Unravelling the link between occupational inhalants and rheumatoid arthritis

• Patients with rheumatoid arthritis can be subdivided on the basis of the presence of anti-citrullinated protein antibodies.
• Different genetic and environmental risk factors are associated with ACPA-positive and ACPA-negative RA.
• In ACPA-positive RA, asymptomatic autoimmunity appears to start in the lungs, and a “second hit” (eg, infection) initiates the transition to inflammatory arthritis.
• Tobacco smoking, silica exposure and inhalant-related occupations are associated with increased risk of RA, particularly ACPA-positive RA.

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If you look at Peter Paul Rubens’ painting The Three Graces, you will see that the grace on the left has a deformity of the ring and little fingers of the right hand. The distal interphalangeal joints are in hyperextension, which is a position that the hand cannot adopt unless the finger has suffered an accident or is rheumatic – the Boutonnière deformity.

The art historians among you will know that the artist's second wife, Hélène Fourment, was a model for the graces and was age 23 when the painting was completed. Rubens himself also suffered from a “gouty” arthritis of the hands, feet and knees. Rheumatologist Thierry Appelboom, writing in the “Heberden Historical Series” of Rheumatology, hypothesised that in Rubens’ home of Antwerp, in the early part of the 17th century, an infectious agent might have been imported by seafarers returning from the New World, resulting in an “epidemic” of rheumatoid arthritis (RA).¹

The best known environmental “finger on the trigger” is smoking tobacco. I became aware of the association through our cohort of 3358 Vietnam veterans, with 25 cases observed and 14.7 expected over the follow-up period, a standardised hospitalisation ratio of 1.70, 95 per cent confidence interval (CI) 1.03–2.36.

The mechanism is a little complex but known to be associated with citrullination of arginine. Citrulline is an amino acid, not coded in DNA, but produced from arginine via post-translational modification.

In RA, and also other autoimmune diseases such as systemic lupus erythematosus, citrullinated proteins are targeted by autoantibodies – anti-citrullinated protein antibodies (ACPAs), assayed in the clinic as anti-cyclic citrullinated peptides (anti-CCP antibody test).

Apart from RA, ACPAs are also found in the cell debris following neuronal destruction in Alzheimer disease, and after smoking tobacco.

The molecular basis arises from the alleles of the HLADRB1 gene – part of the major histocompatibility complex (MHC) on chromosome 6 – that encode a conserved five amino acid sequence in the third hypervariable region of the HLADR beta chain, known as the “shared epitope”. The SE is involved in presenting antigen to helper T-cells and is associated with RA susceptibility and with the presence of ACPAs in patients with RA.

The point, which I have come to at last, is that ACPApositive RA has a peculiar factor: the citrulline autoimmunity is initiated outside the joints, in the lung, and “primes” the immune system. A “second hit” initiates the transition from asymptomatic autoimmunity to inflammatory arthritis, and that could be from a viral infection, trauma or localised joint inflammation.

ACPA-negative RA has been more difficult to study because the search must be widened beyond the MHC – the associations between the HLA-DRB1 alleles and ACPA-negative RA are much weaker. We are on a hunt for the places in the genome where people differ. We are looking for differences in a single base pair of adenine, cytosine, thymine and guanine, the bonds between which form the “rungs of the ladder” in the DNA double helix. These are single nucleotide polymorphisms, or SNPs, most of which occur in non-coding areas and don’t impact on disease risk, but it is important to find the ones that do.

Don’t stop reading, we will keep the momentum going. In the words of the Bard, William Shakespeare, “once more unto the breach, dear friends, once more”.

We now have a mechanism by which an occupational exposure can cause RA. Silica exposure is a case in point. Recent meta-analyses have confirmed the association between occupational silica exposure and RA, as well as the interaction with smoking.^2,3 The mechanism is less clear, but it is certainly inflammatory in nature, with release of interleukins, particularly interleukin-1 beta, from pulmonary macrophages.

Having defined the mechanism, what does the epidemiology say, and will it help with risk management?

RA associated with occupation was first mentioned by Snorrason in 1951.⁴ He examined a total of 573 patients admitted to the Municipal Hospital of Bispebjerg, Copenhagen. The postulate was that RA was a disease of the lower classes of society – it was formerly called arthritis pauperum. Not so. School principals, those in business or the “liberal professions”, barristers, physicians, authors, etc, were just as prone as employees and “workmen”, the latter category including housemaids.

If you remember, epidemiological methods were undergoing development in the 1940s and 1950s. The cohort method, which is good for looking at rare exposures and risk of disease, was being used in cohorts of asbestos workers and “smoking doctors”.

The case-control design is good for finding the cause of disease, which is what they did in the Swedish Epidemiological Investigation of Rheumatoid Arthritis study between 1996 and 2013. In Sweden, almost all cases of RA are referred to a rheumatology unit, and with most of the rheumatology units participating, they ended up with 3973 cases enrolled in the study, along with 7681 controls.

Both cases and controls were asked to answer an extensive questionnaire, comprising questions on heredity, demography, socioeconomics, work history, lifestyle factors, environmental factors and psychosocial factors.

The results were presented by occupation, confirming that airborne exposures may have an effect – bricklayers and concrete workers (odds ratio [OR] 2.9, 95 per cent CI 1.4–5.7), material handling operators (OR 2.4, 95 per cent CI 1.3–4.4), and electrical and electronics workers (OR 2.1, 95 per cent CI 1.1–3.8) all had increased risk of ACPApositive RA.⁵

Bricklayers and concrete workers (OR 2.4, 95 per cent CI 1.0–5.7) and electrical and electronics workers (OR 2.6, 95 per cent CI 1.3–5.0) had increased risk of ACPA-negative RA. The only risk in women was for assistant nurses and attendants, for ACPA-positive disease (OR 1.3, 95 per cent CI 1.1–1.6).⁵

A subsequent review added farming, being in the military, scrap recycling and coal mining to the occupations with increased risk for developing RA, all of which are associated with airborne exposures and the latter with silica.⁶

The learning points here are, as usual, to take an occupational and environmental history in those with suspected RA (systemic upset with muscle and joint pains and stiffness), enquire about a second hit in terms of trauma or viral infection, ask for anti-CCP on the lab form, and get the patient to a rheumatologist with all due speed.

I would say make an ACC claim, but good luck with that. Unlike Rubens, I am graceless.

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