The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
REVIEW ARTICLE

Is Male Rheumatoid Arthritis an Occupational Disease? A Review



Dan Murphy1, 2, 3, *, David Hutchinson1, 2
1 Rheumatology Department, Royal Cornwall Hospital, Truro, Cornwall TR1 3LH, UK
2 University of Exeter Medical School, Cornwall Campus, Knowledge Spa, Truro, Cornwall, TR1 3HD, UK
3 St. Austell Healthcare Group, Wheal Northey Surgery, St Austell, Cornwall, PL25 3EF, UK

Abstract

Background:

Rheumatoid arthritis (RA) is a systemic, inflammatory disease with an estimated global prevalence of 0.3–1.0%. An unexplained association exists between low formal education and the development of RA independent of smoking. It is established that RA is initiated in the lungs and that various occupations associated with dust, fume and metal inhalation can increase the risk of RA development.

Objective:

The objective of this review is to evaluate published clinical reports related to occupations associated with RA development. We highlight the concept of a “double-hit” phenomenon involving adsorption of toxic metals from cigarette smoke by dust residing in the lung as a result of various work exposures. We discuss the relevant pathophysiological consequences of these inhalational exposures in relation to RA associated autoantibody production.

Method:

A thorough literature search was performed using available databases including Pubmed, Embase, and Cochrane database to cover all relative reports, using combinations of keywords: rheumatoid arthritis, rheumatoid factor, anti-citrullinated peptide antibody silica, dust, fumes, metals, cadmium, cigarette smoking, asbestos, mining, bronchial associated lymphoid tissue, heat shock protein 70, and adsorption.

Conclusion:

We postulate that the inhalation of dust, metals and fumes is a significant trigger factor for RA development in male patients and that male RA should be considered an occupational disease. To the best of our knowledge, this is the first review of occupations as a risk factor for RA in relation to the potential underlying pathophysiology.

Keywords: Silica, Dust, Occupation, Inhalation, Cadmium, Cigarette smoking, Bronchial associated lymphoid tissue, Adsorption, Rheumatoid arthritis.


Article Information


Identifiers and Pagination:

Year: 2017
Volume: 11
First Page: 88
Last Page: 105
Publisher Id: TORJ-11-88
DOI: 10.2174/1874312901711010088

Article History:

Received Date: 17/05/2017
Revision Received Date: 21/06/2017
Acceptance Date: 09/07/2017
Electronic publication date: 27/07/2017
Collection year: 2017

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© 2017 Murphy and Hutchinson.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Rheumatology Department, Royal Cornwall Hospital, Truro, TR1 3LH, UK; Tel: 01872 250000; E-mail: daniel.murphy8@nhs.net




1. INTRODUCTION

1.1. Background

Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease with an estimated global prevalence of 0.3–1.0% [1World Health Organization Chronic rheumatic conditions Available at: http://www.who.int/chp/topics/rheumatic/en/ Accessed on: 9th May], and primarily targets the small joints of the hands [2Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423(6937): 356-61.
[http://dx.doi.org/10.1038/nature01661] [PMID: 12748655]
]. The overall cost to the individual with RA as a consequence of fatigue, joint inflammation and the subsequent development of joint deformities are impaired physical functioning, reduced work productivity and activities of daily living [3Englbrecht M, Kruckow M, Araujo E, Rech J, Schett G. The interaction of physical function and emotional well-being in rheumatoid arthritis--what is the impact on disease activity and coping? Semin Arthritis Rheum 2013; 42(5): 482-91.
[http://dx.doi.org/10.1016/j.semarthrit.2012.09.003] [PMID: 23369659]
]. The overall economic cost of RA to society is substantial. A study of RA patients in Norfolk UK with longstanding disease of 10-15 years reported an annual cost of approximately £3000 per patient (2013 prices) for direct health care alone [4Nikiphorou E, Davies C, Mugford M, et al. Direct health costs of inflammatory polyarthritis 10 years after disease onset: results from the Norfolk Arthritis Register. J Rheumatol 2015; 42(5): 794-8.
[http://dx.doi.org/10.3899/jrheum.140528] [PMID: 25834202]
]. Therefore studies identifying potential causes of RA that are avoidable and are of huge importance to at risk individuals and also wider society.

Literature has established the lung as a primary site for disease development [5Perry E, Kelly C, Eggleton P, De Soyza A, Hutchinson D. The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury? Rheumatology (Oxford) 2014; 53(11): 1940-50.
[http://dx.doi.org/10.1093/rheumatology/keu195] [PMID: 24831057]
], although the exact aetiology remains unclear. Whilst genetic susceptibility plays a role, concordance rates of 9.1% (95% CI 1.9 to 24.3) in monozygotic twins have been found [6Svendsen AJ, Kyvik KO, Houen G, et al. On the origin of rheumatoid arthritis: The impact of environment and genes--a population based twin study. PLoS One 2013; 8(2): e57304.
[http://dx.doi.org/10.1371/journal.pone.0057304] [PMID: 23468964]
] suggesting that environmental factors are of great importance regarding the pathogenesis of RA.

Cigarette smoking has emerged as an important risk factor for RA, with a strong association between ever smoking and RA in monozygotic twin pairs demonstrating an odds ratio (OR) 12.0, (95% CI 1.78–513) [7Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum 1996; 39(5): 732-5.
[http://dx.doi.org/10.1002/art.1780390504] [PMID: 8639169]
]. Smoking, as the most important environmental trigger factor for RA, associates with rheumatoid factor (RF) and antibodies to citrullinated peptide antigens (ACPA) rather than RF and ACPA negative RA [8Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 2003; 62(9): 835-41.
[http://dx.doi.org/10.1136/ard.62.9.835] [PMID: 12922955]
].

Further inhaled environmental risk factors for RA have been suggested including exposure to silica [9Klockars M, Koskela RS, Järvinen E, Kolari PJ, Rossi A. Silica exposure and rheumatoid arthritis: a follow up study of granite workers 1940-81. Br Med J (Clin Res Ed) 1987; 294(6578): 997-1000.
[http://dx.doi.org/10.1136/bmj.294.6578.997] [PMID: 2823951]
-13Blanc PD, 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(10): 1094-101.
[http://dx.doi.org/10.1016/j.amjmed.2015.05.001] [PMID: 26007670]
], construction work [13Blanc PD, 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(10): 1094-101.
[http://dx.doi.org/10.1016/j.amjmed.2015.05.001] [PMID: 26007670]
-15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
], asbestos [16Olsson ÅR, Skogh T, Axelson O, Wingren G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med 2004; 61(3): 233-8.
[http://dx.doi.org/10.1136/oem.2003.007971] [PMID: 14985518]
, 17Noonan CW, Pfau JC, Larson TC, Spence MR. Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect 2006; 114(8): 1243-7.
[http://dx.doi.org/10.1289/ehp.9203] [PMID: 16882533]
], mineral oils [18Sverdrup B, Källberg H, Bengtsson C, et al. Association between occupational exposure to mineral oil and rheumatoid arthritis: Results from the Swedish EIRA case-control study. Arthritis Res Ther 2005; 7(6): R1296-303.
[http://dx.doi.org/10.1186/ar1824] [PMID: 16277683]
, 19Lundberg I, Alfredsson L, Plato N, Sverdrup B, Klareskog L, Kleinau S. Occupation, occupational exposure to chemicals and rheumatological disease. A register based cohort study. Scand J Rheumatol 1994; 23(6): 305-10.
[http://dx.doi.org/10.3109/03009749409099278] [PMID: 7801054]
] farming and pesticide exposure [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
, 16Olsson ÅR, Skogh T, Axelson O, Wingren G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med 2004; 61(3): 233-8.
[http://dx.doi.org/10.1136/oem.2003.007971] [PMID: 14985518]
, 19Lundberg I, Alfredsson L, Plato N, Sverdrup B, Klareskog L, Kleinau S. Occupation, occupational exposure to chemicals and rheumatological disease. A register based cohort study. Scand J Rheumatol 1994; 23(6): 305-10.
[http://dx.doi.org/10.3109/03009749409099278] [PMID: 7801054]
, 20Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. Rheumatoid arthritis in agricultural health study spouses: Associations with pesticides and other farm exposures. Environ Health Perspect 2016; 124(11): 1728-34.
[PMID: 27285288]
], electrical and electronics work [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
, 15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
], textiles [21Too CL, Muhamad NA, Ilar A, et al. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study. Ann Rheum Dis 2016; 75(6): 997-1002.
[http://dx.doi.org/10.1136/annrheumdis-2015-208278] [PMID: 26681695]
] and roadside dust [22Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect 2009; 117(7): 1065-9.
[http://dx.doi.org/10.1289/ehp.0800503] [PMID: 19654914]
, 23De Roos AJ, Koehoorn M, Tamburic L, Davies HW, Brauer M. Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis. Environ Health Perspect 2014; 122(10): 1075-80.
[http://dx.doi.org/10.1289/ehp.1307413] [PMID: 24905961]
]. Specific occupations have been associated with ACPA positive RA [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
, 15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
, 18Sverdrup B, Källberg H, Bengtsson C, et al. Association between occupational exposure to mineral oil and rheumatoid arthritis: Results from the Swedish EIRA case-control study. Arthritis Res Ther 2005; 7(6): R1296-303.
[http://dx.doi.org/10.1186/ar1824] [PMID: 16277683]
, 20Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. Rheumatoid arthritis in agricultural health study spouses: Associations with pesticides and other farm exposures. Environ Health Perspect 2016; 124(11): 1728-34.
[PMID: 27285288]
, 22Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect 2009; 117(7): 1065-9.
[http://dx.doi.org/10.1289/ehp.0800503] [PMID: 19654914]
].

