In recent decades, the presence of comorbidities in patients with rheumatoid arthritis has become more pronounced since the new therapies have changed the natural course of the disease.1 Although one of the most significant comorbidities is cardiovascular disease, as a result of a process of accelerated atheromatosis in the context of inflammation and lipid metabolism disorders, other disorders are also common.2 Alterations in lipid metabolism, both quantitative and qualitative, observed in these patients have been linked to the inflammatory process itself, although the mechanisms involved have not been well defined.3 Nevertheless, altered lipid metabolism as well as inflammation can affect other organs or systems.4 In this regard, it is known that, in the context of inflammation, the endothelial function of the gallbladder is altered, and consequently the recycling of lipids could be decreased.5 At the same time, it is known that one of the main risk factors involved in the pathogenesis of cholesterol gallstones, which constitute 80% of stones,6 is alterations in lipid metabolism.7,8 Thus, patients with chronic inflammatory disease may present a higher prevalence of gallstones. In fact, in a small number of studies, a higher prevalence of gallstones has been observed in patients with systemic lupus, antiphospholipid syndrome, and rheumatoid arthritis.9,10 In addition, other conditions associated with an increased incidence of gallstones such as age, female gender, sedentary lifestyle and, possibly, chronic intake of non-steroidal antiinflammatory drugs (NSAIDs)11 are present in rheumatoid arthritis. The purpose of this study was to assess the prevalence of gallstones in patients with established rheumatoid arthritis compared with the general population, and its relationship with lipid metabolism disorders and other risk factors.

Of 108 patients with RA, 84 were women and 24 men. Only two men had gallstone disease and none had undergone cholecystectomy. Therefore, only women were included in the study. The main demographic, clinical and laboratory features of RA participants are summarized in Table 1. Patients in the two groups, with and without gallstone disease, were similar in most variables assessed, except for age and menopausal status, which were significantly greater in the patients with GD. None had a history of gastrectomy.

Serum lipid, lipoprotein and apolipoprotein values in women with RA and in controls are shown in Table 2. No significant differences in TC, LDL-c and its main protein, apoB, values were found between groups. However, although no significant differences were found in plasma levels of HDL-c and its main protein, apoA-I, between patients with or without gallstone disease, a significantly higher HDL3-c subfraction and higher apoA-I/HDL and HDL3-c/TC ratios were observed in the former. This difference in the HDL3-c subfraction remained after adjustment for age and triglycerides (Fig. 1).

Figure 1.

Serum HDL3-c concentrations in female RA patients with and without gallstone disease.

*Adjusted model with age and triglycerides as covariates.

Serum HDL3-c concentrations are expressed as mean and 95% confidence interval.

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The prevalence of gallstone disease stratified by age in RA patients and controls is shown in Table 3. Female RA patients aged 60 or over had a significantly higher prevalence of gallstone disease compared to the general population of the same age. It could also been observed, that these patients present a higher prevalence of cholecystectomy than controls.

Female RA patients ages 60 or over, compared to controls, presented an OR of 2.8 (95% CI: 1.3–6.0) (Fig. 2) to have gallstone disease. Adjusting for age female RA patients had an OR of 2.3 (95% CI: 1.3–4.1).

Figure 2.

Odds ratio of gallstone disease in female RA patients compared to female controls.

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To our knowledge, this is the first study to assess the prevalence of GD in patients with RA in western countries. It shows that female patients with RA ≥60 years of age had a significantly higher prevalence of gallstone disease compared to the general population of the same age and gender. This high prevalence is independent of age (OR age-adjusted 2.3). General population studies have shown age and female sex to be among some of the most important risk factors for developing GD.16 Thus, as would be expected, older and menopausal RA women would have a higher prevalence of GD. Nevertheless, the present study shows that this prevalence is higher than expected in the general population compared for age and gender.

Biliary lithiasis in RA has received little attention and few studies have been conducted on this topic. A study by Ito et al. in 224 RA patients in Japan (182 female)9 showed a significantly higher incidence of gallstones (including post-cholecystectomy patients) mainly cholesterol stones in female RA patients than in female control (15.4% and 5.2%, respectively). In that study, RA patients were older and had an increased incidence of hypercholesterolemia than controls and, in agreement with our study, the prevalence of GD in male RA patients was very low. Pamuk et al. studied the prevalence of GD in 113 RA patients in Turkey (92 female)10 and possible related factors. That study showed female RA patients to have a significantly higher prevalence of gallstone disease (including cholecystectomy) compared to controls (22.8% and 11.7%, respectively) and only older age was significantly associated with the presence of GD in RA. In our study, female RA patients also had a higher prevalence of GS than controls, although higher than that observed in the abovementioned studies (33.3% in RA and 15.6% in controls). This difference could be explained by the fact that GD is more common in western countries and its incidence continues to rise.11

