Fall 2020: Behçet’s Disease: A Canadian Perspective

INTRO: Dr. Jan Dutz is a specialist in dermatology, rheumatology, and immunology. He is a professor, and head of the department of dermatology and skin science at the University of British Columbia, Senior Scientist at the BC Children’s Hospital Research Institute. This session is about Behçet’s disease, which we don’t see often, but is a challenge to treat.

Dr. Dutz: This presentation is about Behçet disease and how it may be relevant to your dermatological practice. Let’s start with an overview. Behçet’s disease is:

  • Chronic, multi-system inflammation, initially recognized as variable vessel vasculitis affecting both the veins and the arteries
  • Characterized by oral (98%) and genital (80%) aphthous ulcers
  • Initially, it was the association of oral, genital, and eye inflammation that Hulusi Behçet in Turkey discovered.
  • The most common symptoms are oral ulcers, either major or minor ulcers, and even herpetiform ulcers. The ulcers are painful and occasionally can scar.
  • It’s not just cutaneous, but you can get ocular disease, which is a significant cause of morbidity in Meditteranean countries.
  • As a rheumatologist, I see patients with neurologic disease, vascular disease, joint disease, and gastrointestinal disease. Most patients initially present with oral ulcers, then oral and genital ulcers, as well as other skin lesions.
  • It’s a disorder that is most frequent along the Mediterranean and along the so-called silk road. In North America, the incidence is about 5 per 100,000, but it is likely underrecognized.
  • The clinical manifestation differs from the North American population and the Silk Road population. (ex. More common in men in the Silk road population, where it is more common in women in the North American population).
  • Pathergy is more predictive in the Silk Road/Meditteranean population than it is in the Caucasian population.
  • HLA-B51 is predictive of more severe disease and is seen more commonly in the Meditteranean population. In the Caucasian population with Behçet’s disease, about 15% are HLA-B51 positive, but 50%-80% in the Silk Road population.
  • Generally more severe in the Silk Road population with systemic disease and more GI involvement.

Clinical manifestations are dependent on genetic predisposition and several environmental factors.

  • Herpes infections, bacterial infections, heat shock proteins, and possibly pollution can act as environmental factors leading to immune response activation.
  • Multifactorial immune response – number of cytokines upregulated in the T Cells in the lesions, and those include IL-2, IL-6, IL-12, IL-17, IL-23, TNF Alpha, and Interferon Gamma which leads to the clinical manifestations.
  • Family history – HLA-B51, IL-10, IL-23RAL12-B2.

 

Diagnosis Challenges

These patients often present with oral ulcers. Ulcers themselves are not very specific. Ulcers can be seen in multiple skin diseases, such as Stevens-Johnson Syndrome, bullous disorders, lichen planus, they can be herpes simplex virus, auto-inflammatory conditions such as Pfapa, or as a result of drug toxicity from methotrexate. There are many pathways to oral ulcers, so patients with severe oral ulcers may not have a correct diagnosis made right away.

We classify Behçet’s disease to help with this. These criteria were initially made in 1990.

Recurrent oral ulcers (3 times or more in 12 months) + two of the following symptoms:

  • Recurrent genital ulceration
  • Eye lesions
  • Skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules in patients not on corticosteroid treatment)
  • Positive pathergy test

In 2006, some modifications were made to a point system and added vascular lesions and their importance in this disorder.

 

Pathergy

Pathergy is when a minor trauma to the skin leads to the development of skin lesions or ulcers. The standard test uses a 20 gauge needle to prick the skin and reexamine it in 24 hours. Pathergy is a characteristic of Behçet’s disease, but again, this is more common in the Meditteranean population than in the North American and European populations. Note that it is characteristic but not diagnostic as it also presents in other neutrophil disorders such as pyoderma gangrenosum.

The Burden of Behçet’s disease (8:30)

Let’s focus on the oral manifestations that are more common in the patients we would see in North America. Oral ulcers seen in Behçet’s disease are more persistent and more painful than those in recurrent aphthous stomatitis. This results in difficulty eating, speaking, and maintaining oral hygiene.

Other burdens include internal organ involvement, but this is more common in the Meditteranean population. Young males tend to have the worst disease. The standardized mortality ratio can be as high as 10. It’s because these men often get a concomitant vascular disease and neurological involvement. GI involvement and eye involvement have been the most common in the patients that I’ve looked after.

How do we manage Behçet’s disease?

It’s a disease that can affect multiple organs. The ones we see most commonly are the ones that get recurrent oral and genital ulcers. For management, I’ve traditionally used:

  • Oral Colchicine, topical sucralfate, and then move on to other agents if that fails
  • For GI disease, we’ve used TNF inhibitors and collaboration with gastroenterologists
  • For joint disease, I’ve used azathioprine
  • For eye disease, I’ve used cyclosporine and TNF inhibitors – again collaborating with ophthalmologists

Again in North America, the most common manifestations are oral lesions, genital lesions, and skin lesions, and these are the relevant ones for dermatologists. Once diagnosed, however, the follow-up with these patients is multi-disciplinary. You have to involve the gastroenterologist if there are GI symptoms. You have to involve the rheumatologist if there are joint or vascular symptoms. These patients can also have an increased rate of thrombosis if they have active vascular inflammation, usually treated with anti-inflammatories rather than anti-coagulation.

EULAR or European League Against Rheumatism has come up with a treatment system for mucocutaneous involvement.

