Psoriasis, atopic dermatitis and Malassezia
Microbes which live on our skin have long been suspected of contributing to chronic inflammation, in particular seborrheic dermatitis, psoriasis and atopic dermatitis. Many researchers have investigated the role of fungi, in particular Malassezia, in these diseases (Findley et al 2013). Malassezia are now known to cause seborrheic dermatitis (Gupta et al 2004), yet it took a century to figure this out. Why was it so hard to come to this conclusion?
Case-control studies can show that a microbe probably causes a disease by demonstrating that people who don't have the microbe never develop the disease. These studies look for a specific pattern: all patients have the microbe in question, while many healthy controls don’t. For example, researchers managed to pin cervical cancer on HPV because nearly all patients had oncogenic HPV strains, as compared to only ~20% of healthy controls (Munoz et al 2003). Unfortunately, this method does not work for Malassezia on the skin because all humans are positive: we all have Malassezia on our skin for our entire lives (Nagata et al 2012; Findley et al 2013; Tett et al 2017)!
If cases and controls were all negative for Malassezia, we could conclude that this fungus causes no skin diseases. In reality, cases and controls are all positive for Malassezia, so we can’t conclude anything: Malassezia could be causing disease in genetically predisposed individuals only.
This extremely high prevalence on the skin is why it took so long to conclude that Malassezia causes seborrheic dermatitis. What won scientists and doctors over is the fact that many antifungal compounds improve seborrheic dermatitis symptoms—as long as they are applied to the skin. These compounds reduce Malassezia populations, but do not eliminate them outright, which means that if antifungal treatment is stopped, Malassezia and seborrheic dermatitis return.
Similar studies were run in psoriasis and atopic dermatitis, in the hope that antifungal drugs applied to the skin would reduce symptoms like they did in seborrheic dermatitis, and thus pin these diseases on Malassezia too. Their results were variable and weak, and no firm conclusion could be reached as to the involvement of Malassezia in psoriasis and atopic dermatitis. However, researchers noticed something very strange: while antifungal drugs applied directly to the skin were not very effective, oral antifungal drugs which never reached the skin seemed to work quite well (Crutcher et al 1984; Ganor 1988; Buslau et al 1989; Ascioglu et al 1991; Kitamura et al 1997; Adachi et al 1999)! What could possibly explain this?
There’s a very important immunological difference between seborrheic dermatitis, psoriasis and atopic dermatitis, which can explain why antifungals applied to the skin were not effective in the latter:
In seborrheic dermatitis, the adaptive immune response against Malassezia is too weak (Neuber et al 1996).
Too strong an adaptive immune response is like being allergic to peanuts: even trace amounts of peanuts are enough for the immune system to launch a full-scale attack against the peanut invader! Peanuts don’t kill people: the immune response against peanuts kills people. This analogy can explain why antifungal drugs applied to skin are effective in seborrheic dermatitis, but not in psoriasis or atopic dermatitis, as detailed below.
Seborrheic dermatitis occurs in people whose adaptive immune system is too weak to properly do its job—specifically, T cells fail to keep Malassezia populations at tolerable levels on the skin. This is why immunocompromised and immunosuppressed patients have an extremely high risk of seborrheic dermatitis (Borda et al 2015; Lally et al 2010). Antifungal drugs which lower Malassezia populations on this skin can do the T cells’ job for them, and cure seborrheic dermatitis, as long as these drugs are regularly applied to the skin.
Psoriasis and atopic dermatitis are similar to peanut allergies: reducing Malassezia levels using antifungal drugs helps a little bit, but the adaptive immune system of these patients is so sensitive that even trace amounts of Malassezia remaining on the skin can trigger disease. This is like giving someone who is allergic to peanuts one peanut instead of ten: will they be ten times less sick? No! Either they won’t be sick at all (if this amount is below the immune detection threshold), or they will enter anaphylactic shock!
While this can explain why antifungals applied to the skin are not effective in psoriasis and atopic dermatitis, it does not explain why oral antifungal drugs which do not reach the skin are effective. Any guesses? Check upcoming blog posts for the answer!
Animated psoriasis video: https://youtu.be/I7FSKlwIxMA