TNF inhibitor treatment tactics

Dr. FernandezWith a lengthy history in dermatology and rheumatology, tumor necrosis factor alpha (TNFa) inhibitors have earned new indications while accumulating reassuring safety data, says an expert at the American Academy of Dermatology 75th Annual Meeting. Keeping patients on these drugs when they are working sometimes requires aggressively managing TNF-induced psoriasiform reactions, he added.

Dermatologists are somewhat spoiled with the plethora of biologic choices for treating moderate to severe psoriasis, says Anthony P. Fernandez, M.D., Ph.D. He is director of medical dermatology in the departments of dermatology and pathology at Cleveland Clinic.

All about experience

"What makes the TNF inhibitors stand out from those other options? Because they have been out longer, we have more experience (with them)," with commensurate efficacy and safety data gleaned from real-world patients, he says. Etanercept, adalimumab and infliximab began earning U.S. Food and Drug Administration (FDA) approval for psoriatic arthritis in 2002, followed by approvals for psoriasis in 2004 through 2008 (See the latest safety and efficacy information).

Clinically, Dr. Fernandez says, dermatologists may be underutilizing the strategy of combining a TNF inhibitor with methotrexate.

"There seems to be good evidence that combining etanercept with methotrexate is more effective than etanercept or methotrexate alone.¹ Combining infliximab or adalimumab with methotrexate also may result in better efficacy in the appropriate patient population, but we probably need better data to support that.,” says Dr. Fernandez. One issue is that research has not yet established the optimum methotrexate dose to boost biologic results -- "How low can we go to prevent anti-drug antibodies and maximize efficacy and safety?"

Regarding psoriasis comorbidities, Dr. Fernandez says, Psoriasis Longitudinal Assessment and Registry (PSOLAR) data reveal that major adverse cardiovascular events in patients with psoriasis remain extremely low with TNF alpha inhibitors.²

"Perhaps more importantly," he says, "we are accumulating a large body of evidence to suggest that TNF inhibitors can improve a number of parameters associated with cardiovascular event risk." These parameters include insulin resistance, several pro-inflammatory cytokines and vascular measures including carotid intima media thickness and aortic stiffness. Whether TNF inhibitors can decrease cardiovascular events has not yet been confirmed, says Dr. Fernandez, although trials of this type are underway.

Increasing indications

In 2015, adalimumab became the only FDA-approved treatment for hidradenitis suppurativa (HS), based on results from the Efficacy and Safety Study of Adalimumab in

47-year-old female with pyoderma gangrenosum; after 17 months' treatment with adalimumab.Treatment of Hidradenitis Suppurativa (PIONEER I and II) trials.³ In PIONEER II, "Patients were allowed to continue antibiotics if they were on them." Among such patients, 58.9% reached the clinical endpoint of 50% reductions in abscesses and inflammatory lesion counts at week 12, versus 41.8% among adalimumab-treated patients in PIONEER I who were not using antibiotics. Because treating HS with adalimumab requires weekly dosing, he adds, it's reassuring that both groups experienced similar rates of serious adverse events. Furthermore, says Dr. Fernandez, emerging long-term data for the weekly dose show consistent safety and sustained efficacy.⁴

"In my experience, adalimumab is less effective in HS than in psoriasis." Accordingly, Dr. Fernandez says it's critical to set appropriate patient expectations. "Adalimumab will not wipe away their scarring or other disfiguring aspects of the disease. We're really looking to calm down the inflammatory component and associated pain." By the same token, he advised against discontinuing previous treatments that provided partial efficacy, with the caveat that it is always particularly important to consider the risk-benefit ratio of long-term antibiotic use.

Regarding etanercept in children, a 5-year safety study requested by the FDA has shown that the drug maintained efficacy, and that adverse events were uncommon, with only one considered to be related to etanercept.⁵ In September 2016, etanercept became the only systemic therapy approved for moderate-to-severe psoriasis in children and adolescents.

"Whether or not TNF inhibitors will continue to attain new indications is unclear. But clearly, they play a very important off-label role in treating several challenging conditions," Dr. Fernandez says.

Dr. Fernandez also reports that one of his patients with pityriasis rubra pilaris who had failed a combination of cyclosporine, prednisone and acitretin cleared with adalimumab. A patient with Crohn's disease and pyoderma gangrenosum completely cleared with infliximab, he added, without needing long-term prednisone.

