Several groups are investigating events that precede onset of rheumatoid arthritis within 3 to 6 months as potential triggers of its onset. Most if not all scientists and clinicians agree that these events only trigger rheumatoid arthritis in susceptible people and that no single event or substance triggers all cases of RA. For example, Leirisalo-Repo reported that approx. 10-21% of RA patients had an infection within 6 months of onset of RA. (Leirisalo-Repo 2005, Curr. Opin. Rheumatol., 17:433-439) No single infectious agent but rather infection by one of several agents preceded the onset of RA. Most patients with synovitis did not progress to RA.(Soderlin et al. 2003, J. Rheumatol., 30:459-464) I recently summarized that four types of events or exposure to substances can trigger RA-like symptoms in susceptible patients (Molnar-Kimber and Kimber 2012, Med. Hypotheses, 78:123-129). The four general types of causes for inducing the onset of RA symptoms are (i) infections with one or more of 14 distinct pathogens, (ii) physical trauma that is not resolved, (iii) exposure to excess environmental toxin, and (iv) food incompatibility (allergy, intolerance, sensitivity). An example of an environmental toxin is smoke, which is a hot research topic in the rheumatoid arthritis field (Costenbader et al. 2012, Autoimmun. Rev., 11:604-609; Di Giuseppe et al. 2013, Arthrit. Res. Ther., 15:R56; Lundberg et al. 2013, Ann. Rheum. Dis., 72:652-658). The effect of smoking on the musculoskeletal system and on responses of rheumatoid arthritis patients to immune targeted therapies was recently reviewed (Molnar-Kimber 2012, J. Clin. Cell. Immunol. , S6:). These four types of documented triggers do not account for all cases of RA so additional triggers need to be identified.

Each type of trigger differentially affects the joints and elicits different immune and inflammatory responses in a recent article (op cit). Based on personal experience with triggering of RA flares and resolution over a decade, I proposed that the type of cause/ trigger of RA or RA flare may differentially affect the response to therapy (op cit).

In addition, several types of predisposing factors can influence the susceptibility of each person. For example, genetic predispositions, including the HLA-DR shared epitope, comprise one type of predisposing factors. Other predisposing factors are involved because many RA patients do not have the shared epitope. Karlson and Deane (2012, Rheum. Dis. clinics North Am. 38: 405-26) discuss environmental –gene interactions that affect the risk for onset of RA and provide a multistep development schema for the onset of RA.

Identification of the cause of RA onset in a population is hindered by the heterogeneity of the population. However, I believe that each patient has one or more predisposing factors and the exposure to the “trigger” can act like the proverbial snowball that starts the avalanche of RA symptoms.

Hope this helps, Sujit Kashyap.

Thanks for replying.

The most important genetic factor, HLA-DRB1 is usually underrated, because what really matters is the HLA-DRB1 genotype in a given individual.

Odds ratios conferred by HLA-DRB1 genotypes range from 0.20 to 28.

Some genotypes are almost only found in patients.

The simple answer is that the epidemiology suggests that nothing external triggers RA in most cases - there is so little evidence for clustering around environmental factors. (Smoking predisposes but is not a temporally related trigger.) This is entirely as expected since this is an autoimmune disease based on dysregulation of antibody production. Antibody production is based on an internal stochastic mechanism and so it would not be surprising for dysregulation to arise stochastically from within. And beyond the genetic link the epidemiology is stochastic. People forget that Paul Stastny who found the DR link always liked to point this out in his lectures on RA causation. So the likely answer is that the disease starts when a regulatory error is thrown up by chance within the B cell lineage, (some antibody species that 'cross-talk' with regulatory ligands) which fits with the absence of any evidence of external trigger. This basic viewpoint was the rationale for developing the use of rituximab in RA at UCL. The results are consistent with the idea.

So no need to go on looking for triggers from outside! The epidemiology tells us they are not there.