Citrullination of proteins in the lungs, as found in the longevity-associated RA risk identified in cigarette smoke inhalation [24Di Giuseppe D, Orsini N, Alfredsson L, Askling J, Wolk A. Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women. Arthritis Res Ther 2013; 15(2): R56.
[http://dx.doi.org/10.1186/ar4218] [PMID: 23607815]
], could equally be applied to other inhalational exposures [25Klareskog L, Malmström V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol 2011; 23(2): 92-8.
[http://dx.doi.org/10.1016/j.smim.2011.01.014] [PMID: 21376627]
]. Such exposures predominantly relate to occupation in male populations, though evidence exists linking RA risk to female occupational inhalation, such as recently seen in textile workers [21Too CL, Muhamad NA, Ilar A, et al. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study. Ann Rheum Dis 2016; 75(6): 997-1002.
[http://dx.doi.org/10.1136/annrheumdis-2015-208278] [PMID: 26681695]
] and inhalational exposures in the wider environment [20Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. Rheumatoid arthritis in agricultural health study spouses: Associations with pesticides and other farm exposures. Environ Health Perspect 2016; 124(11): 1728-34.
[PMID: 27285288]
, 22Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect 2009; 117(7): 1065-9.
[http://dx.doi.org/10.1289/ehp.0800503] [PMID: 19654914]
, 25Klareskog L, Malmström V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol 2011; 23(2): 92-8.
[http://dx.doi.org/10.1016/j.smim.2011.01.014] [PMID: 21376627]
, 26Murphy D, Pay J, Benham R, James B, Hutchinson D. Comment on “Rheumatoid arthritis in agricultural health study spouses: Associations with pesticides and other farm exposures”. Environ Health Perspect 2016; 124(11): A196.
[http://dx.doi.org/10.1289/EHP730] [PMID: 27801652]
].

1.2. Key question

Why do people exposed to workplace dust or fumes in addition to cigarette smoke demonstrate a greatly elevated risk of RA?

1.3. Hypothesis

In short, we suggest that RA should be considered an occupational disease as a consequence of dust and fume inhalation in the workplace, as such exposures stimulate immune tolerance breakdown. Furthermore, these exposures form a lung substrate that can adsorb heavy metals from other environmental sources such as cigarette smoke.

We argue that metals have the potential to induce lymphoid tissue in the lung, generating ACPA and RF production locally. We highlight the process of adsorption as critical for RA disease development in men and discuss the pathophysiology of autoantibody generation resulting from occupational inhalation in stimulating RA disease development.

2. METHODS

A literature search was performed using Pubmed, Embase, and Cochrane databases and to cover all relative reports. Titles and abstracts of identified articles were screened for eligibility and relevance to the key question and a priori hypothesis generation as detailed above. Duplicates and reports generated that were not relevant to the study aims were removed. Reference lists of relevant articles were searched for further evidence by hand around mechanisms of action and further hypothesis refinement.

2.1. Occupational Exposure

Initial searches were conducted using the following keywords: “occupation OR mining OR silica”, in combination with disease specific term “Rheumatoid arthritis”. Subsequent searches of disease and exposure detail were made using the terms “Rheumatoid factor OR anti-citrullinated protein antibody/ies”, AND “silica OR dust OR fumes OR metals OR cadmium OR asbestos OR mining”. A separate search was made using the combination terms “rheumatoid AND smoking AND occupation”. Following hypothesis generation and in the process of refinement, further searches were made using the combination terms “Rheumatoid arthritis AND bronchial associated lymphoid tissue OR adsorption OR heat shock protein 70”.

Fig. (1)
Literature retrieval flowchart.


2.2. Appraisal

For occupational exposures, studies were examined for information relevant to output fields of sex, country of study, follow up period and exposure type. Reported or calculable RA risk being statistically significant for increased RA risk (with lower 95% confidence interval greater than 1.0) was used for inclusion.

2.3. Integration

For critical review purposes, statistically significant data pertaining to increased RA risk in male occupational exposures was integrated into a single Table 1, for descriptive comparison. Data not reaching statistical significance was not included in the table, though elements of non-statistical significance are included in the discussion. Heterogeneity in study populations, comparison groups and outcome measures precluded further pooled analysis or systematic review.

Table 1
Occupational exposures previously found to demonstrate significantly increased RA risk in males.


3. INHALATIONAL WORKPLACE EXPOSURES

3.1. Mining/ Quarry Workers

Mining has long been associated with RA [27Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953; 8(1): 29-37.
[http://dx.doi.org/10.1136/thx.8.1.29] [PMID: 13038735]
]. A cohort follow up study of 1026 Finnish granite quarry and processing yard workers from 1940-1981, demonstrated RA incidence rate ratio (defined as award to disability pension for RA), over five times higher than expected, compared to general population statistics. Silica exposure was postulated as the primary mechanism of aetiology [9Klockars M, Koskela RS, Järvinen E, Kolari PJ, Rossi A. Silica exposure and rheumatoid arthritis: a follow up study of granite workers 1940-81. Br Med J (Clin Res Ed) 1987; 294(6578): 997-1000.
[http://dx.doi.org/10.1136/bmj.294.6578.997] [PMID: 2823951]
]. Interestingly, RA was seen in the absence of frank silicosis, suggesting silicosis per se does not account for the observed increased risk of RA and an alternate pathophysiology is likely.

Stolt et al. [11Stolt P, Yahya A, Bengtsson C, et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis 2010; 69(6): 1072-6.
[http://dx.doi.org/10.1136/ard.2009.114694] [PMID: 19966090]
] found elevated ACPA+ RA risk in silica exposed Swedish quarry workers compared to unexposed controls (OR 1.67, 95% CI 1.13–2.48), but no increased risk of ACPA- RA when compared to unexposed controls. This was particularly evident amongst men exposed to stone dust and rock drilling. In terms of outcome, Swedish miners and quarry workers have also demonstrated the highest and most consistent standardised incidence ratios (SIR) across three cohorts of patients hospitalised due to RA (SIR 1.4, 95% CI 1.0-1.9 for 43 RA miners as per 1960 and 1970 census data) [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
].

An association was seen in mortality odds ratio between postulated silica exposure and RA (OR 1.19, 95% CI 1.12-1.25) on analysis of death certificate data from 27 USA states from 1982-1995 [12Calvert GM, Rice FL, Boiano JM, Sheehy JW, Sanderson WT. Occupational silica exposure and risk of various diseases: an analysis using death certificates from 27 states of the United States. Occup Environ Med 2003; 60(2): 122-9.
[http://dx.doi.org/10.1136/oem.60.2.122] [PMID: 12554840]
]. Comparing 15/1237 RA silicotics with 20/6185 RA controls, this study was limited by the death certificate record of occupation rather than complete occupational history, and diseases/conditions contributing to cause of death. Categorisation of silica exposure was made based on occupation type rather than duration or intensity of exposure. However, stringent exclusion criteria would suggest bias towards the null hypothesis, suggesting that the significant risks presented may be an underestimate.

Mining has long been associated with extra-articular RA manifestations such as pulmonary nodules. Caplan’s syndrome, first described in 1953, classically occurs in coal dust exposed RA cases, characterised by development of pulmonary nodules 0.5-5cm throughout the lung field, distinct from silicosis [27Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953; 8(1): 29-37.
[http://dx.doi.org/10.1136/thx.8.1.29] [PMID: 13038735]
]. Given that the lung is an important site of RA initiation [5Perry E, Kelly C, Eggleton P, De Soyza A, Hutchinson D. The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury? Rheumatology (Oxford) 2014; 53(11): 1940-50.
[http://dx.doi.org/10.1093/rheumatology/keu195] [PMID: 24831057]
], this is of contemporary interest in RA aetiology. Radiological changes of Caplan’s syndrome can precede RA development, and regional differences in the incidence of Caplan’s syndrome in coal miners have been noted [28De Capitani EM, Schweller M, Silva CM, Metze K, Cerqueira EM, Bértolo MB. Rheumatoid pneumoconiosis (Caplan’s syndrome) with a classical presentation. J Bras Pneumol 2009; 35(9): 942-6.
[http://dx.doi.org/10.1590/S1806-37132009000900017] [PMID: 19820822]
]. Underground coal miners in Staffordshire, UK, demonstrated a significantly increased risk of RA development (OR 8.47, 95% CI 2.59 to 27.66) [29Turner S, Cherry N. Rheumatoid arthritis in workers exposed to silica in the pottery industry. Occup Environ Med 2000; 57(7): 443-7.
[http://dx.doi.org/10.1136/oem.57.7.443] [PMID: 10854495]
]. Workers exposed to Kaolin (China clay) dust demonstrate the highest prevalence of Caplan’s syndrome ever reported, 12 times higher than the prevalence noted in coal dust associated pneumoconiosis claimants (2/68, 3% [30Wells IP, Bhatt RC, Flanagan M. Kaolinosis: a radiological review. Clin Radiol 1985; 36(6): 579-82.
[http://dx.doi.org/10.1016/S0009-9260(85)80237-3] [PMID: 4064542]
] vs. 37/14000, 0.26% [27Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953; 8(1): 29-37.
[http://dx.doi.org/10.1136/thx.8.1.29] [PMID: 13038735]
]). This raises intriguing questions as to the common components of inhaled dust responsible for RA pulmonary nodule development, and suggests that both dusts are implicated in RA development.

