Background and objective Individuals with psoriasis have increased blood levels of uric acid. However, there is no prospective data on the association between psoriasis and uric acid levels and subsequent development of gout. In this study, we examined the risk of gout among individuals with psoriasis and psoriatic arthritis (PsA) in two cohorts of men and women, the Health Professionals Follow-up Study (HPFS) (1986–2010) and Nurses’ Health Study (NHS) (1998–2010).
Methods 27 751 men and 71 059 women were included in the analysis. Lifetime history of physician-diagnosed incident psoriasis and PsA was confirmed by validated supplementary questionnaires. Incident gout diagnoses were confirmed based on the American College of Rheumatology survey criteria. We used Cox proportional hazards models controlling for potential risk factors to calculate the HRs with 95% CIs of incident gout while simultaneously adjusting for several common risk factors.
Results We documented 2217 incident cases of gout during follow-up. Psoriasis was associated with an increased risk of subsequent gout with a multivariate HR of 1.71 (95% CI 1.36 to 2.15) in the pooled analysis. Risk of gout was substantially augmented among those with psoriasis and concomitant PsA (pooled multivariate HR: 4.95, 95% CI 2.72 to 9.01) when compared to participants without psoriasis.
Conclusions In this prospective study of US women and men, psoriasis and PsA were associated with an increased risk of gout.
- Psoriatic Arthritis
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Psoriasis is a chronic inflammatory skin disorder which may occur in isolation or together with psoriatic arthritis (PsA), an inflammatory seronegative arthritis. Psoriasis is a common disorder with a prevalence of 2–3%, and PsA has been reported to occur in upwards of 25% of those with a diagnosis of psoriasis.1–3 Gout is an inflammatory crystal arthropathy caused by persistent hyperuricaemia (elevation of serum uric acid levels) that deposits uric acid in the joints and soft tissues around the joints, leading to painful episodes of crystal-induced arthritis. The condition can become chronic and lead to joint erosions, damage and marked disability.4 PsA and gout may occur in the same individual, sometimes concurrently, in those with a history of psoriasis.5 ,6
Several studies have shown a correlation between psoriasis, PsA and elevated serum uric acid levels,7–10 with one study further demonstrating a correlation between uric acid levels and psoriasis severity on the psoriasis activity and severity index (PASI).7 Elevated serum uric acid levels correlate with systemic inflammatory markers and, in psoriasis, may be related to increased cell turnover as well as the known systemic inflammation associated with the disease state.9 ,11 Uric acid has been shown to stimulate inflammatory pathways resulting in the secretion of chemokines and inflammatory markers.12 ,13 Coexisting psoriasis and gout has been documented in several case reports; however, no prospective data about the relation between a prior history of psoriasis and the risk of subsequent gout are available to date.14–17
To address this issue, we investigated the association between psoriasis, with and without concomitant arthritis, and risk of subsequent gout using data from a cohort of men in the Health Professionals Follow-up Study (HPFS) and a cohort of women in the Nurses’ Health Study (NHS).
Study participants were from two cohorts, the HPFS and NHS. The HPFS was established in 1986 when 51 529 male health professionals between the ages of 40 and 75 completed a baseline questionnaire. Information on medical history and lifestyle factors was collected biennially via mailed questionnaires in the two cohorts since baseline. The NHS was established in 1976 when 121 701 married female registered nurses ages 30–55 in the USA completed a baseline questionnaire regarding their medical history and lifestyle risk factors. This study was approved by the Institutional Review Board of Brigham and Women's Hospital. The participants’ completion and return of the self-administered questionnaires were considered as informed consent.
