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Biologics next step for treatment of bullous skin disease?

May be an option in patients who do not respond to other regimens, according to presentation at University at Buffalo

While there is a shortage of good evidence-based research on the treatment of autoimmune bullous skin diseases, and no consensus on their treatment, case studies that involve biologic therapies are showing promising results in patients who are not responding to other treatment regimens, according to Dr. David Woodley, professor of dermatology at the Keck School of Medicine, University of Southern California at Los Angeles.

“Evidence-based medicine for autoimmune [bullous] disease is lacking,”said Dr. Woodley during a presentation at the semi-annual Buffalo Rochester Dermatology Society Meeting hosted by the Department of Dermatology, State University of New York at Buffalo. This absence of evidence is due to a number of factors, he said, including the rarity of the conditions, the lack of a consensus on how to treat them, and the fact that placebo treatments may not be possible with some of these conditions because they are so serious and sometimes life-threatening.The standard treatment employed in Dr. Woodley’s clinic for autoimmune bullous disease is prednisone, usually accompanied by nonsteroidal immunosuppressant agents including methotrexate, azathioprine, cyclophosphamide, or mycophenolate, he said.

However, failure of some patients to improve on this regimen has led physicians to consider biologics, said Dr. Woodley.

Experience with biologics

He cited the case of a 71-year-old woman with bullous pemphigoid admitted to the USC Norris Cancer Centre in Los Angeles. The woman had failed outpatient treatment prescribed by multiple dermatologists. The patient was treated with high doses of intravenous methylprednisolone for five days, with the addition of intravenous cyclophosphamide on days one and three.

“Usually you just have to do this once,” said Dr. Woodley. “This particular patient continued to have new blisters despite two cycles of this [treatment], which was new to my experience.” The patient’s IgE levels were 881 units, and her eosinophils were 34%, he said.

Experience with rituximab

The patient’s elevated IgE and severe pruritus spurred the attending doctors to consider omalizumab, frequently used in allergic asthma and chronic idiopathic urticaria, in the hopes it would at least provide some relief from the pruritus, said Dr. Woodley. “Within a very short time [the number of] new blisters fell, and her eosinophils decreased to below one per cent from 34 per cent. She left the hospital on prednisone and 60 mg of cyclophosphamide.

We were able to taper her off of both of these medications over two months and maintain her on monthly injections of omalizumab.”

Dr. Woodley and his colleagues have also conducted a four-centre study of infliximab with a control arm of intravenous placebo. “We showed there was

efficacy, but it was not a slam dunk. Particularly when compared with rituximab.”

There are also case reports in the literature where etanercept and adalimumab were tried for bullous skin disease.

Rituximab is a chimeric monoclonal antibody which depletes B lymphocytes for six to 12 months, currently approved in the U.S. for non-Hodgkin’s lymphoma and rheumatoid arthritis, said Dr. Woodley.

“There have been case reports and series, particularly by Dr. Pascal Joly [head of the dermatologyclinic at Rouen University Hospital, Rouen, France] in the New England Journal of Medicine of the successful treatment of pemphigus, P.folliaceus, PNP [paraneoplastic pemphigus], EBA [epidermolysis bullosa acquisita], and BP [bullous pemphigoid]. There are over 100 citations now just for pemphigus alone.”

In his own practice, Dr. Woodley previously would only try rituximab in patients where he was unable to reduce their prednisone dosage below 20 mg per day, or very young patients where he was concerned about putting them on an immunosuppressant for the rest of their lives, he said.

Rituxumab dosing for dermatology is based on skin surface area, said Dr. Woodley. “Figure 375mg per square meter.”

There are several competing opinions in the literature about how to continue rituximab treatment for autoimmune skin disorders after the initial cycle, Dr. Woodley said. “Most people have patients on other immunosuppressive agents such as prednisone, start rituximab, then taper the other medications,” he said. “But it may be possible to use [rituximab] as monotherapy.”

Longer remissions

Recent evidence in the literature suggests that weekly dosing with rituximab for four consecutive weeks provides longer remission than two week dosing, he said. While he had been primarily recommending dosing every two weeks for the convenience of patients who had to travel long

distances to his clinic, he is now recommending the four consecutive week regimen.

Regarding adverse events from rituximab, “there are a lot of infusion reactions,” he said. The reactions can be reduced by pre-medicating patients with acetaminophen, Benadryl, loratadine,and 100 mg of intravenous hydrocortisone.

“There are rare case reports of prolonged hypogammaglobulin anemia, neutropenia, DVTs [deep vein thrombosis], and pulmonary embolism,” Dr. Woodley said, though like the other adverse events the rate appears to be going down due to reduction in the use of other immunosuppressants and better infusion reaction prophylaxis.

No cases of progressive, multi-focal leukoenchephalopathy have yet been reported with rituximab treatment for autoimmune bullous diseases, though they have been reported in other applications of the drug, he said.

Treat MMP early

Mucous membrane pemphigoid, or cicatricial pemphigoid, is a sub-epidermal disease and the scarring it produces can be devastating, so it should be treated early and aggressively to prevent irreversible sequelae, he said.

“There is no consensus about this, but I think the initial product of choice is Cytoxan [cyclophosphamide],” said Dr. Woodley. “And after I control the patient with Cytoxan and prednisone [together], I try to get them off the prednisone and onto Cytoxan alone. I have had several patients that cannot take Cytoxan or had a relative contraindication. In these patients, I

have used rituximab alone or in combination with monthly IVIG with good results.”

While the literature suggests dapsone has been helpful for mucous membrane pemphigoid, Dr. Woodley said, his experience with it has not been positive.

Non-proprietary and brand names of therapies: omalizumab (Xolair, Novartis), infliximab (Remicade, Janssen), etanercept (Enbrel, Amgen/Wyeth); adalimumab (Humira, AbbVie); rituximab (Rituxan, Roche); cyclophosphamide (Procytox, Baxter).

This article first appeared in the August 2016 issue of The Chronicle of Skin & Allergy

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