In agreement, no single event, infection, or exposure and no single type of cause can account for the development of RA in all patients. However, basic immunology studies and several epidemiologic studies suggest that a perturbation is critical in the onset of RA. For example, only 3% of people carrying the HLA-DR4 shared epitope eventually develop RA. Secondly, the recent study by Svendsen et al (On the origin of rheumatoid arthritis: the impact of environment and genes--a population based twin study, PLoSOne 8:e57304; 2013,) helped elucidate the relative roles of genetic factors, familial shared environmental factors, and unshared environmental factors in the onset of rheumatoid arthritis in twins. They found that “Twelve percent (95% CI 0-76%) of the phenotypic variance in the liability to RA was due to additive genetic effects, 50% (95% CI 0-72%) to shared environmental effects and 38% (95% CI 17-61%) to non-shared environmental effects.” Paper is worth reading. In other words, shared environmental factors (e.g. shared air pollution, diet, etc) contributed 50% of the risk of RA in Caucasian twins and unshared environmental risk factors contributed 38%. Studies that investigate the potential triggers of RA may uncover common and unique factors that perturb the self---non-self recognition mechanisms by the immune system.

I'm not sure we quite agree Kathy. My understanding is that the stepwise acquisition of different autoantibodies and their isotypes over a period of five to ten years before disease onset indicates that no perturbation at the time of onset is of particular importance. The immunological dysregulation started years before. The fact that genetically susceptible individuals still only have a 3% life time incidence is entirely consistent with an otherwise **internal** stochastic mechanism. What worries me about the study you quote is that it appears to suggest that total causality is given just by genetic and environmental effects. This looks like an unjustified **presupposition**.

There has been a longstanding problem that rheumatologists and other physicians have got it into their heads that disease causation is either genetic or environmental. You hear this all the time in lectures from physicians. But the one time we had a plenary presentation from an **epidemiologist** at the American College of Rheumatology he pointed out the third component, which all decent epidemiology textbooks include, which is internal stochastic causation. (And as I mentioned before, Stastny emphasised this in the 1980s.) Internal stochastic events are of huge importance in cancer and there is every reason to think they will be in autoimmunity. What the quoted study calls 'non-shared environmental' could equally well be internal stochastic. And the slow stepwise accumulation of autoantibodies looks very much it will be based on a sequence of stochastic Ig gene mutations that yield a synergistic action on cellular growth control very much like the sequences of 5-10 mutations that are thought to underlie failure of growth control in many cancers. It does not look like a sudden 'triggering' from outside.

And we should expect internal stochasticity to be even more important than cancer because the immune system normally works on the basis of totally unprovoked stochastic mutation - unlike any other organ system it uses randomness to fulfil its basic function. Random mutation in cancer may be provoked by alcohol or sunshine but in the immune system it is driven by activation induced deaminase with no need of any help!

The problem about measuring shared environmental factors is that there is no fixed baseline. However, the data you quote are I think interesting in indicating just how much causality may be due to background environmental factors altering thresholds for disease genesis. I suspect that the younger professional generation has little idea just how devastating the impact of smoking and air pollution was on life expectancy in the 1970s. And not just on purely cardiorespiratory disease. We had young adults with ankylosing spondylitis in respiratory failure. We had rheumatoid patients dying from fulminating extra-articular disease that seemed by 2010 to have almost completely vanished. We think because we have dealt with fog-forming smoke particles quite well in Europe that we have dealt with the problem but I suspect that there is still a huge pollution problem that we now cannot see.

But I think this needs to be distinguished from the traditional idea of a 'trigger', which dates back to rheumatic fever and heart disease, and encourages people to look for irrelevant infections at the time of onset of arthritis. I see it as an issue of altering thresholds, maybe in part through citrullination. I think the old idea of molecular mimicry that was put up to explain rheumatic fever and which probably does not apply even there, is a red herring for autoimmune disease (with one or two possible exceptions). What I think we need to understand is how different translocations and mutations in Ig genes generate B cell clones that feed off each other to produce a persistent dysregulation - just as the cancer people are unravelling the translocations and mutations in growth factor genes etc. It is now clear that inflammation is largely driven by the products of short lived plasma cells, but it seems likely that disease perpetuation is driven by long lived plasma cells, which encourage re-appearance of short lived plasma cells from new B cell clones producing autoantibodies - the cycle being revealed by rituximab therapy.