Ann Rheum Dis 2001;60:984–992 B F LEEB
MATTERS ARISING Management of knee osteoarthritis I read with great interest Dr Jawad’s letter and the authors’ reply about the EULAR recommendations for the management of knee osteoarthritis (OA).1 2 As a member of the ESCISIT task force I feel free to discuss some of the issues raised by Dr Jawad and to give further arguments for the accuracy of the recommendations developed by the group of European experts.3 Although most points of criticism were answered by M Dougados and M Doherty it seems to me that treatment of knee OA with symptomatic slow acting drugs in osteoarthritis (SYSADOA) and cyclo-oxygenase-2 (COX-2) inhibitors needs to be discussed in a diVerent way in the light of recent publications. With respect to SYSADOA, the statement that these substances may modify structure has been strengthened by the publication of Reginster et al, in which glucosamine sulphate (GS) treatment was proved to exert a significant decrease in joint space narrowing compared with placebo during a three year period, indicating the disease modifying eVect of GS for the first time.4 Moreover, symptomatic eYcacy was shown using the WOMAC index as an outcome measure. Other publications dealing with possible disease modifying properties of hyaluronic acid are well known,5 and trials investigating the same issue for chondroitin sulphate (CS) are currently underway. Two meta-analyses6 7 as well as controlled trials have provided evidence for the symptomatic eYcacy of GS and CS and proved their overall excellent tolerability, when compared with treatment with non-steroidal antirheumatic drugs (NSAIDs). With respect to COX-2 inhibitors, to my knowledge no publication exists to show that COX-2 inhibitors, such as Rofecoxib and Celecoxib, are more eYcacious than classical NSAIDs. On the other hand, all the studies indicate better gastrointestinal tolerability of both these new compounds, but some severe gastrointestinal toxicity and dyspepsia, comparable with classical NSAIDs, has been noticed.8 9 When dyspepsia occurs it is not possible to predict erosions or an ulcer and, therefore, endoscopy has to be performed if epigastralgia occurs. This reduces the potential for cost saving with the new compounds and is inconvenient for patients. Thus the advantages of COX-2 inhibitors remain doubtful, taking into account the costs of these compounds, but should be considered carefully in the future. It is obviously necessary to develop and adapt treatment recommendations according to upcoming knowledge all the time. The EULAR recommendations for the treatment of knee OA, however, at the time they were written seemed to summarise all the therapeutic options, including nonpharmacological and surgical options, accurately, even in the light of publications appearing after the end of the literature search in December 1998. Dr Leeb is currently taking part in a trial focused on the disease modifying ability of CS, sponsored by IBSA.
Lower Austrian Centre for Rheumatology, Stockerau Hospital, A-2000 Stockerau, Landstrasse 18, Austria [email protected]
1 Jawad ASM. EULAR recommendations for the management of knee osteoarthritis. Ann Rheum Dis 2001;60:540. 2 Dougados M, Doherty M. EULAR recommendations for the management of knee osteoarthritis - reply. Ann Rheum Dis 2001;60:540. 3 Pendleton A, Arden N, Dougados M, Doherty M, Bannwarth B, Bijlsma JWJ, et al. EULAR recommendations for the management of knee osteoarthritis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2000;59:936–44. 4 Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term eVects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo controlled, trial. Lancet 2001;357:251–6. 5 Listrat V, Ayral X, Patarnello F, Bonvalet JP, Simonnet J, Amor B, et al. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan®) in osteoarthritis of the knee. Osteoarthritis Cartilage 1997;5:153–60. 6 Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000; 27:205–11. 7 McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for the treatment of osteoarthritis: a systemic quality assessment and meta-analysis. JAMA 2000; 283:1469–75. 8 Siverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study. A randomized controlled trial. Celecoxib Longterm Arthritis Safety Study. JAMA 2000;284: 1247–55. 9 Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160: 2998–3003.
