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  • Martin Laurence

Crohn's + vedolizumab = back pain (AS-type)

HLA-B27 and CARD9 gene variants increase the risk of spondyloarthropathies, and point to a chronic fungal infection as the main cause of symptoms (see here for details). Spondyloarthropathy symptoms include inflammatory back pain (sacroiliitis and spondylitis), inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and inflammatory skin disease (psoriasis). In Crohn’s disease and psoriasis, conclusive evidence shows that the fungus Malassezia is the main target of T cells which are causing inflammation. But what about in inflammatory back pain?


Recap 1: Malassezia and psoriasis

We know that Malassezia are the only fungi commonly present on psoriatic lesions of the skin—if a fungus on the skin causes psoriasis, then we can be sure that it is part of the Malassezia genus because it is the only one that is consistently there! In addition:

  1. Applying Malassezia to healthy skin induces psoriatic lesions (Lober et al 1982)

  2. Antibodies against Malassezia are strongly associated with psoriasis (Squiquera et al 1994; Liang et al 2003)

  3. T cells in psoriasis react very strongly to Malassezia proteins (Kanda et al 2002)


Recap 2: Malassezia and Crohn’s disease

The immunological signature of Crohn’s disease is antibodies against fungi, strongly suggesting that the adaptive immune systems of patients are fighting a fungus in the gut (specifically CD4+ T cells). Many different species of fungi are present in the gut, so pinning the blame on Malassezia is more difficult than in psoriasis. Case-control studies in Crohn’s disease (Kellermayer et al 2012) and ulcerative colitis (Richard 2018) point to Malassezia as the causative fungus.


Recap 3: Vedolizumab shows that Crohn’s and psoriasis are the same disease

Based on the above observations, both psoriasis and Crohn’s disease seem to be caused T cells attacking the fungus Malassezia. A good way to test this hypothesis would be to take T cells from the gut in Crohn’s, and place them on the skin to see if a psoriatic lesion appears. The drug vedolizumab does exactly this: it forces T cells in the gut to spread to other organs, including the skin (see here for details). About 5% of Crohn’s patients taking vedolizumab develop psoriasis as a consequence of this treatment (Tadbiri et al 2018; Wendling et al 2018; Sody et al 2017).


The vedolizumab studies have thus demonstrated that these two diseases are in fact the same disease which can affect multiple organs, as we suspected based on heritability and genetics studies (see here and here for details). Before the vedolizumab studies, this question was debatable. It is no longer debatable: Crohn’s and psoriasis are caused by T cells which are attacking the fungus Malassezia.


Vedolizumab shows that all spondyloarthropathy symptoms are the same disease

The vedolizumab studies reported that, in addition to psoriasis, spondyloarthropathy symptoms of the spine and joints are triggered by giving this drug to Crohn’s patients (Tadbiri et al 2018; Varkas et al 2017; Wendling et al 2018). This means that T cells in Crohn’s disease must be recognizing proteins present in the spine and joints, in addition to the skin and gut. In the skin and gut, these are Malassezia proteins. In the spine and joints, the recognized proteins are… what would be your best guess?


Are Malassezia present in our spine and joints?

In psoriasis and Crohn’s disease, Malassezia have been shown to be present in affected organs (skin and gut) by many different research groups. In contrast, direct observations of Malassezia in the spine and joints are lacking: no one has thought of checking this, except one group which reported that Malassezia are the dominant fungal genus in the knee joint (Hammad et al 2018). We must wait for studies by different groups to report similar results to be 100% confident that Malassezia are in fact present in the spine and joints.


In the meantime, we know that T cells in spondyloarthropathies recognize an intracellular protein presented by HLA-B27. CARD9 and antibodies against fungi indicate this protein belongs to a fungus (see here for details). Combined with the vedolizumab studies, this means that Malassezia are probably present in all organs which can be affected in spondyloarthropathies, including the spine and joints.


Summary

Antibodies against fungi and genetic susceptibility genes in AS-type back pain, Crohn’s disease and psoriasis point to a chronic fungal infection as their main cause. The fungus Malassezia is present in the gut and skin, and causes Crohn’s disease and psoriasis. However, Malassezia’s presence in the spine has not been directly tested, so definite proof of its presence is lacking. We can infer its presence in the spine because vedolizumab often triggers back pain in Crohn’s patients by forcing T cells in the gut to patrol the spine.


NB: This post is based on Laurence et al 2018 (simplified for clarity). While many cases of back pain are the results of spondyloarthropathies, others are due to physical trauma, spinal disc herniation, etc.


Animated back pain (AS-type) video (intro): https://youtu.be/S-VhDiqwBnk

Animated back pain (AS-type) video (full): https://youtu.be/e2vpMqmLYQo


Vedolizumab disorients lymphocytes by binding to a4B7-integrin, forcing them to leave the gut.

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