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Dr Erin Wei on Pemphigus Vulgaris Identification and Management
Dr. Erin Wei, MD, is the Director of Bullous Disease Clinic at Brigham and Women's Hospital. She is also an instructor of dermatology at Harvard Medical School in Boston, Massachusetts, and a member of the American Academy of Dermatology. She joined The Dermatologist for an interview prior to her IAS session titled Pemphigus Vulgaris: Strategies for Disease Identification and Management.
What is the pathogenesis of pemphigus vulgaris? How may drugs play a role, and what are the common types of drugs guilty of inducing it?
Pemphigus vulgaris is an autoimmune blistering disease. What that means is your body produces proteins called antibodies, which usually protects you against infections, but in the case of pemphigus, antibodies are instead directed against proteins within one’s own skin.
In pemphigus vulgaris, this is directed against desmoglein molecules (desmoglein 3 with or without desmoglein 1). If you think of the skin as a brick wall, desmogleins are the mortar that binds the bricks (i.e. skin cells) together. These proteins basically interfere with the mortars from adhering. Using that same analogy, any mechanical friction will knock the wall down without the mortar, which is what we see in pemphigus patients, they have skin or mucosa breakage in the areas of trauma or friction.
While most cases of pemphigus are not drug-induced, it is possible for a medication to cause pemphigus. In terms of drugs that induce pemphigus, there are many culprits reported in literature. One group of drug we think of are those that contain a sulfhydryl group, which can, in some cases, bind to desmoglein molecules, disrupting their function and in some cases modify them into an antigen. There are several drugs that have been implicated—at least a dozen or more. However, in many cases, and in my personal clinical experience, these drugs simply unmask the disease. This means the patient already had some genetic predisposition or some clinical disease in which the drug may have unmasked it. In some cases, stopping the drug may be helpful, while in others, the disease continues. If you suspect a drug as the culprit, it is always worthwhile, if it is not an essential drug or if there is a safe alternative, to try stopping it and see if the disease goes away.
What signs/symptoms are common in the early disease course of pemphigus vulgaris? How do these signs/symptoms vary from other forms of pemphigus disease and differential diagnoses?
Pemphigus vulgaris can start either in the mucosa or in the skin. Some patients only have mucosal disease, most commonly in the mouth and less commonly anogenital mucosa or other mucosal surfaces. In some patients, the disease that starts in the mucosa can spread to the skin over time, and vice versa.
Patients, when presenting with early symptoms, diagnosis can be difficult. When the disease starts in the mouth, patients will often complain of bleeding of the gums, and painful sores in their mouth that do not go away. Firm foods, such as potato chips, acidic foods such as tomato, and spicy foods can be difficult to tolerate. The differential for mucosal disease is broad. It ranges from common things that are like canker sores to herpes stomatitis to other autoimmune diseases such as bullous pemphigoid, mucus membrane pemphigoid, systemic lupus erythematosus, IgA bullous dermatosis and epidermolysis bullosa acquisita. Behcet's disease, which is a diagnosis of exclusion, can also present with recurrent sores in the mouth and genitals. The differentials even broader for skin involvement of pemphigus, and include eczema, psoriasis, allergic contact dermatitis, or drug hypersensitivity. A biopsy is essential in these cases. One for H&E and one for direct immunofluorescence (DIF), which has to be taken on intact skin or mucosa. DIF is a special technique to look for antibodies in the skin.
What are the current strategies of treating PV? Are there promising future prospects of treating the disease and, if so, what can you tell us about them?
Current strategies for treating pemphigus vulgaris are focused on targeting autoantibody production. You can think of treatment in several different ways. You can think of it as in what is the fastest way you can get the disease under control and what is your long-term strategy. For instance, systemic steroid is one of the few treatments we have in dermatology that works quickly. This is a chronic disease, for long-term treatments, you have to think of steroid-sparing agents and start these as soon as possible given the long-term side-effects of systemic steroid. The treatment should ideally target the adaptive immune system. Drugs like rituximab have become first-line treatment options for moderate to severe disease. Rituximab essentially resets the immune system, by clearing the cells that are going to become the antibody-producing cells in the body. The autoimmune-producing B cells are much more susceptible given they need constant replenishment. Things you were vaccinated for or exposed to previously, such as tetanus, are much more resistant to rituximab treatment, and do not tend to be affected after a cycle of treatment. In other words, you maintain the part of your immune system that is helpful in fighting infections while getting rid of the bad players. It is a quite good drug to use for these reasons. Rituximab works very reliably in majority of patients with pemphigus. However, one caveat is that in a time of COVID19, you have to think of vaccination along with risk to infection, and time your treatment appropriately to the patient’s vaccine. Ideally, delay treatment if possible until they are fully vaccinated, meaning 2 weeks after the patient has completed the vaccination. Rituximab often take some time to kick in with anywhere between 4 to 12 weeks to fully take its effect. In the immediate term, I typically use another steroid-sparing agent, such as mycophenolate mofetil, which has a medium onset to get patients off of prednisone even faster. Once the steroid-sparing agent kicks in, I taper off the steroids. Concurrently, I have started rituximab so that, by around 3 month mark, I can almost reliably get patients into remission off of therapy. That is typically my treatment strategy given the current armamentarium of drugs I have at my disposal. More on this in my talk.