3.2. Construction Workers

Elevated RA risk has been demonstrated amongst construction workers. Li et al. found significantly elevated risk amongst three cohorts of general construction workers studied, with SIR of 1.4 (95% CI 1.2-1.6), for RA hospitalisations 1964-2004 comparing to census data for occupations over census periods covering 1960-1970 [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
]. No elevated SIR was seen amongst woodworkers or bricklayers. A recent abstract on the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study of 3295 new RA cases in defined Swedish geographical areas compared to 4912 controls, suggested an OR of 2.6 (95% CI 1.3-4.9) for bricklayers and concrete workers [15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
]. However, this abstract does not detail actual numbers in the trades listed, and whilst the authors report that results are adjusted for smoking, no methodology is given. Furthermore, the authors included patients aged 18-70, and only report “last occupation” listed. Given the longevity of risk from the known inhalational insult of smoking [24Di Giuseppe D, Orsini N, Alfredsson L, Askling J, Wolk A. Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women. Arthritis Res Ther 2013; 15(2): R56.
[http://dx.doi.org/10.1186/ar4218] [PMID: 23607815]
], some acknowledgement of risk longevity conferred by other inhalational exposures would be expected. With the notable exception of mineral oil exposure, polarisation of RA risk estimates occurs when a latency period is used in occupational exposures [18Sverdrup B, Källberg H, Bengtsson C, et al. Association between occupational exposure to mineral oil and rheumatoid arthritis: Results from the Swedish EIRA case-control study. Arthritis Res Ther 2005; 7(6): R1296-303.
[http://dx.doi.org/10.1186/ar1824] [PMID: 16277683]
], indicating a long induction period between exposure and RA development. Ergo, an upper age cut off of 70 years may miss those occupationally exposed cases over the age of 50, who may not present until well into their 70s and crucially will not account for multiple occupational co-exposures.

Asbestos exposure, commonly found in historical building trade populations, was found to be an RA risk factor amongst 12/74 incident cases compared to 19/382 referents in multivariate analysis of lifelong occupational exposures (OR 2.5, 95% CI 1.0-6.8) [16Olsson ÅR, Skogh T, Axelson O, Wingren G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med 2004; 61(3): 233-8.
[http://dx.doi.org/10.1136/oem.2003.007971] [PMID: 14985518]
]. Further evidence is found in a case-control study of community residents and workers exposed to asbestos contaminated vermiculite in Montana, USA, who demonstrated a strikingly elevated RA risk in those aged over 65 (OR 3.23 (95% CI 1.31-7.96) [17Noonan CW, Pfau JC, Larson TC, Spence MR. Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect 2006; 114(8): 1243-7.
[http://dx.doi.org/10.1289/ehp.9203] [PMID: 16882533]
]. Interestingly, no significant increased risk was seen in those aged under 65, further highlighting the need to acknowledge a latency period between exposure and disease development.

3.3. Electrical Workers and Workers Exposed to Metal Fumes

Electrical workers demonstrated a non-significant, though consistent elevated RA hospitalisation risk (OR 1.1-1.3, (95% CI 1.0-1.3) [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
]. Ilar et al. suggest an OR of 1.8 (95%CI 1.0-3.1) for ACPA+ RA, and OR 2.1 (95%CI 1.1-4.0) for ACPA- RA, amongst electrical and electronics workers [15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
]. In the UK, electricians represent a subset of construction industry workers with multiple co-exposures. Inhalation of silica, non-silica inorganic, and organic dusts from physical interactions with building industry substrates. Activities such as drilling and chiselling out concrete, wood and gypsum plasterboard are likely to be relevant. Further specific aspects to electrical work involve handling and assembly of componentry that exposes workers to metal fumes. Toxic elements (such as cadmium) have been sequentially reduced and eliminated from solder, plastics and brazing fillers in modern European applications [31 COMMISSION REGULATION (EU) No 494/2011. Amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annex XVII (Cadmium), 2011.]. However, a longitudinal study of ten workers exposed to silver solder in the UK demonstrated the longevity of historical heavy metal fume exposure [32Mason HJ, Williams N, Armitage S, et al. Follow up of workers previously exposed to silver solder containing cadmium. Occup Environ Med 1999; 56(8): 553-8.
[http://dx.doi.org/10.1136/oem.56.8.553] [PMID: 10492654]
].

Other direct metal fume exposed trades demonstrate increased RA risk. An increased RA risk was reported in 29/74 Swedish mechanics, sheet metal workers and welders (OR 1.8, 95% CI 1.0-3.4) [16Olsson ÅR, Skogh T, Axelson O, Wingren G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med 2004; 61(3): 233-8.
[http://dx.doi.org/10.1136/oem.2003.007971] [PMID: 14985518]
]. A single cohort of Li et al’s study [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
] showed a significantly elevated SIR of 1.2 (95%CI 1.1-1.4) amongst foundry workers, with two large cohorts of mechanics and metal workers demonstrating slight, though insignificant, SIR of 1.1 (95%CI 1.0-1.1) and 1.0 (95% CI 1.0-1.1) respectively. Ilar et al. [15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
] suggest an OR of 2.6 (OR 1.0-7.4) for ACPA+ RA in smelters and metal foundry workers. A retrospective cohort study of workers recycling scrap metals at an electrical arc furnace in Italy noted 3/331 incident cases of RA over a 20 year follow up period, a dramatically increased RR of 6.18 (95%CI 2.00-19.02), when compared to 420/20332 incident RA cases in the same town over the same period [33Cappelletti R, Ceppi M, Claudatus J, Gennaro V. Health status of male steel workers at an electric arc furnace (EAF) in Trentino, Italy. J Occup Med Toxicol 2016; 11: 7.
[http://dx.doi.org/10.1186/s12995-016-0095-8] [PMID: 26900394]
]. Despite the relatively small sample size and lack of directly comparable working group, this cohort demonstrated an appreciably elevated RA risk, thought due to foundry dust exposure containing a range of potential toxins including heavy metals [34Murphy D, James B, Hutchinson D. Could the significantly increased risk of rheumatoid arthritis reported in Italian male steel workers be explained by occupational exposure to cadmium? J Occup Med Toxicol 2016; 11: 21.
[http://dx.doi.org/10.1186/s12995-016-0111-z] [PMID: 27152117]
].

3.4. Mechanics and Workers Exposed to Mineral Oils

In an analysis of 281 cases to 507 referents aged 25-75 years presenting to a single secondary care hospital in southeast Sweden, an increased though non-significant RA risk was seen amongst machine and engine repairers (OR 2.1, 95% CI 0.8-5.6), with specific exposure to hydraulic oils demonstrating an OR of 1.8, (95% CI 0.7-4.3) [35Olsson ÅR, Skogh T, Wingren G. Occupational determinants for rheumatoid arthritis. Scand J Work Envron Health 2000; pp. 243-9.]. Li et al. found that engine and motor operators demonstrated consistent though insignificant SIR elevation across three cohorts (SIR 1.1-1.2, 95% CI 1.0-1.5 combined) [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
].

A report on the EIRA study compared 135 RA males exposed to different types of mineral oil to 132 controls, comparing seropositive and seronegative RA [18Sverdrup B, Källberg H, Bengtsson C, et al. Association between occupational exposure to mineral oil and rheumatoid arthritis: Results from the Swedish EIRA case-control study. Arthritis Res Ther 2005; 7(6): R1296-303.
[http://dx.doi.org/10.1186/ar1824] [PMID: 16277683]
]. Exposure to any mineral oil demonstrated an increased risk (OR 1.3, 95%CI 1.0-1.3), with motor oil exposure (OR 1.2, 95%CI 0.9-1.8) carrying higher risk than others. When subdivided by autoantibody positivity, significantly increased risk to any mineral oil exposure was only seen in seropositive disease (ACPA+ OR 1.6, 95%CI 1.1-2.2). No significant increased risk for asphalt exposure was seen, unlike findings elsewhere (OR 14.0, 95%CI 1.2-99.9), albeit in limited numbers (4 cases: 1 referent) [16Olsson ÅR, Skogh T, Axelson O, Wingren G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med 2004; 61(3): 233-8.
[http://dx.doi.org/10.1136/oem.2003.007971] [PMID: 14985518]
]. Limited correction for smoking was made via “ever” and “never” smoker categories. The authors noted a possible interaction between smoking and mineral oil exposure, but report an inability to reach a firm conclusion due to small numbers (ACPA+ RA attributable portion due to interaction= 0.5, 95%CI -0.2-1.2). No attributable portion was reported for RF+ RA.

