Episodes of diffuse musculo-skeletal pain appearing in and around a joint region without a clear diagnosis, etiology and therapy are still a major problem in general medicine. A clear diagnosed gout is the most common inflammatory arthritic disease, affecting about 1% to 2% of the population [1]. Prevalence is expected to increase due to changes in diet – such as high intake of meat, fructose and beer - and the ageing of the population [2]. Clinically, gout is defined as a deposition disease, i.e. diagnosis is confirmed by the presence of monosodium urate crystals in the synovial fluid or tophi in soft tissue [1]. These crystals are responsible for acute episodes of inflammation as well as long-term sequelae due to chronic inflammation of gout [3].

The deposition of monosodium urate results from untreated hyperuricemia. The crystallization process is temperature and pH-dependent and occurs when the theoretical saturation threshold of 6.8 mg/dL (~400 µmol/L) serum urate at 37°C is exceeded [4]. Accordingly, lowering the serum urate level and depleting the body urate pool are the established goals in the treatment of gout. To achieve this, the serum urate must be reduced below the saturation point of monosodium urate under physiological conditions. Based on these conclusions, the European League against Rheumatism (EULAR) and American Society of Rheumatism Task Forces for Gout recommend lowering serum urate levels to a target of ≤6 mg/dL (360 µmol/L) [5, 6]. For patients with tophaceous disease manifestation, the British Society of Rheumatology (BSR) and American College of Rheumatology (ACR) proposed an even stricter serum urate target of <5 mg/dL (<300 µmol/L) [5, 7]. Hence, the establishment of a target value results from biochemical observations, i.e. the crystallization process, and not from epidemiological results.

Although hyperuricemia is an established risk factor for gout with a prevalence in the US of more than 21% [8, 9] there is still debate regarding the diagnostic value of serum urate levels. There are case reports indicating that many people with higher serum urate levels do not develop gout, while others presenting with crystal proven gout have “nearly” normal serum urate levels at the time of investigation [10]. While the usefulness of urate-lowering treatment in patients with clinical manifestations of hyperuricemia has been established, its use in asymptomatic hyperuricemia is still the object of several controversies [11]. Nevertheless evidence rises for uric acid in non-gouty patients to be an independent cardiovascular and metabolic risk factor. Asymptomatic hyperuricemia is both associated with as well as a predictor of hypertension, renal deficiency and diabetes. Therefore, uric acid is increasingly seen as part of the metabolic syndrome [12].

Since evidence for subclinical musculo-skeletal involvement in otherwise asymptomatic individuals with hyperuricemia is lacking, urate lowering therapy to date is only indicated and reimbursed in cases of confirmed gout. Current international guidelines do not address the pharmacologic management of asymptomatic hyperuricemia due to a paucity of prospective, randomized, controlled intervention trials in that area [13]. Still there are no data available how many patients with asymptomatic hyperuricemia have to be treated to prevent one patient with gout (number needed to treat/number needed to harm). However, in a cross-sectional controlled study ultrasound findings demonstrate the signs of present monosodium urate crystal tissue deposition in both intra and extra-articular structures from asymptomatic hyperuremic individuals [14]. The present study addresses the issue whether slightly elevated urate levels are associated with musculo-skeletal pain.

The present cross-sectional study evaluated the relationship between hyperuricemia and musculo-skeletal pain. In this population of generally healthy subjects (including patients with controlled mild hypertension, hyperlipidemia, and /or not insulin dependent diabetes) presenting for their annual routine check-up, mean urate levels were within the normal to slightly elevated range, whereby both, men and women, showed an increase with age, which was much stronger in women. Results indicate a possible impact of the urate level on unspecific joint pain. This correlation was significant for overall joint pain as well as for the most commonly pain-affected locations lumbar spine, cervical spine, shoulder, and knee. A comparison of urate levels demonstrated consistently higher urate levels in patients experiencing joint pain than in pain-free patients, independent of gender and across the relevant age group >40 years, which covers the broad majority of this population. A similar relationship between urate level and musculo-skeletal pain was indicated in a 1-year longitudinal study linking urate levels in women with chronic non-gouty pain to the number of pain locations [16]. The authors suggested more intensive care and rehabilitation measures for patients featuring a relatively high serum urate level, yet still within the reference range, along with pain at multiple locations [16].