Assessment of exposures (psoriasis and psoriatic arthritis)
In 2008, we queried cohort participants about physician-diagnosed psoriasis and the diagnosis date in the HPFS (before 1986, 1986–1990, 1991–1995, 1996–2000, 2001–2004, and 2005 or later) and NHS (1997 or before, 1998–2001, 2002–2005, 2006–2007 and 2008). We confirmed self-reported psoriasis using the Psoriasis Screening Tool (PST) questionnaire, which inquired about the type of clinicians making the diagnosis and phenotypes.18 A pilot study showed a sensitivity of 99% and a specificity of 94% for PST in psoriasis screening.18 Diagnoses of psoriasis with concomitant PsA were confirmed using the psoriatic arthritis screening and evaluation (PASE) questionnaire, which includes a symptom scale with seven items and a function scale with eight items.19 Women chose one of five categories relating to agreement (strongly agree to strongly disagree) for each item. A total score of 47 or greater has been shown to identify PsA with a high sensitivity and specificity in our pilot studies as well as in cohort PsA diagnosis validation.18–20 PASE has good test–retest reliability.21
Assessment of outcome (gout)
We ascertained incident cases of gout using the American College of Rheumatology gout survey criteria, as previously described.9 ,22–24 In HPFS, the participants were asked biennially since baseline whether they had received a physician diagnosis of gout and, if so, the date of first occurrence. In the NHS, the participants were asked for diagnoses of incident gout in 1982, 1984, 1986, 1988, 2002, and biennially thereafter. Starting in 2001, we mailed a supplementary questionnaire to participants with self-reported incident gout diagnosed during the follow-up to confirm the report and to ascertain whether the cases met the American College of Rheumatology (ACR) gout survey criteria.25 The primary end point in this study was incident cases of gout that met 6 or more of the 11 gout criteria (more than one attack of acute arthritis, maximum inflammation developed within 1 day, oligoarthritis attack, redness observed over joints, painful or swollen first metatarsophalangeal joint, unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus, hyperuricaemia, asymmetric swelling within a joint, and complete termination of an attack).9 ,23–27 The overall response rate for the supplementary gout questionnaire was around 80% in both cohorts.9 ,24 Two board-certified rheumatologists reviewed the medical records from a sample of 76 men and 56 women in 2001. Of the76 men, 26 (34%) did not have relevant and complete records. Among the remaining 50 men, the rate of concordance between the diagnosis of gout according to the criteria of the American College of Rheumatology and the diagnosis of gout according to our review of the medical records was 94% (47/50).9 The concordance rate was similar in women (91%, 51/56).24
Information on weight, smoking, diuretics use, aspirin use, and personal histories of type 2 diabetes and hypertension, and menopausal status and postmenopausal hormones use (for women) was collected biennially during follow-up. Height was reported at cohort baseline. Body mass index was calculated as weight in kilograms divided by height in m2 for each follow-up period. Physical activity was assessed biennially in the HPFS and in 1998, 2000, 2004 and 2008 in the NHS. Information on dietary intake was collected using a validated food-frequency questionnaire, and was available in 1986, 1990, 1994, 1998, 2002 and 2006 in the HPFS, and in 1998, 2002 and 2006 in the NHS.28–30
Participants who did not respond to the psoriasis questions in 2008 or self-reported psoriasis that occurred before the baseline were excluded from the analysis. A total of 27 751 men and 71 059 women were included in the present analysis; they contributed person-years of follow-up from the return date of the baseline questionnaire to the diagnosis date of gout or the end of follow-up (1 June 2010), whichever came first. We ensured that the exposure (psoriasis/PsA) occurred before the outcome (gout).
We used Cox proportional hazards analyses to estimate the age- and multivariate-adjusted relative risks (HRs) and 95% CIs for the association between history of psoriasis/PsA and risk of incident gout. Multivariate-adjusted HRs were calculated after adjusting for age, body mass index (BMI), alcohol, physical activity, smoking status, hypertension, type 2 diabetes, diuretics use, aspirin use, and daily average intakes of total vitamin C, coffee, total meats, seafood, total dairy foods and free fructose. All the covariates were updated during follow-up to account for changes over time. For the pooled analysis, we tested the between-study heterogeneity and estimated the overall association from a random-effects model.31 As a sensitivity analysis, we also examined the association of psoriasis history at baseline (1986 in the HPFS and 1998 in the NHS) and risk of indent gout during the entire follow-up. We further examined the association between history of other inflammatory arthritis (rheumatoid arthritis) and non-inflammatory arthritis (osteoarthritis) and risk of incident gout, and between history of gout and risk of incident psoriasis/PsA. All statistical analyses were performed using SAS V.9.2. All statistical tests were two-tailed, and the significance level was set at p<0.05.
