AAD/NPF Guidelines on Biologic Use in Psoriasis Save

Menter and colleagues from the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) have published their expert consensus guidelines for the use of biologics in psoriasis.

Psoriasis affects 3.2% of the US population. While the majority of patients with mild-to-moderate psoriasis are capable of adequately controlling disease solely with topical medications or phototherapy, many patients with moderate-to-severe disease will require biologic agents, as monotherapy or combined with other topical or systemic medications, to best manage psoriasis.

The AAD/NPF guideline committee included a multidisciplinary group of psoriasis experts consisting of dermatologists (including private practitioners), a rheumatologist, a cardiologist, and representatives from a patient advocacy organization, who reviewed the medical literature aand developed consensus guidelines below. 

Exerpts from their review of biologics : 

• TNF-α inhibitors - there are 4 TNFi approved for use in Psoriasis
  • Etanercept (FDA approval on April 30, 2004)
  • Infliximab (FDA approval on September 27, 2006)
  • Adalimumab (FDA approval on January 22, 2008)
  • Certolizumab (FDA approval on May 27, 2018)
  • Special issues with TNF inhibitors: 
    • Time to response - Definitive response (positive or negative) to TNFi treatment is best ascertained after 12 to 16 weeks of continuous therapy, except for infliximab, for which the best time is after 8 to 10 weeks.
    • Patient weight  - Overweight or obese patients are less likely to respond to TNF-α inhibitors. Therefore, overweight and obese patients frequently require a shorter dose interval or higher doses to achieve a satisfactory response. However, this effect is abrogated with infliximab, for which weight-based dosing is used.  TNF-α-inhibitors may display better responses with doses higher than the FDA-approved dose.In contrast, on the basis of phase II studies and expert opinion, some patients might tolerate and respond to dosing at lower than the FDA-approved dose.
    • Malignancy risk - TNF inhibitors are not associated with a risk of solid tumor or lymphoreticular malignancy. However, the addition of other immunosuppressant agents may alter the safety profile of TNF inhibitors. Patients with a history of solid tumor malignancy who have failed other therapies such as ultraviolet phototherapy, methotrexate, and/or acitretin (if not contraindicated or impractical) may in certain circumstances receive TNF-α inhibitors without expectation of an increased risk of tumor recurrence.
    • HIV - Use caution in patients with pre-existing immunosuppression-related conditions. Patients with HIV may receive TNF-α inhibitors if they are also receiving highly active antiretroviral therapy (HAART) that has effectively normalized their CD4+ T-cell counts and they show no detectable viral load, provided that they have no recent history of opportunistic infection. Note that severe psoriasis can be a manifestation of poorly controlled or poorly managed HIV infection and that the use of HAART is likely to be an effective treatment of psoriasis in such individuals
    • HCV - Patients with a history of or currently active hepatitis C may receive a TNF-α inhibitor for the treatment of psoriasis. Concomitant management with an appropriate health care provider is warranted.
    • HBV - Patients with a history of or currently active hepatitis B may receive a TNF-α inhibitor for the treatment of psoriasis. However, the patient should first be evaluated by an appropriate health care professional and may require concomitant treatment with an approved antiviral medication directed against hepatitis B. A hepatitis B core antibody test in this setting is recommended. Patients with a history of hepatitis B (confirmed resolved infection) do not need to follow up with a specialist, but ongoing monitoring with HB surface antigen, anti-HB core antibody, and liver function tests should be considered along with other ongoing monitoring tests owing to the potential risk of reactivation
    • IBD - Patients with a history of concomitant inflammatory bowel disease (IBD) might benefit from TNF-α inhibitor therapy. In fact, adalimumab, infliximab, and certolizumab are approved for the treatment of IBD.
    • Biosimilars - TNF-α biosimilars approved by the FDA should be considered similar to the reference branded version of the drug and therefore interchangeable. An interchangeable product means that the FDA has concluded that it may be substituted for the reference product without consulting the prescriber. The aforementioned guidelines/recommendation should apply similarly to biosimilar versions of TNF-α inhibitors
• IL-12/IL-23 inhibitors - Ustekinumab (FDA approval on September 25, 2009). Special issues w/ ustekinumab -
  • Time to Response - Definitive response (positive or negative) to treatment with ustekinumab is best ascertained after 12 weeks of continuous therapy. Consider dose escalation (eg, increasing dosing frequency to every 8 weeks or increasing the dose from 45 mg to 90 mg) or the addition of other modalities (such as topical corticosteroids or vitamin D analogues, methotrexate, acitretin, or ultraviolet light) in partially responding patients.
  • Patient weight - Like other biologic therapies, ustekinumab displays higher responses with higher doses.241 Overweight or obese patients often need the higher dose (90 mg) of ustekinumab to achieve the response of lower-weight patients taking the 45 mg dose. Additionally, serum concentrations of ustekinumab were also affected by weight, with lower serum concentrations found in heavier patients at each dose. However, some patients might tolerate and respond to lower dosing (eg, longer intervals of time between doses)
