Background/Purpose: Rheumatoid arthritis (RA) is a chronic
inflammatory disease that leads to progressive joint deformity, destruction,
and disability. While smoking is recognized as a strong environmental risk
factor for the development of RA, the relationship between smoking and the
progression of RA has often been reported to be inconsistent or paradoxical
(“the risk factor paradox”). To summarize the relevant data to date, we
conducted a systematic review of the literature on the impact of smoking on the
risk of RA progression.

Methods: We conducted a mapped search of MEDLINE
and EMBASE databases for articles published from database inception to June
2015. Additional articles were retrieved by a hand-search of relevant
bibliographies. Our search strategy used a combination of mapped subject
headings (i.e., MeSH and Emtree
terms) and keywords for unindexed concepts relating to the themes of RA
progression and smoking/tobacco use. Full-text
articles meeting the following criteria were included in the systematic review:
1) RA patient population; 2) outcome of a change in RA status (e.g., radiologic
progression, functional status, or disease severity); 3) original research
article; and 4) English language. Studies were excluded if they reported the
impact of smoking on the risk of incident RA. Non-human studies, reviews, and
case reports/series were additionally excluded.

Results: We identified 685 unique citations with
our search strategy. Of these, 28 studies met all inclusion criteria and were
included in the systematic review. The main outcomes
reported included radiographic progression (e.g., Larsen or Sharp/van der Heijde score) (n=14 studies), disease activity (e.g., DAS)
(n=13), treatment response (n=6), functional status and disability (e.g., HAQ) (n=7),
achievement of remission (n=2), and total joint replacement (n=1). Overall,
smoking did not have a significant impact on RA outcomes and progression, and
in some studies (n=4) smoking actually conferred a protective impact (see Table). Only two of 14 studies on
radiographic progression reported a hazardous effect, and the impact of smoking
on functional status was non-significant in all studies identified.
Additionally, there was no significant association between smoking status and
achievement of remission.

Conclusion: While smoking is a
well-established risk factor for incident RA, findings from the majority of
studies identified in this systematic review suggest that it does not confer
the same impact on disease progression. Although
biological explanations for these counterintuitive results may exist, an
enticing methodologic explanation is a type of selection bias known as index
event bias. Appropriate methods to correct for this bias
should be explored to determine the true impact of smoking on the risk of RA
progression.