We documented a total of 2217 incident cases of gout during follow-up (1368 cases in men and 849 cases in women, accounting for 4.9% men and 1.2% women included in the study). A total of 292 men and 1329 women reported psoriasis at baseline. An additional 332 men and 1002 women reported psoriasis during follow-up. Baseline characteristics of study participants are shown in table 1. Participants with psoriasis appeared to have higher BMIs, and higher prevalence of smoking, hypertension, type 2 diabetes and diuretics medication. Dietary factors were generally similar between those with and without psoriasis.
Among participants who self-reported psoriasis, the multivariate-adjusted HRs for gout were 1.79 (95% CI 1.30 to 2.47) in men, 1.63 (95% CI 1.17 to 2.27) in women and 1.71 (95% CI 1.36 to 2.15) in the pooled analysis (table 2). Consistent with our results among self-reported psoriasis, we found that participants with confirmed psoriasis had a higher risk of gout in the pooled analysis (HR=1.95, 95% CI 1.02 to 3.75). The multivariate HR appeared to be higher among men with confirmed psoriasis (HR=2.72, 95% CI 1.75 to 4.25) than among women with confirmed psoriasis (HR=1.40, 95% CI 0.90 to 2.19).
We further examined psoriasis without and with concomitant PsA and subsequent risk of gout (table 3). Of note, the risk of incident gout was substantially elevated among those with psoriasis and concomitant PsA (pooled multivariate-adjusted HR=4.95, 95% CI 2.72 to 9.01). The increased risk of gout in association with psoriasis with concomitant PsA was consistent among men and women.
Sensitivity analysis examining the association of baseline psoriasis with risk of incident gout during follow-up showed similar results with the primary analyses (see online supplementary tables S1 and S2). Among those who had a confirmed diagnosis of psoriasis at baseline, the multivariate HR for gout was 1.84 (95% CI 1.09 to 3.09) in the pooled analysis. Risk of incident gout was also substantially increased among those with psoriasis and concomitant PsA at baseline (pooled multivariate HR=5.23, 95% CI 2.70 to 10.1).
In contrast to the strong association between history of psoriasis and risk of gout, there was only a marginal association between history of rheumatoid arthritis and risk of gout (pooled multivariate HR=1.15, 95% CI 0.99 to 1.35) (see online supplementary table S3), and a significant but much weaker association between history of osteoarthritis and risk of gout (pooled multivariate HR=1.15, 95% CI 1.04 to 1.26) (see online supplementary table S4). Heterogeneity test suggested that the association between history of psoriasis and risk of gout was significantly different from that between rheumatoid arthritis (p=0.005 for heterogeneity) and gout and between osteoarthritis and gout (p=0.002 for heterogeneity).
Interestingly, the associations between history of gout and risk of incident psoriasis and PsA were also significant but smaller in magnitude as compared to those between history of psoriasis and PsA and risk of incident gout (see online supplementary table S5). Specifically, the pooled multivariate HRs were 1.53 (95% CI 1.18 to 2.00) for psoriasis and 3.43 (95% CI 1.63 to 7.18) for PsA among those who had a history of gout.
Our findings represent the first prospective evidence demonstrating that a prior history of psoriasis as well as PsA is associated with an increased risk of incident gout based on data from two large US cohorts of men and women. The associations between psoriasis, PsA and incident gout were generally consistent in different statistical analyses, though the risk estimates appeared to be higher among men than in women. This may be associated with gender heterogeneity since more frequent and severe gout were reported among men than among women.32 The incidence of gout has been shown to rise with age among both women and men, with a decrease in the male : female ratio by age: ages 15–44 (1.7 vs 0.1 per 1000); 45–64 (10.6 vs 1.3 per 1000); >65 (12.2 vs 3.0 per 1000). These and other data indicate that women have a far lower prevalence of gout compared to men and that gender differences get smaller as age increases, but that men still far outnumber women with gout.33–36 Overall the risk estimates were substantial and demonstrate a clear association between a prior history of psoriasis, with or without concomitant PsA, and incident gout.