3.5. Farm Workers

Farming has long been associated with increased RA risk. A small but persistent SIR was noted in 821 RA farmers in Li et al's combined cohort as per 1960-1970 data (SIR 1.1, 95% CI 1.1-1.2) [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
]. A further study of incident cases in Sweden found an OR 2.4 (95% CI 1.1-5.2) amongst 20 farm worker RA cases to 41 referents [16Olsson ÅR, Skogh T, Axelson O, Wingren G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med 2004; 61(3): 233-8.
[http://dx.doi.org/10.1136/oem.2003.007971] [PMID: 14985518]
]. Interestingly, this study examined potential exposures which farm workers may encounter. On multivariate analysis with adjustment for age and smoking, no statistically significant increased risk was found for exposure to pesticides, farm animals, mineral oils or organic dusts. However, subsequent pooled analysis of specific occupational exposures with at least 50 exposed subjects amongst 176 cases and 630 referents, with adjustment for age and smoking, showed statistically significant increased risk amongst those exposed to crops and forage (OR 3.2, 95% CI 1.6-6.7 for >20 years exposure), and for fertilisers (OR 3.0, 95% CI 1.3-3.8). No dose-duration relationship was observed.

A longitudinal American study of 23570 spouses of pesticide license applicants from 1993-1997 found no association of RA with growing up on a farm or years living on a farm, on structured follow up interview in 2010 [19Lundberg I, Alfredsson L, Plato N, Sverdrup B, Klareskog L, Kleinau S. Occupation, occupational exposure to chemicals and rheumatological disease. A register based cohort study. Scand J Rheumatol 1994; 23(6): 305-10.
[http://dx.doi.org/10.3109/03009749409099278] [PMID: 7801054]
]. Detailed exposure analysis of 271 RA cases revealed increased risk from lifetime pesticide use (OR 1.4, 95% CI 1.0-1.6), and application of chemical fertilizers (OR 1.7, 95% CI 1.1-2.7). Amongst specific pesticides examined, an elevated but non-significant risk was seen for DDT (OR 1.9, 95% CI 0.97-3.6). Significant risks were seen for maneb/ manecozeb fungicides (OR 3.3, 95% CI 1.5-7.1), and chemical fertilizers (OR 1.7, 95% CI 1.1-2.7).

4. DISCUSSION

Low formal education has consistently been found to be associated with RA [36Uhlig T, Hagen KB, Kvien TK. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol 1999; 26(1): 47-54.
[PMID: 9918239]
-38Bergström U, Jacobsson LT, Nilsson JÅ, Wirfält E, Turesson C. Smoking, low formal level of education, alcohol consumption, and the risk of rheumatoid arthritis. Scand J Rheumatol 2013; 42(2): 123-30.
[http://dx.doi.org/10.3109/03009742.2012.723744] [PMID: 23126587]
]. All the occupations listed in Table 1 require no formal academic qualifications and it is noteworthy that no study as yet has considered an individual’s occupation as a confounding factor when considering low formal education levels as a risk factor for RA development. Likewise the stark contrast in mortality reported by Pincus et al. [39Pincus T, Callahan LF. Formal education as a marker for increased mortality and morbidity in rheumatoid arthritis. J Chronic Dis 1985; 38(12): 973-84.
[http://dx.doi.org/10.1016/0021-9681(85)90095-5] [PMID: 4066893]
] in RA patients over a nine year period with a low formal education (45% mortality) compared to those with the highest formal education (5% mortality) has not been explained. However, occupations undertaken by working class individuals that expose them to vapours, gas, dust or fumes greatly increases the risk of chronic obstructive pulmonary disease (COPD) particularly in smokers, with an OR 14.1 (9.33-21.2) compared to never smokers with no such work exposures [40Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of COPD: dusty trades revisited. Thorax 2009; 64(1): 6-12.
[http://dx.doi.org/10.1136/thx.2008.099390] [PMID: 18678700]
]. The “double-hit” of occupational exposure and smoking combined risk was far higher than the OR of 6.71 (4.58-9.82) in those smokers without such work exposures (Fig. 2).

Whist the contribution of occupational exposures to chronic obstructive airways disease has been acknowledged [41Balmes J, Becklake M, Blanc P, et al. American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003; 167(5): 787-97.
[http://dx.doi.org/10.1164/rccm.167.5.787] [PMID: 12598220]
], these occupations demonstrate only modest odds ratio rises in non-smokers. This is exemplified by Blanc’s study where significant but only modest differences were seen in never smokers when combined into broad categories of vapours, gas, dust and fume exposure in the longest held occupation (OR 1.98 (1.26-3.09) [40Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of COPD: dusty trades revisited. Thorax 2009; 64(1): 6-12.
[http://dx.doi.org/10.1136/thx.2008.099390] [PMID: 18678700]
]. The impact of these exposures becomes particularly apparent when occurring in combination with smoking Fig. (2). This phenomenon is highly relevant to RA as men who work in dusty trades are highly likely to have smoked as the vast majority of male RA patients have been smokers (77%) [8Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 2003; 62(9): 835-41.
[http://dx.doi.org/10.1136/ard.62.9.835] [PMID: 12922955]
].

Fig. (2)
COPD risk: interaction between smoking and vapour/gas/dust/fume (VGDF) exposure. Adapted from Blanc et al [40Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of COPD: dusty trades revisited. Thorax 2009; 64(1): 6-12.
[http://dx.doi.org/10.1136/thx.2008.099390] [PMID: 18678700]
].


Occupational risk alongside smoking delivers a substantial “double-hit” for disease development. For example, silica dust exposure and smoking combined confer an increased risk of ACPA positive RA [11Stolt P, Yahya A, Bengtsson C, et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis 2010; 69(6): 1072-6.
[http://dx.doi.org/10.1136/ard.2009.114694] [PMID: 19966090]
, 15Ilar A, Wiebert P, Klareskog L, Alfredsson L, Bengtsson C. Occupation and risk of developing rheumatoid arthritis. In: American College of Rheumatology Meeting Abstracts number:2016. 2014. Available at: http://acrabstracts.org/ abstract/occupation-and-risk-of-developing-rheumatoid-arthritis/ Accessed on: 16th November 2016.
[http://dx.doi.org/10.1136/annrheumdis-2016-eular.4054]
, 18Sverdrup B, Källberg H, Bengtsson C, et al. Association between occupational exposure to mineral oil and rheumatoid arthritis: Results from the Swedish EIRA case-control study. Arthritis Res Ther 2005; 7(6): R1296-303.
[http://dx.doi.org/10.1186/ar1824] [PMID: 16277683]
]. Interestingly, a pronounced risk interaction of silica dust and cigarette smoking for ACPA+ RA development was seen amongst co-exposed workers: silica only, OR 1.15 (95% CI 0.42-3.15); current smoking, OR 2.78 (95% CI 1.77-4.38); silica + current smoking OR 7.36 (95% CI 3.31-16.38), rising to OR 14.9, (95% CI 5.32-37.84) for >20 pack years smoked Fig. (3). This risk exceeded the expected separate effects of silica exposure and current smoking, indicating an interaction between these exposures (attributable proportion due to interaction = 0.60 95% CI 0.26-0.95). No explanation for this important interaction has been proposed in the literature.


Fig. (3)
Risk interaction of ACPA+ RA in Swedish quarry workers with smoking and silica dust exposure, compared to unexposed never smoking controls, adapted from Stolt et al [11Stolt P, Yahya A, Bengtsson C, et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis 2010; 69(6): 1072-6.
[http://dx.doi.org/10.1136/ard.2009.114694] [PMID: 19966090]
].


Fig. (4)
Relative RA risk: interaction between dust exposure and smoking amongst Swedish construction workers, adapted from Blanc et al [13Blanc PD, 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(10): 1094-101.
[http://dx.doi.org/10.1016/j.amjmed.2015.05.001] [PMID: 26007670]
].


Recent analysis of 240,983 construction industry workers in Sweden suggested that “other inorganic” dusts are independent RA risk factors, in addition to silica [13Blanc PD, 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(10): 1094-101.
[http://dx.doi.org/10.1016/j.amjmed.2015.05.001] [PMID: 26007670]
]. Among ever smokers, both silica and other inorganic dust exposure were associated with increased RA risk: RR 1.36 (95% CI 1.11-1.68) and 1.42 (95% CI 1.17-1.73) respectively. However, no increased risk was seen amongst dust-exposed never smokers Fig. (4). This poses interesting questions, both as to the risk posed by inorganic dusts other than silica, and to the pathophysiology of the risk interaction of dust and cigarette smoke co-exposure.

