To orient us, it's helpful to think of autoimmune diseases using the following paradigm where a person has an initial genetic risk, followed by a pre-clinical phase of autoimmunity, which can eventually progress to a clinically apparent autoimmune disease. The following figure comes from a paper published by Deane, Norris, and Holers pertaining to rheumatoid arthritis. But we believe that this model of disease development applies to other autoimmune diseases.
This figure suggests that there is an existing genetic risk and some environmental factor such as smoking triggers an autoimmune response. This autoimmune response is usually asymptomatic and might be present for years and might never progress to clinically apparent disease. Some people might even lose their pre-clinical autoimmunity. In some cases, eventually another factor such as another environmental exposure (maybe the person never stopped smoking) causes the progression to clinically apparent disease.
This paradigm presents us with interesting prevention strategies where we can target individuals with a genetic predisposition to a disease, and if we know what environmental factors might cause autoimmunity, we can eliminate these exposures to prevent autoimmunity. We might also try and prevent progression to clinically apparent disease by eliminating exposures or treatment with mild immunosuppressives to prevent disease manifestation. Unfortunately for this prevention paradigm, many autoimmune diseases are not well understood and can have a complex etiology.
A question to consider would be if prevention of disease such as avoidance of gluten to prevent Celiac's disease is even feasible, given the unknown etiology?
Or would it be more effective to just treat clinical autoimmune diseases such as insulin use for type 1 diabetics?
I remain optimistic and believe that advancing scientific evidence will eventually shed light on the etiology of many autoimmune diseases, allowing us to consider such prevention strategies.
Sources:
Deane KD, Norris JM, Holers VM. Preclinical Rheumatoid Arthritis: Identification, Evaluation, and Future Directions for Investigation. Rheumatic Disease Clinics of North America 2010;36:213–41.
Hey Ryan,
ReplyDeleteInteresting post. If only it was as simple as stop eating gluten... For instance, if I wanted to decrease my risk of developing an autoimmune disease such as RA, what would you recommend I do? Do you think we know enough about the pathogenesis of RA to feel confident in your response?
Hi Curtis,
ReplyDeleteAs for your question on the pathogenesis of RA, my answer is a solid 'no'. There is not enough known about its pathogenesis to yet be able to prevent autoimmunity or the clinical outcome of RA. You raise an interesting question on prevention of RA. Most etiologic studies of RA are either retrospective or case-control studies. As a fellow epidemiologist, I know you are aware of the uncertainty of such designs. However, I think the evidence is strong enough to say that by not smoking, one could reduce their risk for development of RA. However, I think the outright prevention of RA is not practical in the foreseeable future.
I thought this prevention of autoimmune diseases talk at ACR was definitely thought provoking. However, I would say RA is too complex of an autoimmune disease to think about prevention right now (perhaps in my lifetime though). I think this paradigm of prevention is more likely to be viable in the future for autoimmune diseases like type 1 diabetes where risk factors as well as the mechanisms of disease are a little better understood.
I would say that after attending the annual ACR meeting this year, the focus is definitely on treatment and management of the disease(which is to be expected since most members were clinicians).
I think another interesting question that I'd like your take on would be, given the low prevalence of RA in general (about 1% of the US population), if prevention was possible, would it even make sense from a public health and economic perspective? Given that there are effective disease treatment and management practices.
One last question I would like your opinion on would be on a phrase that was emphasized a couple times where 'if we can predict a disease, we can prevent disease'. Do you think this statement holds water?
Ryan,
ReplyDeleteGreat response and you pose some very interesting questions. It is almost as if you study this disease...
Given the low prevalence of RA, it isn't very feasible to conduct the gold standard (at least to observational studies) prospective cohort study. Therefore, it doesn't surprise me that designs of lesser quality, but more feasibility, were conducted (e.g. case-control). Also, given the prevalence, would it be an effective (with regard to cost) strategy to prevent RA? As usual with epidemiology - it depends. What would the intervention consist of? Of course targeted intervention efforts would be necessary, universal prevention would not be very efficient. If we target smokers, do we just add this to the list of a 1,000,000 other reasons why one shouldn't smoke? If we couple this with other intervention efforts, does it become worth it?
“If we can predict a disease, we can prevent disease” sounds nice; however, we can adequately predict obesity based on several factors: sedentary lifestyle, poor nutrition, genetics, and other factors, yet it is very difficult to “prevent”. Randomized trials have shown short-term benefits in reducing fat mass and cardiometabolic risk factors through exercise, diet or both, but subsequent follow-up (after the intervention was complete) display regression back to baseline values. This is suggestive of behaviors not being adopted. Obesity is a different morbidity than RA, but I am just providing an example where I don’t believe that statement “holds much water”. Others would be smoking and lung cancer or COPD. In my opinion, being able to predict disease is a good thing and clearly provides a foundation for preventing it, but by no means guarantees the prevention of certain outcomes.
Hi Ryan and Curtis.
ReplyDeleteI like that your post has become a conversation. :)
Answering your question, Ryan, I don’t think that prevention (especially anything involving immunosuppressive drugs, given that there are definite risks to suppressing the immune system) makes sense if it only targets a disease as uncommon as RA. Furthermore, how many people have a predisposition for RA and never get it? I would imagine that it could be relatively high. However, if there are preventions that would address common factors that we see across a whole spectrum of autoimmune diseases, it would make sense from a public health perspective. For example, would a therapy that targeted Treg prevent many of the Type IV immunopathologies? Would it be beneficial (or not harmful) for the people who would never actually get an autoimmune disease?
Suppose the hygiene / old friends hypothesis is true. We talked in class about the Iowa study of Crohn’s and whipworm therapy (Summers RW, et al. 2005. Trichuris suis therapy in Crohn’s disease. Gut 54: 87-90). Could this type of therapy be beneficial in cell-mediated immunopathologies? Could some version of that be beneficial preventively? The American Worm Project? It would be a pretty rough PR campaign.
Someone recently posted about Boswellia / Frankincense and how it might push the immune response from Th1 to Th2. Could small doses of something like this be a possible preventive measure?
If we consider the number of people with Type IV immunopathologies and chronic frustrated immune responses, it’s a lot of people. Would it be possible to find some kind of therapy that would prevent many of these conditions? Could we identify people susceptible to these pathologies? Prevention is pretty difficult to study, which could actually be the biggest stumbling block to this whole line of thinking though.
Maggie,
ReplyDeleteI would very interested in the promotion of "The American Worm Project". First, don't call it that :) Maybe we could consult fast-food chains on how they get people to eat things that would by itself taste awful? I would assume, just like fetal transplant, that the goal is to identify the beneficial substances, isolate those, and remove the filler (pun intended).
Good point - I think it's actually possible that fast food chains have already implemented the American Worm Project without our knowledge. ;)
ReplyDeleteMy research involves the association with RA and various HLA molecules, and from what we've found, this association comes from the ability of these HLA to bind citrullinated peptides, which occur from (namely) smoking, and other environmental factors that increase inflammation and activate PAD enzymes (which convert arginine to citrulline). To get to your prevention idea, I think the key is going to be decreasing inflammation (obviously) but not doing so in a way that broadly immunosupresses someone. I'm thinking, for example, of things like exercise that almost immediately increase circulating Treg numbers and antiinflammatory cytokines. Alternatively for treatment, what if we just blocked the HLA binding that peptide? It seems a viable option, and indeed there are people working on it!
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