A new study has provided evidence that antibiotic usage is associated with an increased risk of developing rheumatoid arthritis.
Researchers from Keele University and the Quadram Institute analysed data from primary care medical records.
They found that the odds of developing rheumatoid arthritis were 60% higher in those exposed to antibiotics than in those not exposed.
The odds increased with the number of antibiotics treatments, and how recently they were taken.
Rheumatoid arthritis affects 400,000 people in the UK and this study suggests it affects 26 in 100,000 people who have taken antibiotics.
Rheumatoid arthritis is likely to be caused by a complex mix of genetics and different environmental factors, so this study isn’t reason to stop taking antibiotics where they are needed.
But it does open up a new avenue of exploration to finding the triggers, which could be vital in the search for ways of preventing this condition.
Although this study was large, it can’t say for sure whether it is the antibiotics that increase the risk, or the infection itself.
The type of infection was important.
Upper respiratory tract infections treated with antibiotics were more associated with rheumatoid arthritis cases, but this association wasn’t seen in untreated cases.
The analysis of the type of antibiotic showed that all classes increased the risk of developing rheumatoid arthritis, so this suggests the risk could be derived from the antibiotics.
This has also been seen in other recent studies associating antibiotic usage with an increased risk of other autoimmune conditions, including type 1 diabetes and autoimmune liver disease.
As well as targeting the bacteria behind infections, antibiotics affect the microbiome.
This complex ecosystem of microbes helps maintain our own health and plays an important role in modulating the immune system.
A number of small studies have found that the microbiome in people with rheumatoid arthritis is less diverse, but this is the first study that has investigated the effect of antibiotic usage.
Professor Christian Mallen, Head of School for Primary, Community and Social Care at Keele University, said:
“This exciting work offers another glimpse into the complexity of understanding rheumatoid arthritis, opening the door for future work in this area. New collaborations, such as the one between the Quadram Institute and Keele University, allow exciting new interdisciplinary research that is needed to progress understanding in this field.”
Dr. Lindsay Hall, Group Leader at the Quadram Institute on the Norwich Research Park, said: “The more we learn about the complexity of the microbiome, and how factors including antibiotics impact these diverse microbial ecosystems, the more insights we have into how this may alter key health outcomes.
The challenge now is to unpick the mechanisms that link the microbes to different conditions, including RA, so that we can develop new therapeutics.”
The study was published in BMC Medicine.
Antibiotics are prescribed to treat a wide range of bacterial infections including respiratory, gastrointestinal (GI), and urinary tract infections.
In the UK, around 30% of all patients registered in primary care receive at least one antibiotic prescription per year [1].
As well as targeting bacterial pathogens, antibiotics can also disturb the gut microbiota. This highly diverse and dynamic microbial ecosystem plays an integral part in human health, modulating host metabolism and immunity [2,3,4].
Importantly, the microbiota can be influenced by numerous factors, with antibiotic treatment suggested as among the most significant [5].
Antibiotic treatment can significantly disturb the gut, oral, and skin microbiota, leading to an immediate reduction in microbial abundance and species diversity.
There is a significant body of data indicating that antibiotic usage, particularly during childhood, is a major risk factor for increasing susceptibility to infections and development of atopy and inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) [6].
More recently, studies indicate antibiotic usage appears to increase the risk of autoimmune conditions, including type 1 diabetes, autoimmune liver disease, and juvenile idiopathic arthritis (JIA) [7,8,9,10].
RA is a chronic autoimmune inflammatory disease, which is characterised by autoimmune antibody production, which directly leads to bone joint destruction, and associated RA pathology. One of the autoantibodies associated with RA (antibodies to citrullinated peptide antigens (ACPA)) is produced in response to bacterial components that closely mimic host cell receptors, e.g. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans [11, 12].
Indeed, prior infections, and gingivitis in particular, have been identified as potential risk factors for RA development [13].