Here we suggest that silica and non-silica inorganic dusts act as an adsorber of heavy metals entering the lung via cigarette smoke. Cigarette smoke contains the metals aluminium, cadmium, chromium, copper, lead, manganese, mercury, nickel, selenium, vanadium and zinc. Cadmium has emerged as the most important of these metals in terms of increased levels relative to non-smokers and the associated increased risk of cardiovascular disease and COPD [42Bernhard D, Rossmann A, Wick G. Metals in cigarette smoke. IUBMB Life 2005; 57(12): 805-9.
[http://dx.doi.org/10.1080/15216540500459667] [PMID: 16393783]
].

It has been hypothesised that inhalation of the metal cadmium links the established risk of smoking for RA and many of the occupations demonstrated to have an elevated RA risk [43Hutchinson 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(5): 570-3.
[http://dx.doi.org/10.1111/1756-185X.12673] [PMID: 26082350]
]. Recent South Korean literature reports a significant RA OR rise of 1.62 per 1µg/L increase in serum cadmium, and a smaller significant OR rise in serum lead [44Joo SH, Go DJ, Ahn EY, Kwon HM, Lee J, Song YW. Higher Serum Heavy Metals Concentrations Are Associated with Rheumatoid Arthritis : A Study of the Korean National Health and Nutrition Examination Survey (KNHANES) [abstract]. Arthritis Rheumatol 2016. 68 (suppl 10). http://acrabstracts.org/abstract/ higher-serum-heavy-metals-concentrations-are-associated-with-rheumatoid-arthritis-a-study-of-the-korean-national-health-and-nutrition-examination-survey-knhanes/ accessed 9th November 2016]. Importantly cadmium has recently been demonstrated to citrullinate intracellular cytokeratins [45Hutchinson D, Muller J, McCarthy JE, Gun’ko Y, Verma N, Bi X, et al. Cadmium nanoparticles citrullinate intracellular cytokeratins: cadmium potentially links rheumatoid arthritis to smoking and numerous working class occupations. EULAR17-3620. Abstract in press], which may potentially lead to immune tolerance breakdown and ACPA generation. Furthermore in micromolar concentrations (1–10 μM range), cadmium is associated with a pro-inflammatory state [46Olszowski T, Baranowska-Bosiacka I, Gutowska I, Chlubek D. Pro-inflammatory properties of cadmium. Acta Biochim Pol 2012; 59(4): 475-82.
[PMID: 23240106]
], and high dose administration to Wistar rats has been shown to exacerbate collagen induced arthritis disease development, demonstrating pro-inflammatory cytokine expression [47Ansari MM, Neha , Khan HA. Effect of cadmium chloride exposure during the induction of collagen induced arthritis. Chem Biol Interact 2015; 238: 55-65.
[http://dx.doi.org/10.1016/j.cbi.2015.06.001] [PMID: 26070417]
].

5. LIMITATIONS OF EVIDENCE

Over the course of an occupational lifetime, many workers will be exposed to multiple agents. For example, in less skilled labouring construction workers, co-exposure to silica dust, inorganic non-silica dust and wood dust is common. This is particularly true in poorer populations, where trade sub-specialisation and adherence to health and safety legislation will be less evident. As previously described, lower socio-economic status is linked with RA [36Uhlig T, Hagen KB, Kvien TK. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol 1999; 26(1): 47-54.
[PMID: 9918239]
-38Bergström U, Jacobsson LT, Nilsson JÅ, Wirfält E, Turesson C. Smoking, low formal level of education, alcohol consumption, and the risk of rheumatoid arthritis. Scand J Rheumatol 2013; 42(2): 123-30.
[http://dx.doi.org/10.3109/03009742.2012.723744] [PMID: 23126587]
]. Given the longevity of increased risk for RA found in smoking [24Di Giuseppe D, Orsini N, Alfredsson L, Askling J, Wolk A. Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women. Arthritis Res Ther 2013; 15(2): R56.
[http://dx.doi.org/10.1186/ar4218] [PMID: 23607815]
], occupational exposure to dust or fumes may not present until long after exposure cessation.

Therefore, studies may be confounded by multiple inhalational insults, even when correcting for smoking. Blanc et al. [13Blanc PD, 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(10): 1094-101.
[http://dx.doi.org/10.1016/j.amjmed.2015.05.001] [PMID: 26007670]
] excluded 40645 workers who were exposed to wood dust, gas or fumes to reduce confounding in their analysis of silica vs. non-silica dust exposed construction workers. In the above study, capturing data from occupational health service records for unionised construction workers existing from 1968-1993, culminated in enrolment of approximately 80% of the eligible workers. Analysis of the “missing” 20% and the excluded, co-exposed workers would be interesting; one would suggest predominance towards lower socio-economic status groups. Such workers are more likely to reside in unskilled “itinerant” trades, and thus become excluded from analysis. Non-unionised workers are not mentioned, which may have limited relevance in Swedish construction but is highly relevant when generalising findings elsewhere. We suggest many co-exposed cases of interest may have been excluded, underestimating risk.

As with construction workers, farmers perform a heterogenous mix of tasks in their work which can result in inhalation exposures. Soil type, rainfall and wind patterns affect aerosolisation of particles. Oil exposures from machinery vary, along with solvent, concrete, cement and general building dust exposure from the variety of tasks that some farmers perform. Metal fumes from welding have been associated with increased RA risk amongst spouses of farmers [20Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. Rheumatoid arthritis in agricultural health study spouses: Associations with pesticides and other farm exposures. Environ Health Perspect 2016; 124(11): 1728-34.
[PMID: 27285288]
]. We have previously suggested that heavy metal-laden particle inhalation may be an RA risk factor for farmers using pesticides and fertilisers [26Murphy D, Pay J, Benham R, James B, Hutchinson D. Comment on “Rheumatoid arthritis in agricultural health study spouses: Associations with pesticides and other farm exposures”. Environ Health Perspect 2016; 124(11): A196.
[http://dx.doi.org/10.1289/EHP730] [PMID: 27801652]
]. Maneb and mancozeb fungicides are approximately 21% manganese by weight. Their use associates with increased levels in residential house dust, with concentrations declining with distance from use. Long-term Mancozeb use has shown evidence of wider environmental contamination [48Melgar C, Geissen V, Cram S, et al. Pollutants in drainage channels following long-term application of mancozeb to banana plantations in southeastern Mexico. J Soil Sci Plant Nutr 2008; 171: 597-604.
[http://dx.doi.org/10.1002/jpln.200700171]
]. Additionally, cadmium exposure from phosphate fertiliser may account for the RA risk seen in farmers. Rates of cadmium contamination in soil can range from 0.3 to 1.2 g/ha from contaminated fertiliser application [49Mortvedt JJ. Cadmium levels in soils and plants from some long-term soil fertility experiments in the United States of America. J Environ Qual 1987; 16: 137-42.
[http://dx.doi.org/10.2134/jeq1987.00472425001600020008x]
], though this specific risk is largely of historical significance due to controls on the use of such fertilisers. Detailed information of exposure type and duration and intensity is needed to refine the potential risks that farmers face.

Swedish case referent studies utilising census defined occupations and hospitalisation records dominate the literature for occupational risk in RA. Whilst illuminating, such studies do have limitations. Patients in manual jobs may present to hospital more readily as they may be unable to complete tasks that would not present a problem in sedentary occupations, leading to possible risk overestimation in hospitalisation data. Symptomatic RA patients pre-census may have already switched from “heavier” manual occupations to lighter trades, whilst similarly symptomatic patients in those lighter trades may have been able to continue in the same occupation. As such, single cohort registry data may underestimate risk in heavier, manual trades, and overestimate risk in lighter occupational categories in which working conditions can be adapted to meet the needs of RA patients. Comparing occupation and socioeconomic status based on historical census occupation data, Li et al's [14Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol 2008; 35(6): 986-91.
[PMID: 18464310]
] study was limited to those requiring hospital treatment, therefore misses non-hospitalised disease occurrence. Linking RA hospitalisation to preceding census occupation may reflect selection bias towards ill health, and is a criticism that can be levelled at all large cohort surveys measuring disease incidence via hospitalisation records. In having a cohort of patients who held the same job in 1960 and 1970, this study includes patients who held the same occupation over a ten-year period, and may mitigate against occupational selection bias. Given these caveats, one may expect sedentary occupations to predominate, and the mix of active technical and mechanical occupations seen here and elsewhere is therefore likely to be an underestimate. Demonstrating elevated RA risk over different census reference periods, a strong argument can be made for miners, engine and motor operators, construction workers, electrical workers and farmers having an increased risk of RA.

Extrapolating Swedish data to represent populations around the world has limitations. Cigarette smoking in Sweden has a fascinating reverse social class gradient on analysis of 55,000 participants in the 1960 census, with both long term and heavy smoking being twice as common amongst non-manual workers as manual workers, and ten times more common than in those working in farming and agriculture [50Vågerö D, Norell SE. Mortality and social class in Sweden--exploring a new epidemiological tool. Scand J Soc Med 1989; 17(1): 49-58.
[http://dx.doi.org/10.1177/140349488901700109] [PMID: 2711146]
]. This trend is opposite to the UK, where smoking has consistently shown a lower socio-economic class predominance; in 1982, 49% unskilled working men smoked, compared to 20% non-manual professionals [51Townsend J. Cigarette tax, economic welfare and social class patterns of smoking. Appl Econ 1987; 19: 355-65.
[http://dx.doi.org/10.1080/00036848700000007]
]. Inhalational co-exposure to dust and cigarette smoke is therefore less likely in the Swedish populations reported than in UK equivalents.