Predominant Oral/Genital Ulcers: Topical corticosteroids – I tend to use clobetasol and instruct patients to apply gauze to the lesion first to dry and then apply it and hold it to the lesion before bed when you make less saliva. If that doesn’t work, I move on to sucralfate, and if that fails, I move on to Colchicine. I use the same treatment paradigm for genital disease.

Recurrent lesions: If these don’t work, I move on to treatments like azathioprine. I have not used thalidomide or interferon-alpha. I have used TNF Alpha antagonists, and I have used Apremilast.

Papulopustular lesions: I usually treat with topical clindamycin in an alcohol base.

We’ve had Colchicine for many years, but studies have not been unequivocal in showing the benefit of Colchicine. Studies have been done using relatively high doses of Colchicine (over 0.6mg/day), which is what we normally use. Only 1 in 3 studies have shown a statistically significant benefit.

Summary:

  • Behçet’s disease is a chronic multi-system disorder.
  • Oral ulcers are the hallmark of the disease.
  • This makes diagnosis complicated as oral ulcers are common in other diseases.
  • It has a significant psychological impact because of recurrent pain, difficulty speaking, eating, which leads to impaired quality of life.
  • Management should be tailored to the individual needs of the patient.

Apremilast in Behçet’s disease (13:45)

Apremilast is a PDE4 inhibitor that prevents the degradation of cAMP. It decreases many inflammatory cytokines, including TNF alpha, IL-2, IL-8, IL-12, IL-17, and IFN-gamma, which have been implicated in Behçet’s disease.

In 2012, an investigative study in the New England Journal demonstrated the efficacy of Apremilast in reducing oral ulcers in a phase II study of Apremilast vs. placebo.

A year ago, a RELIEF study, a placebo-controlled, double-blinded phase III study, compared Apremilast again compared to a placebo. It included patients from the Meditteranean, Europeans, Japanese, and North American.

Criteria: Men and women above 18 years of age, active oral ulcers, at least three times in the previous year despite using at least one non-biologic medication. Patients with severe systemic disease and severe eye disease were excluded from the study. The primary endpoint was the area under the curve for the total number of oral ulcers. The endpoint of treatment was 12 weeks, with an active phase of 52 weeks of treatment following this. Finally, an observational follow-up period for four weeks was done.

The primary endpoints were the number of oral ulcers over time, so these are dermatological measurements. Current and recurrent ulcers at each timepoint. 282 patients were assessed, of which 207 qualified, and they were divided into the placebo arm and the treatment arm with Apremilast. The discontinuation rates were 10% to 20%, and it was higher in the placebo group than in the Apremilast group.

Patient characteristics: Average age is 40 years old. Slightly more women. An equal proportion of patients from Asia as Europe. About 10% to 15% were from North America. Patients had Behçet’s disease for an average of 7 years with a significant number of oral ulcers and considerable pain. Many patients had tried several treatments, including Colchicine, oral steroids, and other immunosuppressive agents.

Results: A significant difference can be seen favoring Apremilast vs. placebo at two weeks, and this was maintained for 12 weeks. There was also a significant change in pain in those patients. In addition, there is a substantial decrease in the numbers and persistence of oral ulcers and pain. Other sub-factors were also considered.

  • Those that responded best to treatment had a disease duration under six years, and those with less than five ulcers.
  • Those with longer disease duration or more ulcers did not respond as well but had a wider confidence interval.
  • Prior treatments did not make any significant difference. The Apremilast arm also had a larger number of patients with complete resolution of oral ulcers.
  • The extended study had patients in the placebo arm moved to treatment from week 12 into week 28. These patients also reduced the mean number of ulcers and decreased pain once treatment started.

Adverse events:

  • Increase in diarrhea
  • Increase in nausea and headache

These were somewhat expected outcomes, but the adverse events were loaded to the front end of the trial and tended to decrease over time.

Serious adverse events:

  • Very few cases of migraine
  • One patient had a worsening of ulcers and had to discontinue
  • No deaths or other serious problems

Summary and takeaway:

  • Apremilast 30mg twice daily demonstrated significant benefit for oral ulcers.
    Over the 12 week, randomized period, patients on Apremilast improved the number and pain of oral ulcers and overall disease activity measures.
  • 50% reduction in the mean number of oral ulcers starting at week one, continuing up to week 12.
  • About 50% had complete resolution of oral ulcers by week 12.

Extension study: Not published yet, but an extension study was presented at EULAR while we were at the World Congress of Dermatology. These patients were followed for up to one year, and they maintained an excellent response.

  • Mean reduction of oral ulcers, and about 50-50% had complete resolution by week 12 and maintained for up to 1 year.
  • Once the drug is stopped, the response is lost. Apremilast does not cure the disease, but it does control the symptoms.
  • These responses were consistent across many of the subgroups.
  • Less than 1 in 10 discontinued the study within the one-year study period, and more are from the placebo arm.
  • For more detailed information and recommended sources, please refer to the video below at 26:57.

Questions and Answers:

Q: Do you go to Colchicine, or do you go straight to Apremilast?

A: In terms of access, in my practice, I still put patients on Colchicine first. I do echo what was found in the clinical data, however. I don’t find Colchicine to be wonderfully effective. I usually combine it with topicals such as sucralfate and the steroids that I pointed out earlier. Next on that treatment ladder is Apremilast, and I’ve found success with that.

Dr. Lynde: Thank you, Dr. Dutz and Amgen, for putting on that Open Session.