Bronchiectasis (BR) and smoking are risk factors for rheumatoid arthritis (RA) development. The mechanisms by which smoking and BR trigger RA are unknown, but are associated with concurrent rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) positivity. Anti-carbamylated protein antibodies (anti-CarP) have also been observed in BR patients and can be induced by smoking. Given that RF only has one antigen, immunoglobulin G (IgG) we have suggested that post-translational modifications to the Fc region of the heavy chain of IgG (IgGH) are a potential explanation for the clustering of the RA-associated autoantibodies in RA. Protein analysis was undertaken on 22 individuals. Four of the individuals had a diagnosis of BR at the time of protein analysis and subsequently developed RA up to 18 months following blood sampling. Four smoking RA patients and 4 patients with both BR and RA and 10 healthy controls were also studied. We identified modified arginines (Arg) frequently in the variable region and CH3 domains of IgG in patients and control subjects alike, but only observed carbamylated Lys and/or citrullinated Arg modifications in the RF binding site of the IgG CH2 domain of 5/12 (41.7%) patients investigated (1 BR, 2 RA and 2 BRRA), but in no control subjects (0/10, 0%) p=0.02. This is the first report of citrullination and carbamylation at the RF binding site of IgG in RA. These results point towards the concept of a universal antigen in RA, an antigen that is post-translationally modified at the Fc region of IgGH.

Multiple chronic disease risks have been identified in Italian furnace workers. A range of potential toxins have been identified in foundry dust. We suggest that the heavy metal cadmium (Cd) plays an important role in the development of chronic diseases, notably rheumatoid arthrits, and propose that research into the mechanism of action be undertaken to discover the aetiology of this link.

Competing interests We confirm that this manuscript constitutes the original work of the authors detailed above and is not under consideration for publication elsewhere. The authors confirm that they have no conflicts of interest to declare in the preparation of this work, having equal data access and all had a role in preparation of the letter as detailed above.

We read with interest the report on rheumatologic disease risk (including seropositive rheumatoid arthritis) associated with occupational dust exposure in male construction workers.1Blanc P.D. Järvholm B. Torén K. Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.Am J Med. 2015; 128: 1094-1101Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar We welcome the important finding of non-silica-based inorganic dust as an independent risk factor for rheumatoid arthritis. However, we would be interested to know if the cohort of those exposed to wood dust excluded from the study are also at increased risk. We have found a strikingly high prevalence (18%) of carpentry in our male rheumatoid arthritis population in Cornwall, UK (n = 398). Wood dust exposure has long been linked with pulmonary disease.2Jacobsen G. Schaumburg I. Sigsgaard T. Schlünssen V. Non-malignant respiratory diseases and occupational exposure to wood dust. Part I. Fresh wood and mixed wood industry.Ann Agric Environ Med. 2010; 17: 15-28PubMed Google Scholar Emerging literature suggests that the initiation of seropositive rheumatoid arthritis occurs in the lung via citrullination.3Perry E. Kelly C. Eggleton P. De Soyza A. Hutchinson D. The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury?.Rheumatology. 2014; 53: 1940-1950Crossref PubMed Scopus (36) Google Scholar Blanc et al1Blanc P.D. Järvholm B. Torén K. Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.Am J Med. 2015; 128: 1094-1101Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar demonstrate that among ever smokers, both silica and other inorganic dust exposure associate with increased rheumatoid arthritis risk (relative risk 1.36; 95% confidence interval [CI], 1.11-1.68 and 1.42; 95% CI, 1.17-1.73, respectively). Among never smokers, neither exposure was associated with a significantly raised rheumatoid arthritis risk. This may be explained by concurrent exposures to cadmium within cigarette smoke and the dusts described above. Cadmium-containing cigarette smoke upregulates calreticulin expression and subsequent potential citrullination.4Hutchinson D. Cadmium, one of the villains behind the curtain: has exposure to cadmium helped to pull the strings of seropositive rheumatoid arthritis pathogenesis all along?.Int J Rheum Dis. 2015; 18: 570-573Crossref PubMed Scopus (25) Google Scholar, 5Hinkle P.M. Shanshala E.D. Nelson E.J. Measurement of intracellular cadmium with fluorescent dyes. Further evidence for the role of calcium channels in cadmium uptake.J Biol Chem. 1992; 267: 25553-25559Abstract Full Text PDF PubMed Google Scholar, 6Nguyen T.O. Capra J.D. Sontheimer R.D. Calreticulin is transcriptionally upregulated by heat shock, calcium and heavy metals.Mol Immunol. 1996; 33: 379-386Crossref PubMed Scopus (67) Google Scholar Silica and carbon nanoparticles induce citrullination of cytokeratins and plectins, but not calreticulin.7Mohamed B.M. Verma N.K. Davies A.M. et al.Citrullination of proteins: a common post-translational modification pathway induced by different nanoparticles in vitro and in vivo.Nanomedicine (Lond). 2012; 7: 1181-1195Crossref PubMed Scopus (73) Google Scholar Citrullinated calreticulin is overabundant in the rheumatoid arthritis synovium and enhances shared epitope-activated signaling.8Ling S. Cline E.N. Haug T.S. Fox D.A. Holoshitz J. Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling.Arthritis Rheum. 2013; 65: 618-626Crossref PubMed Scopus (47) Google Scholar Woodworkers may have a greatly enhanced risk of rheumatoid arthritis independent of smoking due to a combined occupational exposure to silica, wood-derived carbon nanoparticles, and cadmium. It would be of great interest to learn how occupational wood dust exposure compares with inorganic dust exposure for imparting excess risk of rheumatologic disease. Prospective Risk of Rheumatologic Disease Associated with Occupational Exposure in a Cohort of Male Construction WorkersThe American Journal of MedicineVol. 128Issue 10PreviewThe association between occupational exposure and autoimmune disease is well recognized for silica, and suspected for other inhalants. We used a large cohort to estimate the risks of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and dermatomyositis associated with silica and other occupational exposures. Full-Text PDF