Triggered by the crystallization of urate within the joints, gout can lead to substantial morbidity by causing severe pain. While the role of hyperuricemia in the manifestation of gout is established, it is still under debate whether elevated urate levels alone are already an indication to start anti-gout treatment. According to the developed evidence-based recommendations for the diagnosis and management of gout [1, 5, 6] a raised serum urate level alone is not specific to gout [1, 6]. Nevertheless the degree of hyperuricemia is a strong predictor for an increased risk to develop gout [9]. Rheumatologic guidelines recommend a target value for uric acid in gout patients (men and women) of < 6 mg/dl [5-7].

Emerging evidence suggests that gout is independently associated with all-cause mortality [8, 17, 18] as well as cardiovascular mortality [19]. Furthermore, several studies demonstrated that elevated urate levels were associated with an increased risk for cardiovascular mortality in CKD patients [20-22], thus strengthening the necessity to lower urate before the development of gout. Notably, for the first time, Stack et al. provided evidence in a population-based cohort trial that not only gout but also hyperuricemia alone is associated with total and cardiovascular mortality. In this context, other epidemiological studies indicated that an elevated serum urate level alone is an independent predictor of the development of chronic kidney disease (CKD) in patients with normal renal function [23] and progression of renal disease in hyperuricemic patients achieving uric acid lowering therapy could be decelerated [24]. Consequently, several interventional studies showed beneficial effects of urate lowering therapies.

The potential additional benefits of urate lowering therapy before the manifestation of gout outlined above are backed up by ultrasonographic findings. In a cross-sectional controlled study morphostructural changes suggestive for monosodium urate deposition induced by chronic hyperuricemia were found in both intra- and extra-articular structures of clinically asymptomatic individuals [14]. Similarly, ultrasonographic examinations of patients with asymptomatic hyperuricemia revealed sonographic findings implicating an as yet silent precipitation of urate crystals [25]. This corresponds to our observation that high-sensitive CRP does not correlate with an increase in urate level and pain. Therefore, one possible crystal-mediated inflammation appears to be of a nature that is not perceptible by serological findings. In addition, crystal-independent mechanisms might be involved. Oxidative pathways seem to participate in local and systemic damage to joints. The damage seems to be based on the increased activity of xanthine oxidase in hyperuricemia, resulting in the production of reactive oxygen species (ROS) [26]. It is noteworthy that ROS generated via activated xanthine oxidase is also playing a major role in the cardio-renal-metabolic syndrome [27].

In both ultrasonographic studies, patients with asymptomatic hyperuricemia had a mean urate level of 8.1 mg/dL (482 mmol/L) [14, 25]. In consistence with our findings, these data suggest that longstanding, untreated hyperuricemia might cause joint complaints, (e.g. unspecific pain), even if asymptomatic, probably presenting as diverse and unspecific pain. Dalbeth and coworkers introduced a new staging system for gout dividing asymptomatic hyperuricemia in two stages: hyperuricemia with and without crystal deposition [28]. Considering our findings and those of others crystal depositions should no longer be staged as asymptomatic. In this context, the sudden rise in patients with joint pain from 30.8% to 60.9% between urate levels 5.0 and 5.5 mg/dL is particularly noteworthy and may be indicative of a possible need to correct established norm values. Randomized controlled trials are required to investigate whether urate lowering therapy has a positive effect on patients with hyperuricemia and unspecific musculo-skeletal problems.

The study has several limitations that need to be addressed. The patient reported outcome of pain is subjective and may lead to an over or underrepresentation of actual results. This cross-sectional study was carried out in a single center, therefore center bias cannot be ruled out. However, in order to minimize bias, laboratory check-ups were performed by residents who had little contact with the patients before the examination. On purpose, we forewent the use of a validated pain inventory as usually applied in pain clinics and pain studies, because only a few patients had these included in their routine check-up examination. Furthermore, there might have been a preselection in the sense of predominately pain oriented or pain-focused patients. Imaging to detect uric acid deposits in effected joints associated with pain was not performed.

Overall, the large number of patients forms a solid data base, and the statistics performed indicate that the observed association between urate levels and musculo-skeletal pain was not random.

In this population of generally healthy subjects presenting for their annual routine check-up, results indicate the possibility of a significant impact of urate levels on joint pain.

The increasing evidence showing depositions at elevated urate levels without a previous gout attack should stimulate further discussion whether start of gout management should be started earlier. Randomized controlled trials should be undertaken to clarify the link between elevated urate levels, monosodium urate depositions and discomfort in the patients.

This study was reviewed and approved by federal state law established Ethics Committees Counselling (reference no. OB.99).

The authors confirm that this article content has no conflict of interest.