Our group has previously reported on musculoskeletal pain presentation among psoriasis patients presenting to a combined dermatology–rheumatology clinic.5 ,6 Psoriasis patients with new onset musculoskeletal complaints were diagnosed with PsA, osteoarthritis, crystal arthopathy including gout and combinations of these diagnoses.5 ,6 Clinically, an awareness of the relationship between psoriasis, PsA and gout is therefore particularly important when evaluating the psoriasis patient for possible inflammatory arthritis symptoms. In those individuals presenting with an asymmetric, inflammatory synovitis, our findings clearly highlight the need to consider inflammatory crystal arthopathy in the differential diagnosis of psoriasis patients presenting with an acutely inflamed joint(s). Several case reports and series have reported the diagnostic challenge and often-missed clinical presentation of concomitant psoriasis, PsA and gout.14–17
Psoriasis is a common inflammatory skin disorder, with reports of up to 25% of patients having concomitant PsA.1–3 Psoriasis disease activity has been variably associated with elevated serum uric acid levels in several studies.7 ,10 ,37 ,38 One recent study compared 119 psoriasis subjects to an equal number of matched controls and found statistically significant higher serum uric acid levels and higher prevalence of asymptomatic hyperuricaemia among psoriasis subjects; psoriasis was the strongest predictor of hyperuricaemia after adjusting for age, sex and metabolic syndrome features.39 Both psoriasis and PsA have been associated with elevated serum uric acid levels, which have been attributed at least in part to the purine metabolites of increased cell turnover as seen in psoriasis skin disease.9 ,11 Interestingly, a recent study has revealed the presence of more monosodium urate crystals in the synovial fluid of patients with PsA in comparison to other previously diagnosed joint diseases.40 Hyperuricaemia has also been correlated with markers of systemic inflammation, including C-reactive protein (CRP).41 In one study, serum CRP and uric acid levels were increased among subjects with psoriasis (n=25) as compared to controls (n=50).8 CRP levels were up to 20-fold higher among those with psoriasis in this study, and serum uric acid levels were significantly higher compared to control groups, with nearly 25% of those with psoriasis having a uric acid level of more than 10 mg/dL. In the psoriasis group, CRP decreased by nearly 50%, and a fall in uric acid was observed in nearly 80% of subjects, after 12 weeks of psoriasis treatment.8 A cross-sectional study on the correlation of serum uric acid with psoriasis disease severity in 198 Korean patients found that serum uric acid in psoriasis patients is positively associated with PASI, extent of skin involvement and BMI for both genders independently.7 Elevated serum uric acid levels were present in 45% of PsA patients in one observational study.42 While no definitive unifying mechanism exists, one may speculate about immunologic stimulation of cellular pattern recognition receptors, which may drive systemic inflammation in psoriasis via tissue injury response.43 In gout this may be further driven by response to urate crystals (themselves a known damage-associated molecular pattern—‘DAMP’).43
Psoriasis, PsA, hyperuricaemia and gout have all been tied to the metabolic syndrome and positively associated with cardiovascular risk.44 Among individuals with PsA, a significant correlation between serum uric acid levels and subclinical atherosclerosis was found as indicated by increased carotid intima-medial thickness.37 ,38 ,45 Onat et al46 showed that elevated uric acid levels correlate with a pro-inflammatory state and high-density lipoprotein dysfunction and that risk of coronary heart disease is independently predicted by elevated uric acid levels in non-diabetic men, modulated by the metabolic syndrome and gender. Elevated uric acid (hyperuricaemia), the direct cause of gout, has also been independently associated with the development of diabetes and essential hypertension and has been identified as an independent risk factor for all-cause and cardiovascular mortality.44 ,47 Cassano et al48 evaluated the role of serum uric acid in conditioning the association of psoriasis with the metabolic syndrome. In their study, serum uric acid levels were significantly higher among psoriasis subjects than controls and their results indicated a trend towards a correlation between serum uric acid levels and the risk of metabolic syndrome in psoriasis patients. Despite the metabolic syndrome risk factors commonly shared by those with gout and psoriasis, our findings demonstrated an independent association between psoriasis and gout even after adjusting for BMI, hypertension, diabetes, smoking and relevant dietary factors.
