Rheumatology Advance Access originally published online on December 13, 2005
Rheumatology 2006 45(2):229-230; doi:10.1093/rheumatology/kei196
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LETTER TO THE EDITOR |
Sequential synovial fluid sampling suggests plasma and synovial fluid IL-6 vary independently in rheumatoid arthritis
Academic Rheumatology, University of Bristol, Bristol Royal Infirmary and 1 Henry Wellcome Laboratories for Integrated Neuroscience and Endocrinology, University of Bristol, Bristol, UK
Correspondence to: M. G. Perry, Academic Rheumatology Unit, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK. E-mail: mark.g.perry{at}bristol.ac.uk
SIR, Inflammatory cytokines, including interleukin-6 (IL-6), are raised in rheumatoid arthritis (RA). Single paired daytime samples show that the IL-6 and TNF-
concentrations in synovial fluid exceed blood concentrations during the day [1–3], and these and other data suggest that joints are the source. Recent data have shown that plasma IL-6 in RA follows a circadian pattern with a peak at 6 a.m. [4]. If IL-6 is generated inside joints and diffuses into plasma, it might be expected that the synovial fluid IL-6 concentration would also undergo a large diurnal variation. Such investigations necessitate the development of a safe and acceptable synovial catheter allowing sequential synovial fluid sampling. Following the approval of the United Bristol Healthcare Trust Research Ethics Committee, we undertook a daytime pilot study for this purpose. In addition we obtained preliminary data for IL-6 variations in paired synovial fluid and plasma samples.
We recruited six volunteers aged 36–64 yr with RA according to the criteria of the American College of Rheumatology. Each volunteer had active disease (at least three swollen and three tender joints) and a large knee effusion. After establishing the technique, we obtained paired blood and synovial fluid samples in three patients. One patient was taking prednisolone 7.5 mg daily, but no other patient was taking glucocorticoids and none had had intra-articular or intra-muscular glucocorticoids for more than 10 weeks. After we had obtained written consent, each patient was admitted and remained on bed rest between 8.30 a.m. and 5.30 p.m. With the patient on the bed, we used an aseptic non-touch technique including sterile gown and gloves to insert a synovial catheter. The knee was exposed, a large area of skin carefully cleaned with iodine 1% antiseptic solution, and sterile drapes were used to produce an aseptic field. Up to 2 ml bupivacaine 0.5% was infiltrated under the skin adjacent to the lateral parapatellar joint space and towards the synovial membrane. After local anaesthesia was obtained, a sterile disposable intravenous (i.v.) cannula (14 gauge BD Venflon; Becton Dickinson Infusion Therapy, Sweden) was inserted into the parapatellar joint space. The cannula was connected to a three-way tap with flexible extension (BD Connecta Plus 3; Becton Dickinson Infusion Therapy). Sterile film wound dressings (C-View; Unomedical, UK) enabled the synovial cannula to remain perpendicular to the skin. After taking microbiological and orthopaedic advice, we chose not to use prophylactic antibiotics. A standard i.v. cannula was used for sequential blood sampling. No samples were taken for at least 1 h after cannulae insertion. The i.v. cannula was flushed with 10 ml 0.9% saline after insertion and before and after each blood sample. The first 2 ml of each sample taken from the knee and the first 4 ml of each sample taken from the i.v. cannula were discarded. Paired blood and synovial fluid samples were taken through the day. Plasma and synovial fluid samples were stored at –80°C and analysed using solid-phase sandwich ELISA (enzyme-linked immunosorbent assay) kits (Diaclone Research, detection limit 2 pg/ml, inter- and intra-assay variation <6%). A colleague not directly involved in the project asked each volunteer for comments about their experience.
The synovial catheter allowed sequential synovial fluid sampling over 8 h. From the independent interviews, the procedure was acceptable to volunteers. The only adverse effect noted was slight knee stiffness in two volunteers, and there were no other adverse effects. In addition we obtained a small number of paired synovial fluid and blood samples (Fig. 1). Plasma IL-6 decreased exponentially by 95%, from a mean [95% confidence interval (CI)] of 19.1 (34.1, 4.1) pg/ml at 10 a.m. to <2 (<2, <2) pg/ml at 5 p.m. (paired t-test, P<0.05). These results are similar to previously published data [4]. Synovial fluid IL-6 changed little during the 8 h (non-significant decrease of 30%), with 10 a.m. IL-6 mean (95% CI) 12.0 (17.5, 6.5) ng/ml and 5 p.m. mean 7.9 (11.1, 4.7) ng/ml. The patient with the highest synovial fluid IL-6 concentration had the lowest plasma IL-6 concentration.
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Developing a safe and acceptable synovial catheter was the prime reason for this study. We found that sequential synovial fluid samples can be taken safely through a synovial catheter over 8 h by a technique that is acceptable to volunteers and avoids repeated arthrocentesis. Our very preliminary values are similar to previous single time-point data [1, 3, 4], but in addition they suggest that there is not a straightforward relationship between synovial fluid and plasma IL-6. A variation was reported in blood IL-6 from normal volunteers with sleep deprivation, but our blood variation is four times greater than the maximum seen in these normal volunteers [5]. Although this is a small pilot study with large confidence intervals and one volunteer was taking a low dose of glucocorticoid, the results suggest that plasma IL-6 falls substantially during the day while synovial fluid levels remain relatively unchanged. This challenges the notion that plasma IL-6 is merely a reflection of synovial IL-6 production. The true relationship between synovial fluid and plasma levels needs further investigation, in particular in relation to night-time variation. Such studies should be possible using a synovial catheter.
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Acknowledgments
M.G.P. was funded by the Charitable Trustees of the United Bristol Hospital Trust; L.R. and D.S.J. were funded by the Wellcome Trust.
The authors have declared no conflicts of interest.
References
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- Crofford LJ, Kalogeras KT, Mastorakos G et al. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab 1997;82:1279–83.
[Abstract/Free Full Text] - Vgontzas AN, Papanicolaou DA, Bixler EO et al. Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 1999;84:2603–7.
[Abstract/Free Full Text]
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