6. PATHOPHYSIOLOGIC CONSIDERATIONS OF VAPOUR, GAS DUST AND FUME INHALATION IN RELATION TO RA DEVELOPMENT

6.1. Inducible Bronchial Associated Lymphoid Tissue (iBALT)

The lung is now considered a principal site for the development of ACPA and RF positive RA [5Perry E, Kelly C, Eggleton P, De Soyza A, Hutchinson D. The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury? Rheumatology (Oxford) 2014; 53(11): 1940-50.
[http://dx.doi.org/10.1093/rheumatology/keu195] [PMID: 24831057]
]. A study of established RA demonstrated evidence of iBALT more commonly than in inflammatory lung disease without RA [52Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest 2006; 116(12): 3183-94.
[http://dx.doi.org/10.1172/JCI28756] [PMID: 17143328]
]. iBALT has the appearance of ectopic lymphoid follicles similar to those observed in rheumatoid joints [53Weyand CM, Goronzy JJ. Ectopic germinal center formation in rheumatoid synovitis. Ann N Y Acad Sci 2003; 987: 140-9.
[http://dx.doi.org/10.1111/j.1749-6632.2003.tb06042.x] [PMID: 12727633]
]. iBALT contains numerous B cell follicles containing germinal centres and follicular dendritic cells. Lymphocyte lung infiltration was more frequently found in ACPA-positive RA patients (50%) as compared with ACPA-negative RA patients (17%) and controls (13%). Critically germinal centres, B cells and plasma cells were only found in the lungs of ACPA-positive RA patients [54Reynisdottir G, Olsen H, Joshua V, et al. Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. Ann Rheum Dis 2015; 1-6.
[PMID: 26530319]
].

Cigarette smoking is strongly associated with the development of iBALT as the expression of iBALT was significantly more common in smokers than non-smokers (82% (14/17) v 14% (2/14) respectively) [55Richmond I, Pritchard GE, Ashcroft T, Avery A, Corris PA, Walters EH. Bronchus associated lymphoid tissue (BALT) in human lung: Its distribution in smokers and non-smokers. Thorax 1993; 48(11): 1130-4.
[http://dx.doi.org/10.1136/thx.48.11.1130] [PMID: 8296257]
]. Furthermore silica has also been observed to generate iBALT in a murine model [56Desaki M, Sugawara I, Iwakura Y, Yamamoto K, Takizawa H. Role of interferon-γ in the development of murine bronchus-associated lymphoid tissues induced by silica in vivo. Toxicol Appl Pharmacol 2002; 185(1): 1-7.
[http://dx.doi.org/10.1006/taap.2002.9511] [PMID: 12460731]
]. Rheumatoid pulmonary nodules have also been observed to contain lymphoid aggregates containing B lymphocytes and, in some cases, demonstrate characteristic features of lymphoid follicles [57Highton J, Hung N, Hessian P, Wilsher M. Pulmonary rheumatoid nodules demonstrating features usually associated with rheumatoid synovial membrane. Rheumatology (Oxford) 2007; 46(5): 811-4.
[http://dx.doi.org/10.1093/rheumatology/kel411] [PMID: 17204487]
]. The initial histological examination of the rheumatoid pulmonary nodules in the lungs of Welsh miners with Caplan’s syndrome eluded to the presence of germinal centres with lymphoid collections in the outer collagen layer [58Gough J, Rivers D, Seal RM. Pathological studies of modified pneumoconiosis in coal-miners with rheumatoid arthritis; Caplan’s syndrome. Thorax 1955; 10(1): 9-18.
[http://dx.doi.org/10.1136/thx.10.1.9] [PMID: 14373655]
], which have never been described in peripheral nodules [59Highton J, Hessian PA, Stamp L. The Rheumatoid nodule: peripheral or central to rheumatoid arthritis? Rheumatology (Oxford) 2007; 46(9): 1385-7.
[http://dx.doi.org/10.1093/rheumatology/kem163] [PMID: 17623747]
]. Pulmonary rheumatoid nodules, therefore, have the potential to generate rheumatoid associated autoantibodies and it is unsurprising that pulmonary nodules have been noted to precede the development of RA, invariably being associated with seropositive rather than seronegative disease [60Caplan A, Payne RB, Withey JL. A broader concept of Caplan’s syndrome related to rheumatoid factors. Thorax 1962; 17: 205-12.
[http://dx.doi.org/10.1136/thx.17.3.205] [PMID: 13876317]
]. For example, the presence of pulmonary rheumatoid nodules in Welsh coal miners who had no history, signs, or symptoms of RA was associated with a high prevalence of positive rheumatoid factor tests (60%). The potential importance of pulmonary nodules may have been over looked as on plain chest x-rays lung nodules were present in only 0.3% of RA patients [61Jurik AG, Davidsen D, Graudal H. Prevalence of pulmonary involvement in rheumatoid arthritis and its relationship to some characteristics of the patients. A radiological and clinical study. Scand J Rheumatol 1982; 11(4): 217-24.
[http://dx.doi.org/10.3109/03009748209098194] [PMID: 7178857]
]. However a study utilising CT imaging of the lung demonstrated pulmonary nodules in 22% of RA patients and subpleural micronodules and/or pseudoplaques in a further 17% of patients [62Remy-Jardin M, Remy J, Cortet B, Mauri F, Delcambre B. Lung changes in rheumatoid arthritis: CT findings. Radiology 1994; 193(2): 375-82.
[http://dx.doi.org/10.1148/radiology.193.2.7972746] [PMID: 7972746]
]. We suggest that accumulation of metals in the lung may predispose individuals to rheumatoid pulmonary nodules. The histology of a rheumatoid nodule is that of a granuloma with a palisade of cells proven to be a dual population of macrophages and fibroblastic cells clustered around a central necrotic core of fibrin [63Edwards JC, Wilkinson LS, Pitsillides AA. Palisading cells of rheumatoid nodules: comparison with synovial intimal cells. Ann Rheum Dis 1993; 52(11): 801-5.
[http://dx.doi.org/10.1136/ard.52.11.801] [PMID: 7504437]
]. The macrophages are activated and have the appearance of epithelial cells and are termed epithelioid histiocytes [64Ziff M. The rheumatoid nodule. Arthritis Rheum 1990; 33(6): 761-7.
[http://dx.doi.org/10.1002/art.1780330601] [PMID: 2194460]
]. Occasionally these histiocytes coalesce to form multinucleated giant cells in the rheumatoid nodule. Metal inhalation has been reported to be associated with the development of pulmonary macrophage derived multinucleated giant cells [65Davison AG, Haslam PL, Corrin B, et al. Interstitial lung disease and asthma in hard-metal workers: Bronchoalveolar lavage, ultrastructural, and analytical findings and results of bronchial provocation tests. Thorax 1983; 38(2): 119-28.
[http://dx.doi.org/10.1136/thx.38.2.119] [PMID: 6857569]
]. Metals such as beryllium are also linked to the formation of pulmonary nodules with histological features similar to rheumatoid nodules and can cause a chronic pulmonary granulomatous disease termed berylliosis which may arise long after exposure has ceased with a reported latency period of up to 40 years [66Eisenbud M, Lisson J. Epidemiological aspects of beryllium-induced nonmalignant lung disease: A 30-year update. J Occup Med 1983; 25(3): 196-202.
[http://dx.doi.org/10.1097/00043764-198303000-00012] [PMID: 6842310]
]. Raised levels of the heavy metals cobalt and chromium are associated with complications associated with metal on metal hip replacements. One of these complications includes the formation of tertiary lymphoid tissue around the implant and this tissue is identical to that observed in joints of RA patients [67Mittal S, Revell M, Barone F, et al. Lymphoid aggregates that resemble tertiary lymphoid organs define a specific pathological subset in metal-on-metal hip replacements. PLoS One 2013; 8(5): e63470.
[http://dx.doi.org/10.1371/journal.pone.0063470] [PMID: 23723985]
]. There appears to be an association between significant bodily levels of metals such as copper and cadmium in RA independent of smoking [68Scudder PR, Al-Timimi D, McMurray W, White AG, Zoob BC, Dormandy TL. Serum copper and related variables in rheumatoid arthritis. Ann Rheum Dis 1978; 37(1): 67-70.
[http://dx.doi.org/10.1136/ard.37.1.67] [PMID: 629607]
, 69Afridi HI, Kazi TG, Brabazon D, Naher S. Interaction between zinc, cadmium, and lead in scalp hair samples of Pakistani and Irish smokers rheumatoid arthritis subjects in relation to controls. Biol Trace Elem Res 2012; 148(2): 139-47.
[http://dx.doi.org/10.1007/s12011-012-9352-6] [PMID: 22351104]
]. These data suggest that RA patients are exposed to metals and that heavy metals can induce the development of ectopic lymphoid tissue.