Strengths of our study include the use of two well-characterised, large, prospective cohorts to evaluate the association between psoriasis, psoriatic arthritis and incident gout. The exposures and outcomes of our study were confirmed by use of validated questionnaires, as described above. The development of gout, in the setting of hyperuricaemia among those with psoriasis and/or psoriatic arthritis, is biologically plausible and supported by our data after adjusting for other known risk factors for gout in this population. The availability of detailed cohort follow-up information allowed us to control for a number of important confounders that may have influenced these associations.
We acknowledge some limitations of our study. While we accounted for multiple potential confounders known to be associated with gout, such as diet (eg, seafood and fructose) and medication use (eg, diuretics), it is possible that residual confounding may still remain. One recent study reported a lower sensitivity of PASE, raising the concern about possible misclassification of PsA cases.49 Because PASE picks up individuals with active disease who are potentially more likely to have inflamed joints and increased systemic inflammation, it probably underestimates the number of PsA cases, therefore leading to a conservative estimation of the association of interest. Using a survey approach, we are unable to correlate serum urate levels and quantitative renal function among our subjects. Finally, confirmation of gout cases was based on the ACR criteria for gout, which rely heavily on a presentation of podagra (acute arthritis presentation at the first metatarsophalangeal joint). A recent study demonstrates that at follow-up, among patients with a podagra-like presentation, 77% had gout while the remainder were given a different diagnosis.27
In summary, our study found that among individuals with a prior history of psoriasis in two large cohorts of US men and women, there was an increased risk of incident gout. The risk of gout was substantially augmented among those with psoriasis and concomitant PsA. The association between psoriasis, PsA and gout appeared to be stronger in men than in women. The association between psoriasis/PsA and gout is different from those between rheumatoid and osteoarthritis, and gout. These findings have important implications for clinical practice and for potential disease prevention.
We are deeply indebted to the participants and staff of the Health Professionals Follow-up Study and Nurses’ Health Study for their valuable contributions. The authors wish to thank Tricia Li for her help with data programming support.
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Handling editor Tore K Kvien
JFM and SW contributed equally.
Contributors JFM, SW and AAQ have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All the authors were involved in preparing this manuscript. JFM, SW, JH and AAQ were responsible for the overall study design, data analysis and interpretation of data, and wrote the initial draft of the manuscript. All authors contributed to the critical revision of the manuscript.
Funding This work was supported by Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, a Nurses’ Health Study grant (P01 CA87969) and a Nurses’ Health Study II grant (R01 CA50385). HKC is supported by NIH (NIAMS) grants R01-AR056291, R01-AR065944, P60 AR047785 and R21 AR056042.
Competing interests AAQ serves as a consultant for Abbott, Centocor, Novartis and the Centres for Disease Control and Prevention. JFM serves as a consultant for Biogen Idec, is on an advisory board for Amgen, is an investigator for Amgen and has received investigator initiated research grants from Biogen IDEC. HKC has served on advisory boards for Takeda Pharmaceuticals and Astra-Zeneca Pharmaceuticals and has received investigator initiated research grants from Takeda Pharmaceuticals and Savient Pharmaceuticals.
Ethics approval This study was approved by the Institutional Review Board of Brigham and Women's Hospital (IRB Protocol Title: Psoriasis in large cohort studies, IRB Protocol Number: 2006P001156).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional unpublished data are available beyond that which is published in the study.