Intra-articular methotrexate in knee synovitis

N. Hasso, P. J. Maddison and A. Breslin

Department of Rheumatology, Ysbyty Gwynedd, Bangor, Wales, UK.

Correspondence to: P. J. Maddison, Department of Rheumatology, Ysbyty Gwynedd, Bangor LL57 2PW, UK. E-mail: peter.maddison{at}nww-tr.wales.nhs.uk


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To test whether methotrexate prolongs the effect of intra-articular corticosteroid in suppressing knee synovitis.

Methods. Thirty-eight patients with chronic knee synovitis were randomly allocated to receive intra-articular triamcinolone hexacetonide with or without methotrexate. Variables were knee pain and swelling, assessor and patient global assessment, morning stiffness, ESR and CRP. The primary endpoint was the duration of improvement.

Results. After treatment, both groups of patients demonstrated a significant improvement in all variables. However, there was no significant difference between the two groups in the degree or duration of the response. No side-effects were encountered with methotrexate apart from a slight elevation of transaminase levels in some patients.

Conclusions. In the context of this study, the addition of methotrexate to triamcinolone did not add significantly to the clinical response to intra-articular corticosteroid in chronic knee synovitis. However, further controlled studies using different designs are probably warranted.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Different forms of intra-articular therapy have been used to control chronic knee arthritis as an adjunct to systemic treatment. These include intra-articular (i.a.) steroid injections, chemical synovectomy, surgical synovectomy and arthroscopic wash-outs. They have been used with variable success [1].

The beneficial effects of i.a. corticosteroids have been known for more than 40 yr [2, 3]. Studies have shown that i.a. triamcinolone hexacetonide (TH) is more effective than other preparations in suppressing knee synovitis, showing fewer adverse effects and longer duration of action [4, 5]. Other attempts to prolong the corticosteroid effect have included thorough joint aspiration [6] and bed rest following the injection [7].

Radioactive yttrium and osmic acid have been used in patients refractory to i.a. corticosteroids. Chemical synovectomy with these agents has been found to be more effective in patients with less radiological damage [810], shorter duration of joint disease [8] and localized disease [8]. However, treatment with yttrium has not become a standard therapy, partly because of the inconvenience of using a radioactive material and partly because osmic acid can alter the colour and the other properties of the cartilage [11]. As an alternative, methotrexate (MTX) given i.a. rather than systemically has been assessed. A number of short-term studies have demonstrated a local anti-inflammatory effect [1215] and anecdotal experience suggests that MTX may prolong the effect of i.a. steroids. Consequently, this combination is now being used in a number of rheumatology units for patients with persistent knee synovitis. However, because the evidence base to justify this therapeutic approach is scant, we undertook the present study to assess the efficacy of a single i.a. injection of MTX combined with TH in patients with chronic knee synovitis.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Thirty-eight patients, all over 18 yr of age, with recurrent or persistent knee inflammation in the absence of generalized peripheral joint inflammation were recruited to the trial, which had been approved by the Local Research Ethics Committee of North Wales. Written, informed consent was obtained according to the Declaration of Helsinki. Patients were excluded if they were women of child-bearing age who were not using reliable contraception, had a previous history of MTX intolerance or had other medical conditions, such as leucopenia, thrombocytopenia, impaired liver and renal function.

Study design
This was a single-centre, double-blind, parallel-group study with 24 weeks of follow-up. Subjects were randomly assigned to either of the treatment groups: 20 mg of i.a. MTX plus 20 mg of TH or 20 mg of TH, both diluted with 2 ml of 2% lignocaine. Randomization was computer-generated and MTX was prepared immediately prior to use by the pharmacist. Because it was difficult to mask the colour of the MTX, both the independent assessor and the patient were blinded to the treatment. The injections were given using an aseptic technique by the medial approach. Any knee effusion was aspirated to dryness [14]. MTX was injected first followed by TH to reduce MTX diffusion into the surrounding tissues. The patient was asked to rest for at least 48 h after the injection.