Author’s reply I thank Dr Leeb for his interest in my recent letter about the EULAR recommendations.1 The recent large, randomised, placebo controlled, double blind, prospective trial had shown that glucosamine sulphate (GS) treatment resulted in significantly less medial joint space narrowing of the knee, in addition to significant improvements in pain and disability, which were sustained for the three year duration of the study. However, the general correlation between symptoms and structural changes was poor.2 The symptoms of patients with severe joint space narrowing receiving GS did improve, but this was not associated with slowing down of radiographic structure impairment. Further studies with longer follow up are needed to assess whether these changes are predictive of further clinical progression of osteoarthritis. The year 2000 meta-analysis of the six best designed trials of GS for osteoarthritis reported two possible limitations among the analysed studies. Firstly, only one study had adequately assured randomised allocation.3 The second limitation was that authors were often aYliated with the manufacturers of the product tested. Among the six studies analysed, the one assigned the highest quality score reported the smallest eVect.4 A meta-analysis of seven randomised controlled trials of chondroitin sulphate (CS) in osteoarthritis had shown better pain relief with CS than with placebo at six months;
however, no dose eVect was noted (for example, 2000 and 800 mg/day were similarly eVective).5 A large long term, double blind, randomised controlled trial is needed to confirm the symptomatic benefit of CS in osteoarthritis . The main advantage of GS and CS is their safety, and they are certainly more safe than non-selective, non-steroidal anti-inflammatory drugs (NSAIDs), especially in their eVect on the gastrointestinal tract. With regards to COX-1 sparing NSAIDs, I agree with Dr Leeb, that there is no evidence for any important diVerences in eYcacy between them and non-selective NSAIDs.6 7 Systematic reviews have also found no important diVerences in eYcacy between different NSAIDs, but found diVerences in side eVects related to increased doses of NSAIDs and the nature of the NSAID itself.8 The principal benefit of COX-1 sparing NSAIDs is that they produce analgesia and antiinflammatory eVects comparable with those of the non-selective NSAIDs but cause fewer symptomatic gastric and duodenal ulcers and fewer gastrointestinal symptoms.6 7 The EULAR recommendations need to be revised in the near future. A S M JAWAD
The Royal London Hospital, Bancroft Road, London E1 4DG, UK 1 Jawad ASM. EULAR recommendations for the management of knee osteoarthritis. Ann Rheum Dis 2001;60:540. 2 Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term eVects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo controlled trial. Lancet 2001:357:251–6. 3 McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for the treatment of osteoarthritis: a systemic quality assessment and meta-analysis. JAMA 2000: 283:1469–75. 4 Noack W, Fischer M, Forster KK, Rovatic LC, Setnikar 1. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2: 51–9. 5 Leeb BF, Schweitzer H, Montag K, Smolen JS. A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000; 27:205–11. 6 Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial celecoxib longterm arthritis safety study. JAMA 2000;284: 1247–53. 7 Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520–8. 8 Gotzsche P. Non-steroidal anti-inflammatory drugs. Clinical Evidence 2000;4:641–8.
LETTERS TO THE EDITOR Fenofibrate: a new treatment for hyperuricaemia and gout? Allopurinol is the most commonly used drug in the prevention of gout owing to its eYcacy and good tolerability. However, some patients still experience hyperuricaemia or gout, or
Matters arising, Letters both, despite allopurinol treatment. Fenofibrate is an established treatment for many common lipid disorders and is unique amongst the fibric acid derivatives because of its ability to lower serum urate by increasing renal uric acid clearance.1 This urate lowering property has been demonstrated in healthy volunteers1 and in diabetic and non-diabetic patients with hyperlipidaemia.2–4 To date, no studies have specifically evaluated the urate lowering eVect of fenofibrate in patients with hyperuricaemia receiving established treatment with allopurinol. We report three cases in which micronised fenofibrate, a single dose formulation of the drug, was initiated in patients with established gout and hyperuricaemia, with and without coexisting hyperlipidaemia. Two of these patients were already receiving established allopurinol treatment. PATIENT 1
A 74 year old Chinese man had recurrent attacks of gout aVecting the metatarsophalangeal joints every two to three months for the preceding three years. He had treated hypertension and polygenic hypercholesterolaemia and had been taking allopurinol 300 mg daily for three months, which produced a serum urate range between 0.40 and 0.44 mmol/l. The 24 hour renal uric acid clearance was 6.4 ml/min (reference range 6–11). Treatment was started with micronised fenofibrate 200 mg daily, and three weeks later his urate had fallen by 35% to 0.26 mmol/l, with the 24 hour uric acid clearance rising to 11.5 ml/min (table 1). Alkaline phosphatase activity fell from 77 to 44 U/l, confirming compliance with the fibrate treatment. A temporary withdrawal of fenofibrate treatment for three weeks resulted in an increase in urate to 0.39 mmol/l. Fenofibrate was restarted and he continues to take it in combination with allopurinol. No acute attacks of gout have occurred since fenofibrate was started. PATIENT 2
A 49 year old white man had recurrent episodes of gout aVecting the metatarsophalangeal and knee joints despite having had allopurinol increased from 300 to 600 mg daily six months previously. These episodes occurred every two to three months and usually responded to a short course of indometacin. He was clinically obese but did not drink alcohol and was complying with a low purine diet. His serum urate was 0.58 mmol/l, and when determined three weeks later it measured 0.61 mmol/l with a corresponding 24 hour uric acid clearance of 8.0 ml/min. Micronised fenofibrate 200 mg daily was added to the allopurinol treatment and three weeks later the serum urate had been reduced by 39% to 0.37 mmol/l, with an associated doubling in uric acid clearance
