<i>In vivo</i>detection of monosodium urate crystal deposits by Raman spectroscopy—a pilot study: Table 1

Sir, Gout is the most common inflammatory arthritis and results from prolonged hyperuricaemia [1]. Joint aspiration and examination of the aspirated SF is the gold standard for diagnosing gout [2]. However, joint aspiration is painful, invasive and SF examination has modest interobserver agreement for detecting MSU crystals [3]. Raman spectroscopy (RS) offers a non-invasive method for detecting MSU crystals, as each chemical possesses a unique Raman spectrum [4]. This study reports the use of RS for detecting MSU crystal deposits in the first MTP joint of gout patients. The study was approved by the University of Nottingham Medical School Ethics Committee (Nottingham, UK; reference D11092014 SoM ROD) and all participants gave written informed consent as per the Declaration of Helsinki. Ten patients with OA not known to have gout and 10 patients with gout participating in a community-based trial of nurse-led vs general practitioner–led treatment of gout participated in this study (Table 1). All patients gave blood for serum uric acid measurement and had RS. A Sierra (Snowy Range Instruments, Laramie, WY, USA) Raman spectrometer (785 nm, spectral resolution 4/cm) was used. The patients were seated with their knee flexed and the index foot rested on the floor to avoid movement during testing. The RS device was positioned on the floor and angled such that the laser impacted the medial MTP joint line perpendicularly. The device was placed at a distance of ∼2.7 cm from the first MTP joint in order to position the focal point of the laser on the joint surface. The laser was directed at a point on the medial aspect of the first MTP joint that was identified by A.A., a rheumatologist with >9 years experience. The foot and RS device were covered to remove any light interference. The RS device was set to illuminate with a power of 80 mW and 10 s integration time, repeated five times, with a reference scan before each 10 s scan. The reference scan was subtracted from the recorded scan. The mean of five reference subtracted scans formed the final spectrum. Disease and demographic characteristics of the study participants aThree patients were on febuxostat. bAs per Pelaez-Ballestas et al. [6]. RS: Raman spectroscopy; ULT: urate-lowering treatment. Disease and demographic characteristics of the study participants aThree patients were on febuxostat. bAs per Pelaez-Ballestas et al. [6]. RS: Raman spectroscopy; ULT: urate-lowering treatment. The number of peaks in the averaged Raman spectra from the first MTP joint that matched those from a Raman spectrum of MSU crystals obtained from the gouty tophus of a patient attending the Rheumatology Clinic at St Michael’s Hospital, Toronto, Ontario, Canada, were counted independently by D.C. and F.B. The tophus fluid contained MSU crystals and its Raman spectrum matched previous reports [5]. The Raman spectrum of the tophus discharge was printed on an acetate sheet and overlaid on the RS traces from the patients to identify any peaks related to MSU crystals in vivo. A combination of five spectral peaks that are characteristic of MSU was chosen to increase confidence in the Raman data [5]. Five peaks relating to MSU were present in the first MTP joints of 7 of 10 gout patients and 1 of 10 patients with OA (supplementary Fig. S1, available at Rheumatology Online). The latter observation raises the possibility of asymptomatic MSU crystal deposits. As we did not look for MSU crystals in the first MTP joint by an alternative established technique, we do not know if the absence of MSU crystals in those with gout is a true or false negative finding. We believe that this is a true negative finding since patients with gout were on urate-lowering treatment and had normal serum uric acid for several months prior to RS, and the MSU crystals may have dissolved in this time (Table 1). Similarly, we do not know if the presence of peaks characteristic of MSU crystals in one control patient with OA who did not meet the classification criteria for gout [6] is a false positive or a true positive finding suggesting asymptomatic MSU crystal deposition. However, as this patients’ serum uric acid was 306 μmol/l, we believe that this could be a false positive finding. The sensitivity of RS in detecting MSU crystal deposits in the first MTP joint in this study is comparable to that of US scans [7, 8]. However, we were unable to examine the dorsal aspect of the first MTP joint because the RS device could not be positioned on this surface due to its weight (9 kg) and the need to keep it absolutely still during RS. Therefore it is possible that RS may have an even higher sensitivity for detecting MSU crystal deposits than US. Thus further research is required to compare RS using a fibre-optic probe to allow examination of the dorsal aspect of the foot against US, joint aspiration or dual-energy CT in order to determine if it is able to reliably detect MSU crystal deposits in vivo. Rheumatology key message Raman spectroscopy may offer a non-invasive method for detecting monosodium urate crystals in gout. The authors would like to acknowledge Dr Lawrence Rubin, Consultant Rheumatologist, St Michael’s Hospital, Toronto, ON, Canada, for donating the gouty tophus discharge from one of his patients and Wendy Jenkins and Sally Doherty for their help recruiting the study participants. Funding: This research was funded by the Natural Sciences and Engineering Research Council of Canada Discovery and Idea to Innovation (I2IPJ4915-14) funds and departmental research funds at the University of Nottingham. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data are available at Rheumatology Online.

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