If the patient was taking oral MTX, this was stopped 1 week prior to the injection and restarted 1 week afterwards. Folic acid supplementation was continued throughout.

Subjects were assessed by an independent assessor at baseline and 1 week, 6 weeks, 12 weeks and 24 weeks after the injection. Subjective and objective improvements were assessed using the following measures: patient global assessment of disease activity (PGA) (100 mm visual analogue scale); assessor global assessment of the disease activity (AGA) (five-point scale); knee pain on walking and at rest (100 mm visual analogue scale); knee circumference (cm) at the mid-joint line; duration of morning stiffness (min). Laboratory investigations included full blood count, ESR, CRP, urea and electrolytes, and liver function tests (LFTs).

Statistical analysis
Statistical analysis was based on an intention-to-treat strategy, so that all patients entered into the study were included in the analysis. In the event of relapse requiring a further corticosteroid injection prior to 24 weeks (two patients), the last documented outcome variables were carried forward.

The sample size was based on the premise that, to be clinically useful, the addition of MTX should at least double the duration of the anti-inflammatory effect of TH (taken from the literature as a mean of 4 weeks, S.D. 4 weeks). Based on these parameters, patient numbers were calculated for 80% power and P value of <0.05, and a projected patient dropout during the study of 20%.

The primary endpoints were the duration of effect (weeks) for both groups before a recurrence of knee pain and swelling occurred during the follow-up period. Secondary endpoints were reduction in morning stiffness, AGA, PGA and laboratory measures (ESR, CRP). Repeated measures analysis of variance (ANOVA) was used to compare scores within the groups and between the groups at each time-point.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Forty-four patients with chronic knee synovitis were assessed. Six patients (five with RA, one with seronegative arthritis) were unwilling to consent to the study. Thirty-eight patients were treated; 18 received TH alone and 20 received TH combined with MTX. Two-thirds had seropositive rheumatoid arthritis (12 with RA in the TH group and 13 in the TH plus MTX group) (Table 1). The remainder had some form of seronegative arthritis. All were on a disease-modifying anti-rheumatic drug. Characteristics of the patients at baseline (Table 2) showed that patients receiving TH alone had a higher mean age, a lower score for knee pain at rest and less morning stiffness, but none of the differences reached statistical significance.


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TABLE 1. Demographic features and diagnoses of subjects

 

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TABLE 2. Summary of outcome variables in both treatment groups from baseline to 24 weeks of follow-up

 
Nine patients had a recurrence of knee synovitis sufficient to require repeat i.a. corticosteroid injection (without MTX). These included four patients in the MTX plus TH group who received a repeat injection at 24 weeks, and five in the TH group, of whom two received a repeat injection at 12 weeks and three received one at 24 weeks. This result was not statistically significant.

As summarized in Table 2, knee pain at rest improved significantly in both groups at 1 week (P<0.001) and a significant deterioration in knee pain occurred in both groups between 12 and 24 weeks (P = 0.041). There was no statistically significant difference between the two groups at any of the time periods. The pattern was similar for knee pain on walking. Similarly, knee circumference decreased significantly in both groups at 6 weeks (P = 0.03), with little change in either group during the remainder of the follow-up period. The pattern of response in morning stiffness was similar to that of pain, with significant improvement for both groups at 1 week (P<0.001) and significant deterioration (P = 0.04) between 6 and 12 weeks. CRP showed a transient reduction, which was statistically significant at 1 week (P<0.01) but then rebounded. A similar picture was seen for ESR. Again, no significant difference in the pattern of CRP and ESR was seen between the two groups over the trial period.

