Antifungals in psoriasis and atopic dermatitis
Updated: Jun 17, 2019
Candida in the gut are associated with psoriasis and atopic dermatitis
The presence of Candida in the gut is associated with both psoriasis (Fleisher et al 1925; Soyuer et al 1991; Waldman et al 2001) and atopic dermatitis (Buslau et al 1990; Savolainen et al 1993). Several mechanisms have been proposed to explain this link:
Candida are present on the the skin, and cause inflammation there.
Candida toxins leak from the gut into the bloodstream; these toxins reach the skin, and cause inflammation there.
Candida causes autoimmune T cells to be produced in the gut; these T cells reach the skin, and cause inflammation there.
All three of these hypotheses are grossly inconsistent with observations (see Wednesday’s blog post for details), so they are probably incorrect.
T cells originating in the gut can cause psoriasis, and probably atopic dermatitis
The vedolizumab studies show that T cells in Crohn’s disease and psoriasis are targeting the same antigens (see yesterday’s blog post for details). These antigens are Malassezia proteins (Kanda et al 2002), and T cells on the skin in psoriasis often originate from the gut (Pauls et al 2001; Kilshaw 1999). Vedolizumab can also trigger atopic dermatitis by sending T cells from the gut to the skin (Tadbiri et al 2018), though this occurs less frequently than psoriasis.
Candida and Malassezia look similar to phagocytes and dendritic cells
Candida and Malassezia have the same sugars on their surface: mannan, beta-glucan and chitin. Phagocytes and dendritic cells rely on these sugars to detect microbes. From their point of view, Candida and Malassezia are largely indistinguishable. When Candida are present in the same organ as Malassezia, if phagocytes or dendritic cells decide to attack Candida by calling-up T cells, some T cells detecting Malassezia will inadvertently be called-up too. In atopic dermatitis, an adaptive immune response against Candida is often present in conjunction with an immune response against Malassezia, consistent with T cells being called-up to to attack both of these fungi (Bäck et al 1995; Wüthrich et al 2003; Sonesson et al 2013; Kanda et al 2002; Johansson et al 2002; Johansson et al 2009).
What can we do about this?
This begs the question: if we remove Candida from the gut, will psoriasis and atopic dermatitis symptoms improve? The answer seems to be yes! Several studies have used oral antifungal drugs which are not absorbed into the body to treat psoriasis and atopic dermatitis (see list below). Their results are clear: these drugs help a subset of patients, likely those with Candida in their gut. However, no studies have measured Candida in the gut before giving antifungal drugs; this means the specific therapeutic target of these drugs has not been formally demonstrated yet. Given that Candida in the gut is strongly associated with psoriasis and atopic dermatitis, and that all these drugs are effective against this fungus, Candida is the most likely therapeutic target.
Crutcher et al 1984: oral nystatin reduces psoriasis symptoms.
Ganor 1988: nystatin and amphotericin B reduce psoriasis symptoms.
Buslau et al 1989: oral nystatin reduces psoriasis symptoms.
Ascioglu et al 1991: oral nystatin reduces psoriasis symptoms.
Peeters et al 1992: oral dimethyl fumarate reduces psoriatic arthritis symptoms.
Altmeyer et al 1994: oral dimethyl fumarate reduces psoriasis and psoriatic arthritis symptoms.
Kitamura et al 1997: amphotericin B reduces atopic dermatitis symptoms.
Adachi et al 1999: nystatin and amphotericin B reduce atopic dermatitis symptoms.
It’s important to note that clearing Candida from the gut does not improve psoriasis and atopic dermatitis symptoms in all patients: some patients don't even have Candida in their guts to begin with!
Many additional studies report improvement of symptoms with oral antifungal drugs which are absorbed into the body (itraconazole, fluconazole, ketoconazole). In these studies, is it unclear if the drugs are clearing a fungus in the gut, on the skin or elsewhere. Candida in the gut is only one of many possible therapeutic targets in these studies.
Why not just kill Malassezia with antifungal drugs?
Eliminating Malassezia from the gut and skin would probably be the most effective treatment, but it is unclear if currently available antifungal drugs can do this. For example, ketoconazole shampoo does not completely eliminate Malassezia from the scalp, it only reduces Malassezia populations. This is sufficient to prevent dandruff, but if this shampoo is no longer applied, Malassezia populations rise and dandruff returns. The adaptive immune system can be extremely sensitive to some antigen types (think peanut allergies), which means reducing Malassezia populations might not improve psoriasis and atopic dermatitis symptoms much—rather, complete elimination of Malassezia might be necessary for a cure.
Animated psoriasis video: https://youtu.be/I7FSKlwIxMA