Further animal model evidence strengthens the “double-hit” hypothesis in terms of granuloma formation. Rat lung instilled with cadmium-containing silica nanopaticles demonstrated greater expression of pro-inflammatory cytokines and granuloma formation than lung exposed to cadmium alone or silica nanoparticles alone [70Coccini T, Barni S, Vaccarone R, Mustarelli P, Manzo L, Roda E. Pulmonary toxicity of instilled cadmium-doped silica nanoparticles during acute and subacute stages in rats. Histol Histopathol 2013; 28(2): 195-209.
[PMID: 23275303]
]. Nanoparticle use per se may be of interest as an evolving occupational risk, as inhaled silica and carbon nanoparticles, aerosolised in electronics componentry and production of lightweight materials, can induce lung citrullination and activate peptidyl arginine deaminase [71Mohamed BM, Verma NK, Davies AM, et al. Citrullination of proteins: A common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine (Lond) 2012; 7(8): 1181-95.
[http://dx.doi.org/10.2217/nnm.11.177] [PMID: 22625207]
]. Given that numerous metals are found in cigarette smoke [42Bernhard D, Rossmann A, Wick G. Metals in cigarette smoke. IUBMB Life 2005; 57(12): 805-9.
[http://dx.doi.org/10.1080/15216540500459667] [PMID: 16393783]
], one possible explanation for the association between cigarette smoking and iBALT development is the accumulation of metals in the lungs of smokers; a process likely to be accentuated by the presence of various occupational dusts.

6.2. Enhanced ACPA Generation

It is well documented that the generation of ACPAs occur prior to the development of RA and greatly increase the risk of disease development [72Willemze A, Trouw LA, Toes RE, Huizinga TW. The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol 2012; 8(3): 144-52.
[http://dx.doi.org/10.1038/nrrheum.2011.204] [PMID: 22293763]
]. Examination of bronchoalveolar lavage fluid from RA detected ACPAs and the levels of these antibodies were increased in patients that had more well-developed iBALT [52Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest 2006; 116(12): 3183-94.
[http://dx.doi.org/10.1172/JCI28756] [PMID: 17143328]
]. These data suggest that ACPA antibodies are produced locally in the lung by plasma cells contained within iBALT. In addition to silica and cadmium inducing iBALT, both nanoparticles have been observed to citrullinate intracellular proteins such as cytokeratins [45Hutchinson D, Muller J, McCarthy JE, Gun’ko Y, Verma N, Bi X, et al. Cadmium nanoparticles citrullinate intracellular cytokeratins: cadmium potentially links rheumatoid arthritis to smoking and numerous working class occupations. EULAR17-3620. Abstract in press, 71Mohamed BM, Verma NK, Davies AM, et al. Citrullination of proteins: A common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine (Lond) 2012; 7(8): 1181-95.
[http://dx.doi.org/10.2217/nnm.11.177] [PMID: 22625207]
]. In the case of silica, citrullination occurred via the peptidylargininedeiminase (PAD)-dependent mechanism [71Mohamed BM, Verma NK, Davies AM, et al. Citrullination of proteins: A common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine (Lond) 2012; 7(8): 1181-95.
[http://dx.doi.org/10.2217/nnm.11.177] [PMID: 22625207]
].

6.3. Rheumatoid Factor Production

Rheumatoid factor is an autoantibody directed against the rheumatoid binding site of the Fc of immunoglobulin G (IgG) [73Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: Rheumatoid factors and anticitrullinated protein antibodies. QJM 2010; 103(3): 139-46.
[http://dx.doi.org/10.1093/qjmed/hcp165] [PMID: 19926660]
]. Rheumatoid factor positivity is associated an enhanced risk of RA development [74Aho K, Heliövaara M, Maatela J, Tuomi T, Palosuo T. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 1991; 18(9): 1282-4.
[PMID: 1757925]
]. Rheumatoid factor is more frequently observed in non-RA smokers [75Tuomi T, Heliövaara M, Palosuo T, Aho K. Smoking, lung function, and rheumatoid factors. Ann Rheum Dis 1990; 49(10): 753-6.
[http://dx.doi.org/10.1136/ard.49.10.753] [PMID: 2241263]
], and individuals with lung disease associated with exposure to coal dust [60Caplan A, Payne RB, Withey JL. A broader concept of Caplan’s syndrome related to rheumatoid factors. Thorax 1962; 17: 205-12.
[http://dx.doi.org/10.1136/thx.17.3.205] [PMID: 13876317]
], asbestos [76Pernis B, Vigliani EC, Selikoff IJ. Rheumatoid factor in serum of individuals exposed to asbestos. Ann N Y Acad Sci 1965; 132(1): 112-20.
[http://dx.doi.org/10.1111/j.1749-6632.1965.tb41094.x] [PMID: 5219543]
] and silica [77Vigliani EC, Pernis B. Immunological aspects of silicosis. Bibl Tuberc 1963; 17: 230-79.
[PMID: 13997152]
]. Revealing the processes that result in RF generation may prove insightful for understanding how cigarette smoke and industrial inhalational exposures increase the risk of RA development.

Newkirk et al. [78Newkirk MM, Mitchell S, Procino M, et al. Chronic smoke exposure induces rheumatoid factor and anti-heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease. Eur J Immunol 2012; 42(4): 1051-61.
[http://dx.doi.org/10.1002/eji.201141856] [PMID: 22531929]
] described a mechanism by which cigarette smoke induces either IgM RF or IgA RF to be generated by B cells. This mechanism is dependent on the generation of an IgG immune response to heat shock protein 70 (HSP 70). Complexes of IgG-HSP70 double bind to RF expressing B cells via an interaction with the B cell receptor and CD91 with the subsequent production of IgM RF and IgA RF [78Newkirk MM, Mitchell S, Procino M, et al. Chronic smoke exposure induces rheumatoid factor and anti-heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease. Eur J Immunol 2012; 42(4): 1051-61.
[http://dx.doi.org/10.1002/eji.201141856] [PMID: 22531929]
]. Therefore, environmental insults that associate with the induction of HSP 70 with a secondary IgG response are likely to be important with regards to the generation of IgM RF and IgA RF. HSP 70 expression is enhanced in the rheumatoid joints and an IgG autoantibody response to HSP 70 is significantly raised in recent onset RA (53.0%) compared to normal controls (4%) [79Hayem G, De Bandt M, Palazzo E, et al. Anti-heat shock protein 70 kDa and 90 kDa antibodies in serum of patients with rheumatoid arthritis. Ann Rheum Dis 1999; 58(5): 291-6.
[http://dx.doi.org/10.1136/ard.58.5.291] [PMID: 10225814]
]. Interestingly exposure to dusts alongside heat and noise in the work place can generate a significantly enhanced immune response to HSP 70 (40%) compared to office workers (19%) [80Wu T, Ma J, Chen S, et al. Association of plasma antibodies against the inducible Hsp70 with hypertension and harsh working conditions. Cell Stress Chaperones 2001; 6(4): 394-401.
[http://dx.doi.org/10.1379/1466-1268(2001)006<0394:AOPAAT>2.0.CO;2] [PMID: 11795477]
]. Likewise in smokers of North American Indian origin (an ethnic group with a very high risk for RA) there is a reported significantly increased prevalence of IgG anti-HSP70 positive individuals (40%) as opposed to non-smokers (5%) [78Newkirk MM, Mitchell S, Procino M, et al. Chronic smoke exposure induces rheumatoid factor and anti-heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease. Eur J Immunol 2012; 42(4): 1051-61.
[http://dx.doi.org/10.1002/eji.201141856] [PMID: 22531929]
]. Cadmium and other metals (copper and mercury) are strongly linked to the upregulation of HSP 70 [81Gibney E, Gault J, Williams J. The use of stress proteins as a biomarker of sub-lethal toxicity: induction of heat shock protein 70 by 2-isobutyl piperidine and transition metals at sub-lethal concentrations. Biomarkers 2001; 6(3): 204-17.
[http://dx.doi.org/10.1080/13547500010009573] [PMID: 23886276]
], as is silica [82Wang JB, Suo W, Zhang R, Leng X, Yan HB, Yao L, et al. Expression of heat shock protein 70 in lung and plasma of rats with pulmonary fibrosis induced by SiO2 2012.]. No studies to date have correlated RF levels in RA with dual exposures to various dusts and cigarette smoke and the relationship between RF and IgG HSP 70 autoantibodies.

