Recurrent flares impacting Quality of Life

Behçet’s disease is believed to be an autoimmune disease with a genetic component. The body’s immune system targets the vasculature (veins and arteries) of the individual with Behçet’s Disease. Depending on where this attack takes place, the symptoms experienced by the individual can vary. The most common manifestation is mucocutaneous ulcers, including oral ulcers (mouth ulcers), genital ulcers and leg ulcers. Patients with more severe disease may have involvement of the ocular, nervous and vascular (e.g., primary arteries and veins) systems, leading to more severe and potentially life-threatening aspects of the disease.

Most people have mild to moderate disease, primarily related to mucocutaneous ulcers. The mouth ulcers are the most common, occurring in almost all patients, usually with multiple flares per year. Much like oral mucositis, these ulcers can be very painful and have a significant impact on both productivity and Quality of Life. Oral ulcers can also be prone to scarring, depending on the severity of the ulcer. Genital ulcers are the second most common occurrence. The genital ulcers are very similar to oral ulcers (collectively called aphthous ulcers) but in Behçet’s Disease, genital ulcers are much more prone to scarring and have a significant risk of becoming infected. Leg ulcers (or ulcers of the skin in general) also occur. The major issue is the long time to resolution and potential disrupted blood supply to the ulcer area after healing, leading to a potential post-thrombotic syndrome. Again, the leg ulcers are at significant risk of infection.

Behçet’s Disease is usually at its most severe in individuals in the late teens through middle age, with the severity decreasing as the immune system weakens with age. Because the mucocutaneous manifestations are not life threatening and will ameliorate as the individual ages, treatment options are selected carefully to reduce potential long term side effects or toxicity. In contrast, involvement of other organ systems (ocular, major vasculature, nervous system) is associated with potential lasting consequences and, as such, higher risk treatments are warranted (e.g., biologics).

Behçet’s Disease has a strong genetic component, though there is no single genetic driver. Once triggered, the inflammatory cascade in Behçet’s disease has been shown to include both adaptive and innate immune responses.

Some Quick Facts

Behçet’s Disease is not contagious
Behçet’s Disease flare-ups can be triggered, and the triggers will vary between individuals
Behçet’s Disease is believed to be an autoimmune disease with both genetic and environmental components
Behçet’s Disease is most common in people from the “Silk Road” regions of the world, with highest prevalence in Turkey, Iran, Japan and China
Behçet’s Disease is believed to occur in up to 1 million people worldwide, including about 18,000 people in the US
Most patients with Behçet’s Disease have mild or moderate disease
Behçet’s Disease may become less severe as the individual ages

Symptoms of Behçet’s Disease

The vasculitis induced by Behçet’s Disease can occur in many anatomical regions, leading to a wide range of symptoms. Classical signs of Behçet’s Disease include recurrent oral ulcer flares, as well as genital ulcers; however, many other manifestations are also possible, including in the skin, joints, eyes, cardiovascular system, and nervous system

Symptoms flare up and then go away, often to occur again later. There may be specific triggers for flares for some individuals.

Mouth Ulcers

These are painful sores, also called aphthous ulcers, which can occur in anyone. In Behçet’s Disease however, there are generally more lesions, they are often larger and more painful. They can occur on the lips, tongue and inside of the cheek. Almost all patients with Behçet’s Disease experience mouth ulcers.

Genital Ulcers

Genital ulcers are extremely painful. While similar to mouth ulcers, they often penetrate deeper into the tissue. In males they often form on the scrotum while in females they may develop on the vulva. Genital ulcers in Behçet’s Disease are more prone to scarring.

Skin Ulcers

Skin ulcers can occur anywhere on the body and are sometimes called folliculitis. Other lesions, more serious sores (erythema nodosum) can also form and in Behçet’s Disease, these lesions often ulcerate.

Eye Inflammation

Inflammation can occur due to vascular constriction at either the front or the rear of the eye (posterior or anterior uveitis) and sometimes both occur at the same time. Inflammation at the back of the eye can result in pain, blurry vision, light sensitivity, tearing and redness. Inflammation at the front of the eye is more dangerous as it has fewer obvious symptoms but can permanently damage the retina.