The AGA and PGA were compared using Pearson's product moment correlation coefficients at each time-point. There was moderate agreement between the scores. The correlations were 0.54, P<0.01 at baseline; 0.68, P<0.01 at 1 week; 0.62, P<0.01 at 6 weeks; 0.61, P<0.01 at 12 weeks and 0.58, P<0.01 at 24 weeks. The mean AGA (five-point scale) for the TH group fell from 1.9 at baseline to 1.8 at 24 weeks; the lowest point was at 1 week, when the mean was 1.5. The pattern for the MTX group was different: the baseline mean was 1.8 and the lowest mean was 1.2 at 24 weeks. The ANOVA showed a significant interaction effect of AGA x group (P<0.01). Further examination of the data using t tests to look for differences between the groups showed that AGA at 24 weeks was significantly worse for the TH group than for the MTX plus TH group (P = 0.031). This was the only significant difference found between the two treatment groups. By contrast, the ANOVA of the PGA showed there was a significant change over time (P = 0.016) but a non-significant effect of group (P = 0.51).

All patients tolerated the treatments well. There were no local side-effects from the injection in either group, and no post-injection symptoms were reported by any of the patients. Eleven patients developed minor derangement of LFTs with mild elevation of liver transaminases and alkaline phosphatase between 1 and 6 weeks after the intervention. In eight patients the LFTs returned to normal. Two patients in the TH group, one on myocrisin and the other on sulphasalazine, continued to have mild derangement of LFTs during the trial period. One patient in the MTX plus TH group, who was taking sulphasalazine, continued to have mild elevation of alkaline phosphatase following the trial period.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We conclude from these results that, in the context of this study design, the addition of 20 mg MTX to TH did not enhance or prolong the effect of corticosteroid. Both treatment groups demonstrated a significant response in all the variables measured, which was most marked a week after injection. There was a tendency for the measures, especially knee pain, to deteriorate in the latter half of the follow-up period. However, only a minority developed clinical symptoms severe enough to warrant further joint aspiration and injection. The only statistically significant difference between the groups was the AGA, which improved in the MTX plus TH group compared with the TH group. However, this was not matched by the patients’ assessment or any of the other measures. On the other hand, the procedure was well tolerated. There were no local side-effects and the only sign of systemic toxicity was mild derangement of LFTs in a few patients, which required no intervention.

The results are similar to all the previous randomized studies of i.a. MTX [1620]. However, it is possible that the regimen used was not ideal. For pragmatic reasons we chose to assess the efficacy of MTX given in a single i.a. injection, as a regimen requiring multiple injections would be less feasible in clinical practice. The dose was chosen to avoid side-effects experienced in other studies using a higher dose [20]. However, there is a suggestion in the literature that repeated i.a. injections of MTX might be more effective [13, 15]. Also, attempts to maintain adequate concentrations of MTX within the joint to maximize efficacy have been tried. These include the concurrent administration of systemic leucoverin, a competitive antagonist of MTX, permitting cytotoxic concentrations of MTX in the knee joint for up to 48 h while completely avoiding systemic toxicity [18]. Alternative formulations might also be effective. For example, the use of a single i.a. injection of liposomally conjugated MTX in rat antigen-induced arthritis produced a rapid and sustained anti-inflammatory effect [21].

The type of synovitis might also influence the treatment response. From the literature, better results were generally obtained with patients with psoriatic arthritis [13]. In our study there were too few psoriatic patients to examine this issue. However, both seropositive and seronegative patients did equally well during the trial period, and there was no significant difference between these groups. Nevertheless, a larger sample size with an increased number of psoriatic patients would be required to examine this issue.

