease over 12 weeks in a subanalysis of methotrexate users in the TICOPA (Tight Control of Psoriatic Arthritis) study.

Out of the original 206 patients in the open-label, randomized, controlled TICOPA study, the subanalysis involved 188 who received methotrexate in its first 12 weeks. Substudy authors Dr. Laura C. Coates and Dr. Philip S. Helliwell of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds (England) verified a maximum dose at 12 weeks of at least 15 mg/week in 175, 20 mg/week in 122, and 25 mg/week in 86 (J Rheumatol. Dec 15. doi: 10.3899/jrheum.150614).

©Thinkstock.com

The proportions of patients achieving American College of Rheumatology (ACR) outcomes at 12 weeks were 40.8% for ACR20, 18.8% for ACR50, and 8.6% for ACR70. A total of 22.4% achieved minimal disease activity, defined as meeting five of these seven criteria: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area and Severity Index (PASI) of 1 or less or body surface area involvement of 3 or less, patient pain visual analog score (VAS) of 15 or less, patient global disease activity VAS of 20 or less, health assessment questionnaire of 0.5 or less, and 0-1 tender entheseal points.

Other improvements that occurred at 12 weeks included 27.2% reaching a PASI75, a 62.7% drop in dactylitis incidence, a significant drop of –59.7 in Leeds dactylitis instrument median score, and a significant decrease in the proportion of patients with enthesitis (25.7%). However, the median change in enthesitis score was 0.

Response rates did not differ between patients receiving methotrexate 15 mg/week or higher doses, although there was generally a higher proportion who met various response criteria among those taking greater than 15 mg/week. However, the authors noted that there could be an underestimation of the dose effect because the design of the TICOPA study, which randomized patients to a protocol for tight control of psoriatic arthritis disease activity or standard care, introduced a bias by intentionally escalating treatment doses in patients who continue to have active disease.

The investigators advised that the study results be interpreted in the context of the open-label design of the study, and placed alongside the other observational studies that support its use in psoriatic arthritis.

No relevant conflicts of interest were disclosed.

Patients with psoriatic arthritis taking methotrexate demonstrated an improvement in peripheral joint disease, skin disease, enthesitis, dactylitis, and nail disease over 12 weeks in a subanalysis of methotrexate users in the TICOPA (Tight Control of Psoriatic Arthritis) study.

Out of the original 206 patients in the open-label, randomized, controlled TICOPA study, the subanalysis involved 188 who received methotrexate in its first 12 weeks. Substudy authors Dr. Laura C. Coates and Dr. Philip S. Helliwell of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds (England) verified a maximum dose at 12 weeks of at least 15 mg/week in 175, 20 mg/week in 122, and 25 mg/week in 86 (J Rheumatol. Dec 15. doi: 10.3899/jrheum.150614).

©Thinkstock.com

The proportions of patients achieving American College of Rheumatology (ACR) outcomes at 12 weeks were 40.8% for ACR20, 18.8% for ACR50, and 8.6% for ACR70. A total of 22.4% achieved minimal disease activity, defined as meeting five of these seven criteria: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area and Severity Index (PASI) of 1 or less or body surface area involvement of 3 or less, patient pain visual analog score (VAS) of 15 or less, patient global disease activity VAS of 20 or less, health assessment questionnaire of 0.5 or less, and 0-1 tender entheseal points.

Other improvements that occurred at 12 weeks included 27.2% reaching a PASI75, a 62.7% drop in dactylitis incidence, a significant drop of –59.7 in Leeds dactylitis instrument median score, and a significant decrease in the proportion of patients with enthesitis (25.7%). However, the median change in enthesitis score was 0.

Response rates did not differ between patients receiving methotrexate 15 mg/week or higher doses, although there was generally a higher proportion who met various response criteria among those taking greater than 15 mg/week. However, the authors noted that there could be an underestimation of the dose effect because the design of the TICOPA study, which randomized patients to a protocol for tight control of psoriatic arthritis disease activity or standard care, introduced a bias by intentionally escalating treatment doses in patients who continue to have active disease.

The investigators advised that the study results be interpreted in the context of the open-label design of the study, and placed alongside the other observational studies that support its use in psoriatic arthritis.

No relevant conflicts of interest were disclosed.