Notably, gingivitis is a very common oral infectious disease in the UK population, with most adults having some form of gum disease [14]. However, the proportion of this population who develop RA is extremely low, suggesting other aetiological factors are at play. Several experimental studies have linked the microbiota to the development of inflammatory arthritis. Germ-free mouse models do not develop inflammatory arthritis, and certain bacteria (e.g. segmented filamentous bacteria, a mouse-specific taxa) have been shown to induce inflammatory TH17 responses, which may drive associated immune-mediated pathology and joint destruction [15, 16].
In humans, previous studies have indicated that there are differences in microbiota composition between healthy and disease cohorts.
Although RA microbiota profiles reported have varied between different countries [17, 18], all studies have indicated reduced microbial diversity, which may be associated with external factors such as antibiotic usage.
Thus, the aim of this study was to investigate the association between antibiotic prescriptions and the onset of RA using a large, UK-based, primary care dataset.
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Twenty-two thousand six hundred seventy-seven cases of incident RA cases were individually matched to 90,013 controls. Baseline characteristics of the study population are summarised in Table 1. Compared to controls, a larger proportion of RA cases were obese (BMI > 30; 27% vs. 32%), were more likely to smoke (18% vs. 21%), and had a higher number of comorbidities (no comorbidities 63% vs. 57%).
Antibiotics and RA
RA cases received more antibiotic prescriptions than controls, but over 80% in each group had received a prescription in the 10 years before the index date (Table 2). Penicillins were the most commonly prescribed antibiotics (72% of participants received at least one prescription before index data), followed by macrolides (33%), trimethoprim (31%), cephalosporins (25%), and tetracyclines and quinolones (both 13%). After adjusting for potential confounding factors, the odds of having been exposed to antibiotics were significantly higher in RA cases than in controls (OR 1.60; 95% CI 1.51–1.68). Redefining our index date based on the first referral to the rheumatology did not change our overall finding (adjusted OR = 1.68; 95% CI 1.59–1.76). A frequency-dependent relationship was observed between the number of prescriptions and the odds of RA. The magnitude of association with RA increased with an increasing number of unique antibiotic prescriptions. The timing of antibiotic exposure was important, with higher odds of RA in those last exposed to antibiotics in 1 to 2 years before the index date (OR 1.80; 95% CI 1.70–1.90) than in those last exposed between 5 and 10 years before the index date (OR = 1.57; 95% CI 1.49–1.66).
All classes of antibiotics were associated with higher odds of RA, with clindamycin having the highest odds ratio (Fig. 1). Based on the mode-of-action, the odds of RA were 45% higher in those prescribed antibiotics inducing a bactericidal response (i.e. lyse bacteria) (OR = 1.45; 95% CI 1.39–1.51) compared to those not prescribed antibiotics. The increase in odds was slightly lower with antibiotics inhibiting bacteria (i.e. bacteriostatic) when similar comparisons were made (OR = 1.31; 95% CI 1.27–1.36).
RA and infection
Cases were more likely to have a record of infection before their RA diagnosis (Table 3). This increased odds of RA among those with a previous history of infection ranged between 7% (urinary tract infection; OR = 1.07; 95% CI 1.02–1.12) and 37% (for LRT infections; OR = 1.37; 95% CI 1.32–1.41). A frequency-dependent association also existed between the number of previous infections and the odds of RA. More than 87% of lower respiratory and urinary tract infections were treated with antibiotics within 30 days. This proportion was lower for URT (74%) and GI infections (21%). Those with antibiotic-treated URT infections were more likely to be RA cases. However, the association was not observed for the number of untreated URT infections.
Additional analysis
A total of 1580 (7%) and 3166 (14%) of RA cases received at least one antiviral and antifungal prescription, respectively, before the index date. After adjusting for confounding factors, including antibiotic use, both antifungal (OR = 1.19; 95% CI 1.14–1.24) and antiviral drugs (OR = 1.27; 95% CI 1.20–1.35) were associated with increased risk of RA.
More information: Alyshah Abdul Sultan et al. Antibiotic use and the risk of rheumatoid arthritis: a population-based case-control study, BMC Medicine (2019). DOI: 10.1186/s12916-019-1394-6
Journal information: BMC Medicine
Provided by Keele University