(table 1). Additionally, serum lipids were reduced, together with a reduction in alkaline phosphatase activity. Fenofibrate was temporarily discontinued and the serum urate returned to a higher level. It has been restarted and no further attacks of gout have occurred in 12 months of follow up. PATIENT 3
A 43 year old white man was referred with recurrent episodes of acute gout aVecting the ankle and toe interphalangeal joints every four to six weeks. There was no other medical history of note, but there was a family history of gout. During his most recent attack of gout, the serum urate was 0.35 mmol/l. When repeated after one month the urate was 0.48 mmol/l with a total cholesterol of 8.2 mmol/l and triglycerides 2.4 mmol/l. Treatment with micronised fenofibrate was started, and three weeks later his urate was 0.34 mmol/l (a 29% reduction). Both cholesterol and triglyceride concentrations were also reduced to 7.3 mmol/l and 1.5 mmol/l respectively, and the uric acid clearance rose from 5.8 to 11.2 ml/min. Alkaline phosphatase activity fell from 82 to 72 U/l. He continues to receive micronised fenofibrate 200 mg daily, and further attacks of acute gout have not recurred over a six month follow up period. We have reported three cases of hyperuricaemia in association with recurrent episodes of gout, in which micronised fenofibrate was eVective in further lowering serum urate and in reducing the frequency of gouty attacks. Importantly, two of these patients were already being treated with allopurinol. The urate eVect has been previously shown in patients with hyperlipidaemia treated with fenofibrate,2–4 but this report demonstrates its eYcacy specifically in patients with hyperuricaemia and gout. The reductions in urate shown in these three patients treated with fenofibrate were of similar magnitude to those seen in patients given the drug who had hyperlipidaemia with or without type 2 diabetes and who were not receiving allopurinol treatment.2–4 The doubling in uric acid clearance, which was reversed in two of the patients when fenofibrate was withdrawn, indicates a drug-specific renal eVect. The particularly large reduction in serum urate in the second patient was perhaps a little surprising, but we are certain that this was largely a fenofibrate eVect because a rise in uric acid clearance was seen, together with reductions in alkaline phosphatase activity and serum lipids. Furthermore, he denied any significant lifestyle changes during this period. Importantly, none of these patients has had any adverse eVect, in particular a flare of gout, while taking fenofibrate. Only the second patient wished to take a prophylactic drug against this. Each was advised to
Table 1 EVect of the addition and withdrawal of fenofibrate on serum urate, serum lipids, and uric acid clearance in two patients treated with allopurinol
Patient 1 Serum urate (mmol/l) Uric acid clearance (ml/min) Total cholesterol (mmol/l) Serum triglycerides (mmol/l) Patient 2 Serum urate (mmol/l) Uric acid clearance (ml/min) Total cholesterol (mmol/l) Serum triglyceride (mmol/l)
Allopurinol + fenofibrate combination
Allopurinol (fenofibrate withdrawn)
0.40 6.4 7.4 1.3
0.26 11.5 5.9 1.5
0.39 4.7 7.4 2.4
0.61 8.0 5.4 2.3
0.37 16.4 4.9 2.1
0.46 9.0 5.2 1.9
increase their fluid intake at the time, though uric acid urolithiasis has not been reported previously with fenofibrate. There has been no evidence of an adverse interaction between allopurinol and fenofibrate in the first two patients, who both continue to take this combination. Although unlikely, potential adverse reactions and interactions should be borne in mind when fenofibrate is prescribed for patients with hyperuricaemia, and measures taken to prevent them considered. Serum urate is often raised in hyperlipidaemic patients, particularly those with hypertriglyceridaemia.5 6 The mechanism for the relationship is not clearly defined, though the association may arise through common environmental and genetic risk factors shared by hyperuricaemia and hypertriglyceridaemia, such as obesity and excessive alcohol consumption, or through a primary metabolic defect.5 In contrast, hypertriglyceridaemia has been reported to occur in up to 60% of patients with gout.7 8 Hyperlipidaemia is common in the UK population and is a major risk factor for cardiovascular disease. The relationship between ischaemic heart disease and serum urate is controversial. It has recently been shown that hyperuricaemia may be an independent risk factor for ischaemic heart disease,9 though other studies have not supported this observation.10 A reduction in both hyperlipidaemia and serum urate might therefore be desirable in order to reduce cardiovascular risk. Fenofibrate may oVer a useful dual eVect in this respect, so potentially reducing the need for multiple drug treatments. This specific role for the drug is an important area in need of further study. We have confirmed in our three cases that fenofibrate eVectively lowers serum urate by a uricosuric eVect. Expected reductions in lipids were also seen, suggesting a specific clinical role of this drug in the treatment of the common metabolic abnormality of coexisting hyperuricaemia and hyperlipidaemia. Further, it may be considered in combination with allopurinol in patients with hyperuricaemia who still experience gout despite a lowering in their serum urate. We would encourage further studies to be performed to evaluate the role of fenofibrate alone or in combination with allopurinol in the treatment of gout and hyperuricaemia. Gout remains a common problem in the community—fenofibrate appears to be a long awaited agent with great potential for use in this condition. A L HEPBURN
Rheumatology Section, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK S A KAYE
Rheumatology Department, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, UK M D FEHER
Lipid Clinic, Chelsea and Westminster Hospital Correspondence to: Dr Hepburn
1 Desager J-P, Hulhoven R, Harvengt C. Uricosuric eVect of fenofibrate in healthy volunteers. J Clin Pharmacol 1980;20:560–4. 2 Harvengt C, Heller F, Desager J-P. Hypolipidaemic and hypouricaemic action of fenofibrate in various types of hyperlipoproteinaemia. Artery 1980;7:73–82.