  • Malignancy risk -  There is no definitive evidence that ustekinumab used as monotherapy for moderate-to-severe psoriasis increases the risk of solid tumor or lymphoreticular malignancy.  Patients with a history of solid tumor malignancy who have failed other therapies such as ultraviolet phototherapy, methotrexate, and/or acitretin, if not contraindicated or impractical, may in certain circumstances receive ustekinumab without expectation of an increased risk of tumor recurrence.
  • HIV - Use caution with patients with pre-existing immunosuppression-related conditions. As long as patients with HIV have no recent history of opportunistic infection, they may receive ustekinumab if they are also receiving highly active antiretroviral therapy (HAART) that has effectively normalized their CD4+ T-cell counts and if they show undetectable viral load.  It also should be considered that severe psoriasis may be a manifestation of poorly controlled or poorly managed HIV infection and that the use of HAART is likely to be an effective treatment of psoriasis in such individuals.
  • HCV - In patients with a history of or currently active hepatitis C, ustekinumab might be considered for the treatment of psoriasis. Concomitant management with an appropriate health care provider is warranted.
  • HBV - In patients with currently active hepatitis B, ustekinumab might be considered for the treatment of psoriasis. However, the patient should first be evaluated by an appropriate health care professional and may require concomitant treatment with an approved antiviral medication directed against hepatitis B. A hepatitis B test core antibody test in this setting is recommended. Patients with a history of hepatitis B (confirmed resolved infection) do not need to follow-up with a specialist but require monitoring because of the risk of reactivation.
  • IBD - Patients with a history of concomitant multiple sclerosis and/or IBD might benefit from ustekinumab therapy. Ustekinumab is FDA-approved for the treatment of Crohn's disease.
• IL-17 inhibitors - there are 3 approved IL-17 inhibitors
• • Secukinumab (FDA approval on January 21, 2015)
• • Ixekizumab (FDA approval on March 22, 2016)
  • Brodalumab (FDA approval on February 15, 2017)
  • Special issues with IL-17 inhibitors:
    • Time to response -  Definitive response (positive or negative) to treatment with IL-17 antagonists is best ascertained after 12 weeks of continuous therapy. Consider dose escalation in partially responding patients.  Consider the addition of other modalities (such as topical corticosteroids, methotrexate, or ultraviolet light) in partially responding patients. Although there are no published data supporting combination therapy for the IL-17 inhibitors, there is no reason to consider such combination unsafe.  Given their similar mechanism of action, the efficacies of all IL-17 antagonists are comparable.
    • Malignancy risk - There is no definitive evidence that IL-17 antagonists used as monotherapy for moderate-to-severe psoriasis increase the risk of solid tumor or lymphoreticular malignancy. Long-term safety studies are necessary to more fully evaluate the risk of malignancy related to IL-17 inhibitor use.
    • HIV - Use caution in patients with pre-existing immunosuppression-related conditions (expert opinion).
    • HCV - Patients with a history of or currently active hepatitis C may receive an IL-17 inhibitor for the treatment of psoriasis. Concomitant management with an appropriate health care provider is warranted.
    • HBV - Patients with a currently active hepatitis B may receive an IL-17 inhibitor for the treatment of psoriasis. However, patients should first be evaluated by an appropriate health care professional and may require concomitant treatment with an approved antiviral medication directed against hepatitis B. A hepatitis B core antibody test in this setting is recommended. Patients with a history of hepatitis B (confirmed resolved infection) do not need to follow-up with a specialist but require monitoring because of the risk of reactivation.
    • Candidiasis - Treatment with IL-17 inhibitors is associated with increased risk of infection, particularly by mucocutaneous Candida infection
    • IBD - Patients with a personal history of or active IBD might experience reactivation or worsening of their disease.286 Although the number of patients presenting with this adverse effect in clinical trials was relatively small, it is recommended that the use of IL-17 inhibitors be avoided in patients with a personal history of or active IBD.
    • Depression and Suicidal ideation - Rare cases of suicidal ideation and completed suicides have occurred during brodalumab treatment, resulting in a boxed warning in the package labeling. Therefore, brodalumab can be prescribed by providers only through a restricted program under a risk evaluation and mitigation strategy called the SILIQ risk evaluation and mitigation strategy program (SILIQ is a brand name for brodalumab manufactured by Bausch Health, Laval, Canada). Brodalumab should not be considered as a treatment option in patients with suicidal ideation, recent suicidal behavior, or history of suicidal ideation.  A casual association between treatment with brodalumab and increased risk of suicidal ideation and behavior has not been established.
• IL-23 inhibitors - there are 3 FDA approved IL-23 inhibitors:
• • Guselkumab (FDA approval on July 13, 2017)
  • Tildrakizumab (FDA approval on March 21, 2018)
  • Special issues with IL-17 inhibitors:
    • Time to response -  Definitive response (positive or negative) to treatment with IL-23 antagonists is best ascertained after 12 weeks of continuous therapy. Consider dose escalation in partially responding patients. Consider the addition of other modalities (such as topical corticosteroids or vitamin D analogues, methotrexate, or ultraviolet B light) in partially responding patients. A lthough there are no published data supporting combination therapy for the IL-23 inhibitors, there is no reason to consider such combination therapy unsafe.
    • HIV and immunosuppressed patients - Use caution in patients with pre-existing immunosuppression-related conditions