The authors have declared no conflicts of interest.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Creamer P, Keen M, Zananiri G, Waterton JC et al. Quantitative magnetic resonance imaging of the knee: a method of measuring response to intra-articular treatments. Ann Rheum Dis 1997;56:378–81.[Abstract/Free Full Text]
  2. Hollander JL, Brown CY. Hydrocortisone and cortisone injected into arthritic joints: comparative effect of and use of hydrocortisone as a local antiarthritic agent. J Am Med Assoc 1951;147:1629.[ISI]
  3. Ziff M, Scull E, Ford D, McEwen C, Bunim JJ. Effects in rheumatoid arthritis of hydrocortisone and cortisone injected intra-articularly. Am Arch Intern Med 1952;90:774–84.
  4. Dixon ASJ, Cosh JA, Kersley GD. Local corticosteroid therapy for painful rheumatic states. Clin Trials J 1972;3:14–7.
  5. Bain LS, Balch HW, Wetherly JMR. Intra-articular triamcinolone hexacetonide: Double-blind comparison with methylprenisolone. Br J Clin Pract 1972;26:559–61.[Medline]
  6. Weitoft T, Uddenfeld P. Importance of synovial fluid aspiration when injecting intra-articular corticosteroids. Ann Rheum Dis 2000;59:233–5.[Abstract/Free Full Text]
  7. Chakravarty K, Pharoah PDP, Scott DGI. A randomised controlled study of post-injection rest following intra-articular steroid therapy for knee synovitis. Br J Rheumatol 1994;33:464–8.[ISI][Medline]
  8. Asavatanabodee P, Sholter D, Davis P. Yttrium-90 radiochemical synovectomy in chronic knee synovitis. A one year retrospective review of 133 treatment interventions. J Rheumatol 1997;24:639–42.[ISI][Medline]
  9. Taylor WJ, Corkill MM, Rajapaske CNA. A retrospective review of yttrium-90 synovectomy in the treatment of knee arthritis. Br J Rheumatol 1997;36:1100–5.[CrossRef][ISI][Medline]
  10. Hilliquin P, Le Devic P, Menkes C-J. Comparison of the efficacy of non-surgical synovectomy and joint lavage in knee osteoarthritis with effusions. Rev Rhum Engl Ed 1996;34:93–102.
  11. Oka M, Menkes C, Ruotsi A. Nonsurgical synovectomy. Scand J Rheumatol 1975;38:12(Suppl.):132–3.
  12. Hall G, Head C. Intra-articular methotrexate. Lancet 1975;2:409.
  13. Hall GH, Jones BJM, Head AC, Jones VE. Intra-articular methotrexate. Ann Rheum Dis 1978;38:351–6.[ISI]
  14. Tiliakos NA, Lawrence T, Wilson C. Intra-articular methotrexate in RA. Arthritis Rheum 1982;25:554.
  15. Durk H, Kotter I, Saal JG. Intra-articular methotrexate in corticosteroid resistant monoarthritis. Arthritis Rheum 1994;37(Suppl.):554.
  16. Marks JS, Stewart IM, Hunter JA. Intra-articular methotrexate in RA. Lancet 1976;ii:857–8.
  17. Bird HA, Ring EFJ, Daniel R, Bacon PA. Comparison of intra-articular methotrexate with intra-articular triamcinolone hexacetonide by thermography. Curr Med Res Opin 1977;5:141–6.[ISI][Medline]
  18. Wiggington SM, Chu BCF, Weisman MH, Howell SB. Methotrexate pharmacokinetics after intraarticular injection in patients with rheumatoid arthritis. Arthritis Rheum 1980;23:119–22.[ISI][Medline]
  19. Gao IK, Leins C, Bohlen H, Heilig, Lemmel EM. Inhibition of IL-8 synthesis by i.a. MTX therapy in patients with RA. Z Rheumatol 1998;57:95–100.[CrossRef][ISI][Medline]
  20. Blyth T, Stirling A, Coote J, Land D, Hunter JA. Injection of the rheumatoid knee: does intra-articular methotrexate or rifampicin add to the benefits of triamcinolone hexacetonide? Br J Rheumatol 1998;37:770–2.[CrossRef][ISI][Medline]
  21. Williams AS, Camilleri JP, Goodfellow RM, Williams BD. A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis. Br J Rheumatol 1996;35:719–24.[ISI][Medline]
Submitted 20 September 2003; revised version accepted 17 February 2004.



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