Joints

Restricted blood flow to the joints can cause arthritis or joint pain without the associated swelling.

Lungs

Restricted blood flow in the lung can result in aneurysms of the arteries in the lung and rupture of these aneurysms can lead to lung hemorrhage.

Gastrointestinal

Ulcerations throughout the gastrointestinal tract can occur including the mouth (see mouth ulcers above). When ulcerations occur in the ileum and cecum (small intestine), they may be difficult to distinguish from Crohn’s disease or other inflammatory bowel disease.

Brain

The white matter of the brain tends to be more susceptible to the inflammatory manifestations of Behçet’s Disease, potentially leading to aseptic meningitis (meaning an inflammation not related to infection), as well as headaches, confusion, strokes, personality changes and even, rarely, dementia.

Treatment Options

Treatment options for Behçet’s Disease are determined by the specific manifestations and severity of the disease symptoms. With mucocutaneous manifestations, the goal is to manage the symptoms while minimizing long term toxicity, with the knowledge that symptom severity should decrease with age. In the case of involvement of more critical organ systems (e.g., eye, brain, lung, etc.) where there is the potential for permanent damage or even life threatening events, more aggressive anti-inflammatory (systemic) treatment is utilized.

There are no drugs specifically approved for Behçet’s Disease except for apremilast in the context of oral ulcers.

Oral, Genital and Skin Ulcers

The mainstay of treatment is immunosuppressive therapy, including:

Steroids: both oral and topical steroids are used, primarily as short term treatment of flares. Due to the side effects of steroids, use is minimized where possible.
Colchicine: Originally developed to treat gout, and specifically the inflammation in the joints due to crystals of uric acid that build up in the joints with gout. It is also routinely used as an anti-inflammatory agent in Behçet’s Disease. Although it offers some relief, patients on colchicine can continue to experience significant flares of both oral and genital ulcers.
Apremilast: apremilast is approved for the prevention of oral ulcers; however, discontinuation of treatment leads to immediate resumption of disease. The cost of apremilast generally limits its use in Behçet’s Disease.
Azathioprine: azathioprine is an anti-metabolite (that is, it blocks a pathway by mimicking one of the outcomes of the pathway) and has anti-inflammatory activity. It has a black box warning for risk of malignancy.
Interferon alpha (recombinant proteins) are generally used as an injection. They are often prescribed only after failure to achieve sufficient control with colchicine, apremilast or azathioprine. They are associated with significant black box warnings, including for life-threatening disorders.
TNF alpha inhibitors are also utilized in Behçet’s Disease in an attempt to control inflammatory manifestations. TNF alpha blockers are generally associated with increased risk of serious infections.

Other Organ Involvement

For more life-threatening manifestations of Behçet’s disease additional treatments have been tested, particularly in uveitis, including:

Cyclosporine-A: cyclosporine is an immunosuppressive drug used to prevent transplant rejection and to treat rheumatoid arthritis, among other uses. It may cause kidney damage and/or hypertension.

There are no treatments proven to be effective in randomized clinical trials for vascular, central nervous system or gastrointestinal involvement. There are some treatment approaches developed on the basis of non-randomized data.

Where Soligenix Comes In

SGX945 is an anti-inflammatory treatment that utilizes an Innate Defense Regulator (Dusquetide) that has been shown to reduce the oral ulcers in oral mucositis (SGX942 in Oral Mucositis). It has also been shown to help fight infection and aid in wound healing, which may also be beneficial in the context of the wound scarring and infection risk with mucocutaneous ulcers in Behçet’s Disease. Dusquetide has been shown to be safe and well tolerated in Phase 1, 2 and 3 clinical studies.

SGX945 is administered as a 4-minute IV infusion twice a week. It is intended for use to enhance resolution of oral, genital and skin ulcer flares in Behçet’s Disease.

SGX945 is currently being planned for use in a Phase 2 clinical study in Behçet’s Disease.