Gallstone disease is a common digestive disorder worldwide,17 and, although there are different types of gallstones depending on their composition, most biliary stones in western societies are made of cholesterol, which has been reported in up to 80%–90% of gallstones found at cholecystectomy.18 Even though GD is a multifactorial disease derived from complex interactions between many genetic and environmental factors, impaired cholesterol metabolism has been one of the mechanisms involved in the formation of cholesterol gallstones.19 The first and essential requirement is the supersaturation of bile in cholesterol; however, enhanced cholesterol nucleation, impaired gallbladder emptying with stasis and intestinal hypomotility have also been associated.20 In supersaturated bile, phospholipids solubilize cholesterol into vesicles, which may precipitate in monohydrate crystals and become entrapped in gallbladder mucin gel with bilirubinate, and finally agglomerate into a macroscopic gallstone. Hence, cholesterol gallstone, composed predominantly of cholesterol crystals, results from a biochemical imbalance between lipids and bile salts in the gallbladder bile. Notwithstanding, no definitive association trends between serum lipids and gallstones have been found, except for a high frequency of gallstones in subjects with hypertriglyceridemia (type IV hyperlipoproteinemia).21,22 It has been described that nearly all patients with hypertriglyceridemia have supersaturated gallbladder bile even if they are slim. In this respect, female RA patients with GS in the present study displayed a higher plasma TG level compared to those without GD; however, the differences were not statistically significant. On the other hand, it has been suggested that the gallstone risk varies inversely with plasma total HDL or HDL3 cholesterol, attributing to HDL cholesterol a protective effect against gallstone formation.23,24 Furthermore, some studies in mice showed a genetic link between bile acid synthesis and HDL-cholesterol levels through the gene that regulates the expression of the cholesterol 7-alpha hydroxylase (the rate-limiting enzyme for bile acid biosynthesis and cholesterol elimination).20 Other studies found no association between serum HDL-c concentrations and gallstone disease.15 In line with this, our patients with gallstones had a slightly higher plasma concentration of total HDL-c than those without gallstone disease, although these differences were not statistically significant. By contrast, female RA patients with gallstone in the present study displayed significantly higher HDL3-c levels, even after adjustment for age and triglycerides and apoA-I/HDL and HDL3-c/TC ratios than those without gallstone disease. HDL-c is a source of biliary cholesterol, which forms gallstones.25 Nascent HDL particles are transformed into HDL3 and HDL2 particles as they acquire cholesterol esters from other lipoproteins and cells. In turn, the large and spherical HDL2 particles are transformed into the smaller HDL3 particles after delivering their cholesterol content to the liver where this cholesterol is incorporated into bile. Thus, a higher HDL3-c concentration in patients with GS could be related to a higher rate of liver cholesterol delivery from HDL.

Other studies support the hypothesis of increased biliary catabolism of cholesterol in subjects with gallbladder disease characterized by lower ApoB and higher ApoA-I serum concentrations.26 RA patients with gallstone disease in this study also showed lower ApoB and higher ApoA-I values, but no significant differences were found compared with those without gallstone disease. However, RA patients with GS display a higher apoA-I/HDL-c ratio than those without gallstone disease, which may be explained by the higher protein/lipid ratio of HDL3 particles.

In addition to an excess supply of cholesterol in the liver, impaired gallbladder emptying with stasis could contribute to the formation of gallstones.20 Biliary lipid secretion is regulated by an elaborate network of ATP-binding cassette (ABC) transporters on the hepatocyte canalicular membrane.19 It has been observed that the expression and function of ABC transporters could be decreased in liver in adjuvant-induced arthritis rats27 as an animal model for inflammation, thereby hindering the secretion of bile salts and favoring the formation of gallstones.

Furthermore, higher blood concentrations of inflammatory cytokines (IL-1α, IL-6 and TNF-α) in menopausal women with GS have been observed.28 Moreover, it has been reported that the endothelial functions of the gallbladder for recycling of lipids could be diminished in an inflammatory context.5 Thus, the chronic inflammatory state present in RA patients, related to lipid profile and gallbladder function, might explain the higher prevalence of GS in older female RA patients.

Albeit not the purpose of this study, a further major aspect to mention is that an association of gallstones with cardiovascular disease has been suggested.29 This would be very interesting to consider, taking into account that patients with RA have increased cardiovascular risk compared to the general population,30 as has been widely reported in the literature.

A potential limitation of this manuscript is that the data obtained was compared with the information available from a study of several years. Nevertheless, to our knowledge, it is the only existing reference up to the date in the Spanish population.

Women with RA may have a predisposition to gallstone disease that can manifest in middle age or older compared with women in the general population. This situation could be related to chronic inflammation and HDL metabolism. Gallstone disease could be considered a new co-morbidity in female RA patients which has received little attention, although it contributes greatly to health care costs and patient morbidity.

None of the authors has any conflicts of interest.