Next: Paradoxical reactions

Paradoxical reactions

With millions of patients using TNF inhibitors both on-label and off, he says, "Adverse reactions often happen in the skin. So our role with TNF inhibitors doesn't stop at managing
primary dermatologic diseases. We must try to help people who have other diseases as well" who develop TNF inhibitor-induced psoriasiform reactions. In some cohorts, he says, up to 5% of patients can experience this reaction, which is clearly a class effect.

"It typically occurs in patients without a history of psoriasis who are being prescribed TNF alpha inhibitors for other diseases. It can occur at any time the patients are on the medicine," and the reactions mimic established psoriasis subtypes.

Presently, Dr. Fernandez says, no known risk factors precipitate these reactions, which often occur in patients whose underlying disease is well-controlled by TNF blockers. "These reactions can be severe enough that the question comes up: do we need to stop the TNF inhibitor? It's our job to be aggressive in controlling these reactions when patients are doing well so that they can remain on these often life-changing medications."⁶

In an unpublished study of 102 patients with TNF inhibitor-induced psoriasis treated at Cleveland Clinic, says Dr. Fernandez, "Our results agree with what's already been published – there seems to be overrepresentation of plaque-type psoriasis, palmoplantar pustulosis (PPP) and scalp psoriasis." One such patient with Crohn's disease developed thick plaques, significant alopecia and PPP as a result of infliximab treatment. Taking 15 mg methotrexate weekly for several months controlled these side effects and enabled her to stay on infliximab, says Dr. Fernandez.

Sometimes, he says, the psoriasiform reaction resolves without treatment. "But if it doesn't, utilize your typical psoriasis medications to try to get it under control. Switching TNF inhibitors seems to work in only a minority of cases, and that's what we saw in our cohort as well. Many of our patients responded to topical treatments alone" and remained on TNF inhibitors.

"When we had to use systemic medications, we had some success with all of them," most notably cyclosporine. Increasingly, he says, "I choose cyclosporine to treat this reaction, when it's not responsive to topicals. You don't always have to prescribe 3 to 5 mg/kg. I have patients controlled on very low doses, which is helpful because you start to worry about over-immunosuppression precipitating other problems."

In one such patient, says Dr. Fernandez, cyclosporine 1 mg/kg both resolved adalimumab-induced inverse psoriasis and further helped his HS. "This can sometimes be challenging to diagnose. Histologically, it usually looks like psoriasis." But a few reports suggest that the inflammatory infiltrate more often will include eosinophils and plasma cells, he says.

In a study Dr. Fernandez and colleagues are preparing for publication, eosinophils proved very rare in typical psoriasis. Biopsies of TNF blocker-induced psoriasis revealed confluent parakeratosis, regular psoriasiform hyperplasia and superficial dermal inflammation, he says. "At high power, we have also seen increased eosinophils and plasma cells in some cases, and we are currently further exploring this relationship in a larger formal study to determine whether dermatologists can distinguish between patients who are experiencing this adverse drug reaction and those having an onset or flare of typical psoriasis."

Disclosures: Dr. Fernandez has been a speaker, consultant and researcher for AbbVie. He has also been a speaker for Celgene and a researcher for Roche, Xoma, Corrona and Mallinckrodt.

References

1. Armstrong AW, Bagel J, Van Voorhees AS, Robertson AD, Yamauchi PS. Combining biologic therapies with other systemic treatments in psoriasis: evidence-based, best-practice recommendations from the Medical Board of the National Psoriasis Foundation.

JAMA Dermatol. 2015;151(4):432-8.

2. Bissonnette R, Gottlieb AB, Kerdel F, et al. Analysis of major adverse cardiovascular events in the Psoriasis Longitudinal Assessment and Registry Study (PSOLAR). Poster P3229. Presented at: 75th Annual American Academy of Dermatology Meeting; March 3-7, 2017; Orlando.

3. Kimball AB, Okun MM, Williams DA, et al. Two Phase 3 Trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016;375(5):422-34.

4. Zouboulis CC, Okun MM, Gniadecki R, et al. Adalimumab efficacy is sustained in hidradenitis suppurativa patients at least 2 years with weekly dosing: results from a Phase 3 open-label extension study (PIONEER). Poster P0067. Presented at: 25th Annual European Academy of Dermatology and Venereology Congress; September 28-October 2, 2016; Vienna, Austria.

5. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74(2):280-7.e1-3.

6. Brown G, Wang E, Leon A, et al. Tumor necrosis factor-α inhibitor-induced psoriasis: Systematic review of clinical features, histopathological findings, and management experience. J Am Acad Dermatol. 2017;76(2):334-341.