6.4. Adsorption in Dust Exposure

All the occupations discussed involve inhalation of dust, fumes or particles, with the potential for adsorption of toxic elements such as heavy metals, from concurrent environmental co-exposure (most commonly through cigarette smoke). This process is seen in, but not exclusive to, silica dusts, with adsorption of toxic heavy metals such as cadmium directly onto the intra-pulmonary substrate inhaled previously, dramatically increasing total body levels. We suggest a hypothesis of adsorption of trace elements in vitro onto previously inhaled substrates as a cause of increased, interactive RA risk seen in sequential inhalational exposures. Cadmium has been described as the most important toxin in inhaled cigarette smoke [42Bernhard D, Rossmann A, Wick G. Metals in cigarette smoke. IUBMB Life 2005; 57(12): 805-9.
[http://dx.doi.org/10.1080/15216540500459667] [PMID: 16393783]
]. Adsorption explains the pronounced interaction of silica dust and current smoking >20 pack years co-exposure amongst exposed workers (OR 14.9, 95%CI 5.32-37.84, Fig. (3)), described by Stolt [11Stolt P, Yahya A, Bengtsson C, et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis 2010; 69(6): 1072-6.
[http://dx.doi.org/10.1136/ard.2009.114694] [PMID: 19966090]
], and the attenuation of risk seen by Blanc [13Blanc PD, 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(10): 1094-101.
[http://dx.doi.org/10.1016/j.amjmed.2015.05.001] [PMID: 26007670]
], in silica and non-silica dust exposed never smokers.

Quantification of the exact adsorption capacity of dust varies. In laboratory analysis of a single known adsorption substrate, sorption depends heavily on experimental conditions such as pH, metal concentration, ligand concentration competing ions, and particle size. This is before consideration of the differing adsorption capacities of multiple dusts that workers may be exposed to. For example, a general builder may inhale fine sand, gypsum, cement, and sanded wood. Occupational exposure matrices have a limited ability to capture individual variability within this due to heterogeneity of tasks and substrates, with consequent potential for misclassification bias [83Kauppinen TP, Mutanen PO, Seitsamo JT. Magnitude of misclassification bias when using a job-exposure matrix. Scand J Work Environ Health 1992; 18(2): 105-12.
[http://dx.doi.org/10.5271/sjweh.1604] [PMID: 1604270]
].

Adsorption capability generally results from a net negative charge on structural particles of substrates, attracting and binding positively charged heavy metal particles. Binding potential is enhanced by increasing surface area, seen in finer dust particles [84Bailey SE, Olin TJ, Bricka RM, Adrian DD. A review of potentially low-cost sorbents for heavy metals. Water Res 1999; 33: 2469-79.
[http://dx.doi.org/10.1016/S0043-1354(98)00475-8]
]. Within mineral dusts, occurrence of trace elements depends on principal mineral species of the substrate and individual characteristics of the sorption particle. For example, bituminous coals may display a high affinity for formation of organo-metal complexes and organic acid salts, thereby potentially containing higher trace element levels in situ. Conversely, the aluminiosilicate mineral content of fine dust from anthracite coals has greater potential for further adsorption of heavy metals due to surface charges [85Raask E. The mode of occurrence and concentration of trace elements in coal. Pror Energy Combust Sci 1985; 11(2): 97-118.
[http://dx.doi.org/10.1016/0360-1285(85)90001-2]
]. Various organic dust particles have quantifiably demonstrated adsorption of heavy metals, such as cotton, wood, wool, moss, and waste from paper and seafood industries [84Bailey SE, Olin TJ, Bricka RM, Adrian DD. A review of potentially low-cost sorbents for heavy metals. Water Res 1999; 33: 2469-79.
[http://dx.doi.org/10.1016/S0043-1354(98)00475-8]
]. Of non-silica inorganic dusts, commercial gypsum and industrial gypsum by-product, both widely used in the construction industry for plasters and plasterboards, have demonstrated adsorption of lead and cadmium in solution via sulphate binding [86Raii M, Pham Minh D, Escudero Sanz FJ, Nzihou A. Lead and cadmium removal from aqueous solution using an industrial gypsum by-product. Procedia Eng 2014; 83: 415-22.
[http://dx.doi.org/10.1016/j.proeng.2014.09.050]
]. An interesting analysis on cadmium binding via adsorption demonstrated interaction between sand, cement and clay to which construction workers would be exposed. Clay addition to sand-cement mix (a common process for enhancing mortar plasticity), exposed more ion exchange sites and altered pH, enhancing uptake capacity of cadmium via ion exchange of iron, magnesium and aluminium oxides bound in cement [87Shawabkeh RA. Solidification and stabilization of cadmium ions in sand-cement-clay mixture. J Hazard Mater 2005; 125(1-3): 237-43.
[http://dx.doi.org/10.1016/j.jhazmat.2005.05.037] [PMID: 16006034]
].

We believe it is the “double hit” of inhaled particles with capacity for further adsorption from subsequent inhalation of trace elements that imparts excess risk. Most commonly, this would take the form of inhaled occupational dusts with the ability to adsorb trace elements from cigarette smoke. Further evidence for this compound exposure is demonstrated in Turkish bitumen ashphalters, who demonstrated a six-fold increase in serum cadmium compared to either non-smoking colleagues or control smokers [88Atasoy N, Kanat Y. Determination of the amount of certain heavy metal ions and some specific liver enzymes and levels of testosterone hormone in the blood sera of heavy asphalt workers and rural community in Van, Turkey. Res J Med Sci 2011; 5: 73-9.
[http://dx.doi.org/10.3923/rjmsci.2011.73.79]
] (Fig. 5).

Fig. (5)
Interaction of asphalt exposure and cigarette smoking on serum cadmium levels among Turkish asphalt workers, adapted from Atasoy et al. [88Atasoy N, Kanat Y. Determination of the amount of certain heavy metal ions and some specific liver enzymes and levels of testosterone hormone in the blood sera of heavy asphalt workers and rural community in Van, Turkey. Res J Med Sci 2011; 5: 73-9.
[http://dx.doi.org/10.3923/rjmsci.2011.73.79]
].


7. IMPLICATIONS FOR TREATMENT

It is well established that cigarette smoking reduces the clinical response to both methotrexate and tumour necrosis factor (TNF) inhibitors [89Saevarsdottir S, Wedrén S, Seddighzadeh M, et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: Observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. Arthritis Rheum 2011; 63(1): 26-36.
[http://dx.doi.org/10.1002/art.27758] [PMID: 20862678]
, 90Abhishek A, Butt S, Gadsby K, Zhang W, Deighton CM. Anti-TNF-α agents are less effective for the treatment of rheumatoid arthritis in current smokers. J Clin Rheumatol 2010; 16(1): 15-8.
[http://dx.doi.org/10.1097/RHU.0b013e3181ca4a2a] [PMID: 20051749]
]. Cigarette smoking is strongly associated with the titres of RF [91Wolfe F. The effect of smoking on clinical, laboratory, and radiographic status in rheumatoid arthritis. J Rheumatol 2000; 27(3): 630-7.
[PMID: 10743800]
], and it is noteworthy that a RF titre < 20 IU/ml was highly predictive for remission or low disease activity in RA patients with established disease receiving TNF inhibitors [92Pomirleanu C, Ancuta C, Miu S, Chirieac R. A predictive model for remission and low disease activity in patients with established rheumatoid arthritis receiving TNF blockers. Clin Rheumatol 2013; 32(5): 665-70.
[http://dx.doi.org/10.1007/s10067-012-2146-6] [PMID: 23292520]
]. In this study RA patients with a RF titre < 20 IU/ml were significantly more likely (OR 18.9, 95% CI 10.79-38.36) to be in remission at 12 months than RA patients with a RF titre >20 IU/ml. This is important as our own observations have demonstrated that wood dust exposed carpenters have significantly higher RF titres than non-dust exposed RA cases. Control never smokers (n=40) were noted to have RF titre of 16 IU/ml (IQR 6.7–47.2) compared to carpenter never smokers (n=8) RF titre of 86.4 (IQR 19.5–230.3), p=0.04 [93Bellis K, Whallett M, Murphy D, Hutchinson D. RA in male carpenters: Occupational wood dust exposure increases ACPA and RF seropositivity and significantly raises RF titres 2017; 76(2): 518.]. It is therefore conceivable that individuals who have been exposed to dust in the work place have a blunted response to methotrexate and TNF inhibitors by virtue of high RF titres, generated by inhalational insults as discussed above.

CONCLUSION

A variety of occupations have demonstrated increased risk for RA, primarily identified through Swedish case referent and linkage studies, and involve exposure to inhalational particles, in the form of dust, fumes or both. Global health and safety legislation, working patterns and smoking habits vary considerably. Studying populations where such co-exposures are common may demonstrate further areas of enhanced RA risk.

Interaction is seen between occupational RA risk and cigarette smoking, and we present information to support a hypothesis of heavy metal adsorption onto inhaled dust particles to explain this. Further work is needed to analyse the ability of inhaled dusts to stimulate immune tolerance breakdown in the causation of RA.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

Ongoing funding for research into rheumatoid arthritis is provided to both Dr. D Murphy and Dr. D Hutchinson by Cornwall Arthritis Trust, a registered charity, to whom we are grateful.

ACKNOWLEDGEMENTS

Dr D Murphy: Literature search, drafting and writing of paper.

Dr. D Hutchinson: Literature search, revision/critical appraisal for important intellectual content, approval of final draft.

All individuals listed as authors have contributed substantially to the design, performance, analysis, and reporting of the work. There are no other contributors.

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