The autoimmune disease vitiligo is difficult to treat, partly because the pathogenesis is not yet fully understood. However, much progress has been made recently, according to Dr Marcel Bekkenk, dermatologist at UMC Amsterdam. The discovery that tissue-resident memory T cells (TRMcells) play an important role, provides guidance for new treatments, partly with existing resources.
“Many new insights into the etiology of vitiligo have been added in recent years, and great strides have been made in this regard,” says Bekkenk. “When the first domino falls, we now understand very well why they keep falling after that. The first trigger, on the other hand, remains a major point of discussion. But especially TRMcells seem to play a very important role in vitiligo, because they turn against melanocytes. dr. Tiago Matos obtained his PhD with us on research into this.1 He has shown that TRMcells are very important in many skin diseases. Some of it does not circulate, but resides in the skin and other peripheral tissues. If they don’t function properly, they can cause vitiligo as well as other skin conditions. You can TRMcells inhibit with JAK inhibitors, but they return as soon as you stop this therapy, because some of them barely circulate. The vitiligo then returns, as you cannot reverse the priming against melanocytes – just like you cannot undo the clotting of a boiled egg.”
Bekkenk adds that inhibition of these cells could lead to unacceptable toxicity, including infection. “Very specifically the TRMinhibiting cells that cause vitiligo and thus leaving the others untouched would theoretically be the solution.” However, it is far from that yet. Bekkenk considers healing to be impossible for the time being, certainly for the next 20 years. “I do think we will get better targeted inhibitors. But we have to be careful not to cause too much damage with immunotherapy; also because vitiligo is not a deadly disease. A challenge that is as difficult as it is interesting.”
Medium seeks disease
Research into disease mechanisms and targeted therapy involves collaboration with, among others, rheumatologists, according to Bekkenk; as well as with the pharmaceutical industry. This partly involves repurposing existing resources. “I can’t name names, but it’s a matter of logical thinking: TRMfor example, cells have IL-2 receptors. IL-2 inhibitors have already been in development for other conditions. Another example is JAK inhibitors, which have failed as a treatment for psoriasis, but who knows for vitiligo and other autoimmune diseases.” In any case, the results with the JAK inhibitor ruxolitinib in a cream seem promising.2
Furthermore, new insights for the treatment of vitiligo can also come from the corner of oncology. Autoimmunity and tumor immunology are often related. One way to combat vitiligo is inhibition of TRMcells; but induction of those same cells appears to promote the antitumor immune response. Bekkenk: “The CTLA-4 and PD-1 inhibitors, the checkpoint inhibitors, are anti-tumor drugs due to their immune-stimulating effect. If you can reverse their action, it could be effective for vitiligo. That is being worked on. But then you have to be careful that you don’t increase the chance of a melanoma.”
Vitiligo and skin carcinoma
Pelvisk is also involved in research into the association between vitiligo and certain types of skin carcinoma, especially melanoma. “A melanoma is very immunogenic and has therefore also been shown to be sensitive to immunotherapy. A recent study of ours has very clearly shown that in vitiligo – contrary to what is often assumed – skin cancer occurs less often. This may still be expected with melanoma, but this also turned out to be the case with non-melanoma skin cancer. Non-melanoma skin cancer was included as a kind of control. Curiously, the probability of that was also lower; this was confirmed shortly afterwards in other studies in other countries. In Korea, it has even been shown that certain other cancers, such as lung cancer and certain ENT cancers, are less common in vitiligo. The possible explanation is that the immune system is so ‘on’ in vitiligo that especially cancers that respond well to immunotherapy occur less often. It is difficult to prove, but there is a link.”
Transplant
Transplantation is a realistic treatment option for a very select group of patients with vitiligo. “Dr Albert Wolkerstorfer in particular does a lot of research on this. In non-systemic vitiligo, for example segmental vitiligo, transplantation works particularly well. Since this is a much more localized form, you can transplant pigment cells very nicely without inducing an immune response right away. In the case of non-segmental, (ordinary) vitiligo, it is much less successful, because the immune response remains and will attack the newly transplanted melanocytes again. This way, mopping with the tap remains open.”
VIPOC-meetings in Amsterdam
“Pretty unique”, Bekkenk calls the congress of the VIPOC (Vitiligo International Patient Organizations Committee), the third edition of which was held in Amsterdam between 20 and 23 April 2022. The Dutch patient organization Vitiligo.nl is an active member of the VIPOC. “What makes the congress special is that patient associations from all over the world, researchers, practitioners and patients come together to exchange knowledge and experiences. There has been extensive discussion about what standard therapy should be by vitiligo experts and chairpersons of patient associations from countries around the world. Gaps in knowledge have been discussed and, of course, much attention has been paid to new agents and their possible future place in treatment strategies.”