Other Key Issues in Choosing Biologic Therapies

• The Role of the Dermatologist 
  • Dermatologists should be aware of common adverse events and monitoring recommendations. Additionally, they should educate patients regarding the increased risk of infections, as well as regarding not discontinuing or modifying their treatment without first seeking the advice of their dermatologist. These steps may help ensure initial treatment success and its maintenance over time. Dermatologists and health care providers, in general, should encourage patients to remain up-to-date with age-appropriate vaccines and cancer screening. In addition, dermatologists must consider interacting with appropriate medical colleagues to maximize care for their patients with psoriasis.
• Role of patient preferences
  • Numerous factors need to be discussed with each patient, including the efficacy and safety data to help them make a treatment decision regarding initiation of a biologic or when considering switching biologic treatments.  QOL assessment should be considered and discussed with patients before starting administration of or switching biologic agents.
  • Other factors that can affect patient preference and should be discussed with patients, include dosing schedule, cost, and route of administration. Biologics with less frequent dosing schedule (ie, every 8-12 weeks) may be preferred by some patients over others with more frequent dosing.
• Primary and secondary treatment failure
• • Primary failure - Is defined as initial nonresponse to treatment. Primary failure to respond to a TNF-α-inhibitor does not preclude successful response to a different TNF-α inhibitor. Nevertheless, it may portend reduced efficacy with other TNF-α inhibitors. Regarding IL-12/IL-23 inhibitors, failure of another biologic therapy does not preclude successful response to ustekinumab. 
  • Secondary failure - All biologics approved for use with psoriasis may lose efficacy in a patient who initially responds favorably to this medication (secondary failure). One reason for loss of efficacy may be attributed to the presence of antidrug antibodies. The concomitant use of methotrexate with biologic agents in other immune-mediated diseases has been shown to increase biologic drug survival. Nevertheless, the reported use of methotrexate in combination with biologics for the treatment of psoriasis is limited, and there are no RCTs to make a recommendation for combination therapy at this time
• Switching biologic treatments
  • If clinically needed, all other therapies for psoriasis, including other biologics, may be switched with a different biologic agent with the possibility of improved efficacy, safety, and/or tolerability.
  • There are no evidence-based studies on duration of the interval between discontinuation of the previous medication and initiation of a biologic. This may depend on the treatment that is being discontinued, disease severity, and response to prior treatment, as well as on expert opinion, and it should be assessed on a case-by-case basis. 
• Biologics and surgery
• • On the basis of expert opinion, all biologics can be continued through low-risk surgical procedures in patients with psoriasis and PsA. Low-risk surgical procedures are defined as surgical procedures without a break in sterile technique during which the respiratory, gastrointestinal, and genitourinary tracts are not entered. Moderate- and high-risk surgical procedures include surgical procedures during which the respiratory, gastrointestinal, or genitourinary tract is entered without the presence of contamination. These also include surgical procedures during which there is a major break in sterile technique, spillage from the gastrointestinal tract, or an active infection or devitalized tissue.   Moderate- and high-risk surgical procedures require a case-by-case approach in collaboration with the surgeon(s)/medical team. Risk assessment should consider each patient's individual risk factors and comorbidities. If considered necessary, the biologic agent could be discontinued approximately 3 to 4 half-lives before and until 1 to 2 weeks after elective surgery if there are no postoperative complications.
• Vaccination
  • Inactivated or “dead” vaccines may be given during treatment with all biologics.
  • For administration of live vaccines, consultation with an infectious disease specialist is recommended. Although there is scarce evidence from case series suggesting that varicella zoster, MMR (measles, mumps, and rubella), and yellow fever vaccines could be administered while patients are also taking TNF-α inhibitors, discontinuation of all biologic agents is recommended before administration of a live vaccine. Experts differ on the length of discontinuation before and after administration of live vaccinations. Although some experts advise discontinuation of biologics 2 to 3 half-lives before and after administration of live vaccines, others advice discontinuation of biologics 4 weeks before (or longer depending on the half-life of the biologic) and until 1 to 2 weeks after vaccination. These recommendations are based on experts’ opinion.