Matters arising, Letters
3 Bastow MD, Durrington PN, Ishola M. Hypertriglyceridaemia and hyperuricaemia: eVects of two fibric acid derivatives (bezafibrate and fenofibrate) in a double-blind placebocontrolled trial. Metabolism 1988;37:217–20. 4 Feher MD, Calake M, Foxton J, Cox A, Packard CJ. Atherogenic lipoprotein phenotype in type 2 diabetes: reversal with micronised fenofibrate. Diabetes Metab Rev 1999;15:395–9. 5 Fox HF, John D, DeBruyne S, Dwosh I, Marliss EB. Hyperuricaemia and hypertriglyceridaemia: metabolic basis for the association. Metabolism 1985;34:741–6. 6 Emmerson B. Hyperlipidaemia in hyperuricaemia and gout. Ann Rheum Dis 1998;57:509– 10. 7 Berkowitz D. Blood lipid and uric acid interrelationships. JAMA 1964;190:856–8. 8 Feldman EB, Wallace SL. Hypertriglyceridaemia in gout. Circulation 1964;29:508–13. 9 Fang J, Alderman MH. Serum uric acid and cardiovascular mortality. The NHANES 1/epidemiologic follow-up study 1971–92. JAMA 2000;283:2404–10. 10 Moriarity JT, Folsom AR, Iribarren C, Nieto FJ, Rosamond WD. Serum uric acid and the risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2000;10:136–43.
EVect of leeches therapy (Hirudo medicinalis) in painful osteoarthritis of the knee: a pilot study Leeches therapy was a mainstay in conventional treatment of pain and inflammatory diseases throughout antiquity until the 20th century.1–3 There is now renewed interest in leeches therapy in the field of complementary medicine. Sales of the four principal German traders have increased continuously throughout the past few years and led to an estimated 70 000 treatments (350 000 leeches sold/ year, four to five used for each single treatment) yearly in Germany (Roth M, unpublished data). The majority of these
Figure 1 Treatment with four leeches at typical periarticular sites of the knee joint.
treatments aim at pain reduction in regional pain syndromes, mostly for knee osteoarthritis.2 With the exception of its application in plastic surgery to maintain blood flow in congested skin flaps,4 5 treatment with leeches has, however, never been evaluated in clinical studies. We conducted a non-randomised controlled pilot study to assess the onset of action and the impact of leeches therapy as an adjunctive treatment in knee osteoarthritis. From inpatients whose main diagnosis was severe chronic back pain, we recruited over a period of three months 16 consecutive patients with primary knee osteoarthritis. All patients had had persistent knee pain for more than six months and had definite radiographic signs of knee osteoarthritis without previous injury. Major exclusion criteria were treatment with anticoagulants, secondary osteoarthritis, substantial comorbidity, and intra-articular corticosteroids in the three preceding months. All patients had an in-hospital period of 14 days and received a health education programme, with focus on exercise, physiotherapy, relaxation techniques, and diet. Regular use of non-steroidal anti-inflammatory drugs was stopped throughout the study period. After detailed information all patients were oVered additional treatment with leeches. Ten patients (eight women, mean (SD) age 69 (9) years, mean body mass index (BMI) 28.0 (4.6) kg/m2) agreed and were treated once with four leeches (Zaug GmbH, Biebertal, Germany). Six controls (five women, mean age 68 (8) years, mean BMI 27.3 (3.0) kg/m2) did not wish to be treated with leeches and were treated only conventionally. The leeches were applied by trained doctors topically at the painful knee joint (fig 1), and monitoring was carried out according to published recommendations.4 The primary outcome measure was a change in total knee pain score, assessed by visual analogue scale (VAS, 0 = no pain, 10 = extremely painful) for 10 days daily, starting three days before treatment and, additionally, in a follow up 28 days after treatment. In comparison with the controls, leech application led to rapid relief of knee pain (p