Looking into the future, there are several exciting new treatments coming down the pipeline. I discuss many of these in my IAS session in detail. One of which, that is particularly exciting, is CAAR T cell therapy, which is genetically engineered T cells that are trained to target only the desmoglein-recognizing cells. Once you engineer the patient's cells to do this, they can replenish once the disease recurs. In essence, if this treatment works, it is targeted and it is a “living treatment”, potentially a cure. As I mentioned earlier, rituximab works somewhat slowly so you need something that works quickly. Some of the other more exciting treatments are ancillary treatments to our current treatment strategy which includes the neonatal Fc receptor antagonists that can rapidly lower total immunoglobulin level including your anti-desmoglein immunoglobulin, which is great. However, the neonatal Fc receptor antagonists will be immunosuppressive similar to the BTK inhibitors. There are some other treatments I address in my session, but these are the more notable ones. I am also working on a couple targeted treatments that are in the preclinical stages—roughly looking 5, or 10 years down the line. It is definitely an exciting area for clinicians to be in, and it is an exciting time for patients as well.
What about relapse and recurrence of the disease? A recent study1 in JAMA Dermatology noted that initial PDAI score and anti-desmoglein antibody values may be associated with short-term relapse after rituximab. Are there any other clinical signs that may help clinicians realize relapse sooner?
Although rituximab is great in inducing remission, the majority of the patients will relapse at some point—typically within or around a year. What I normally do is, in that first year after remission, I try to follow these patients every 4 to 6 months or, sometimes, every 3 months. It is important to not only follow these patients clinically, but also serologically. I find two laboratory measures very helpful in getting a sense of their immune recovery. One is CD19, which tells me how fast their immune system is recovering after rituximab, and the other is the anti-desmoglein antibody level. What that tells me is whether they still have residual autoreactive clones in their system.
Patients who are at the highest risk for relapse are those with persistently elevated anti-desmoglein titers during clinical remission; these patients still have autoreactive clones in their system secreting anti-desmoglein antibodies. Quick recovery of their CD19 within the first 6 months after treatment of rituximab may also put them at a higher risk. In patients at high risk of relapse, I offer another cycle of rituximab, usually at about 6 to 12 months post treatment in hopes of inducing prolonged or permanent remission in some cases. While we still need more studies to help us understand whether this strategy is helpful, I find patients do very well with this treatment and monitoring strategy.
After the first year post rituximab, I typically space out their appointments. I also educate the patients about symptoms of their disease coming back. Some of these patients will develop post-traumatic stress disorder (PTSD) symptoms known to occur after sudden life events and illnesses; they will notice little sores or little things on their skin, and become worried that it indicates their illness returning. I have studied this and have found that the rate of PTSD after a diagnosis of pemphigus is as high as that of after a cancer diagnosis. I tell my patient that if they noticed a nonspecific lesion that is transient, it is not as worrisome. However, if the transient lesions are getting more frequent, more numerous, or if they persist more, then that should be a red flag for them to come in. I have an open door policy, if they are concerned, they can always reach me and come in for an appointment. To test if they are active clinically I often will look for the Nikolsky sign; I use a Q-tip in their gums and rub firmly to see if I can induce bleeding or sloughing of skin or mucosa. If the clinical findings are subtle or nonspecific, I always biopsy to evaluate if there is preference of antibodies in the skin. Another helpful objective measure is the desmoglein level. If it is starting to climb back up, that is another sign that their disease is coming back. When there is clear sign the disease is returning, treat early rather than later to avoid the need for heavy immunosuppression and less resulting potential side-effect.
Considering the rarity of pemphigus vulgaris, are there any advice or pearls of wisdom you’d like to share with your colleagues in terms of identifying and treating pemphigus vulgaris?
In terms of diagnosis, one important take-home is do not forget to perform an additional biopsy on intact skin or mucosa for the DIF when pemphigus vulgaris is suspected. Also, it is sometimes helpful in distinguishing between different autoimmune diseases that can present similarly. Serum studies are also helpful in diagnosis, planning for medication taper and monitoring during remission. One caveat is some patients, in the early part of their disease, don't have circulating antibodies. If you do blood work on them and they do not have circulating anti-desmoglein antibodies, that does not mean they do not have pemphigus. Patients can persist in just localized disease for a long time. Biopsy is the gold standard. When in doubt, biopsy and do the DIF. Serum tests can be a good ancillary test, but it does not preclude a diagnosis if it is negative.
In terms of treatments, an important take home is that start steroid-sparing and disease modifying treatment such as rituximab early to prevent long-term consequences of chronic systemic steroid use. In instances of relapse, again treat early to circumvent the need for heavy immunosuppression. It is an exciting field to be in right now given all of the different treatments that are coming down the pipeline. Stay tuned!
Reference:
- Mignard C, Maho-Vaillant M, Golinski ML, et al. Factors Associated With Short-term Relapse in Patients With Pemphigus Who Receive Rituximab as First-line Therapy: A Post Hoc Analysis of a Randomized Clinical Trial. JAMA Dermatol. 2020;156(5):545-552. doi:10.1001/jamadermatol.2020.0290
