Osmic acid revisited: factors that predict a favourable response

R. Bessant, A. Steuer, S. Rigby and M. Gumpel

Department of Rheumatology, Northwick Park Hospital, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. Chemical synovectomy with osmic acid has been used for many years in the treatment of chronic synovitis that is unresponsive to systemic treatment and intra-articular corticosteroid. Our aims were to compare the safety and the efficacy of this procedure with that of alternative treatment modalities, and to identify any factors that may predict the response to treatment.

Methods. A retrospective review of 103 osmic acid injections was performed in 65 patients with chronic knee synovitis, between 1992 and 1998. After a clinical review 6 weeks after injection, the length of remission was determined by telephone survey. Thirty-six months of follow-up was available for 96 injections, with a minimum of 12 months for the remainder. Remission was defined as complete absence of pain and swelling.

Results. Sixty-nine (67.0%) knee joints remained completely free of pain and swelling at 6 months, falling to 52 (50.5%) at 12 months, 32 (31.1%) at 24 months, and 19 (18.4%) at 36 months. Knees with mild radiological changes experienced significantly better results compared with those with moderate or severe changes (P=0.006 and 0.046 respectively). In patients undergoing bilateral injections, there was a correlation between the duration of remission achieved for each of the two knees (r=0.83, P < 0.01). A correlation was also observed between the responses obtained after first and repeated synovectomies of the same knee (r=0.62, P < 0.05). Eighty-six per cent of injections were uncomplicated. Side-effects included pain, which followed 13 injections (12.4%), and two skin burns.

Conclusions. Long-term complete remission was achieved in 18.4% of knees. This treatment may be best reserved for joints with less severe radiological changes. The response to a first osmic acid injection has a strong predictive value when considering further treatment of the same or the contralateral joint.

KEY WORDS: Osmic acid, Chemical synovectomy, Chronic synovitis.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Medical synovectomy, which includes both chemical and radiation synovectomy, may be indicated in the treatment of persistently inflamed and painful joints when previous intra-articular corticosteroid injection or systemic treatment has failed to induce an adequate response. It is performed in order to destroy inflamed synovial tissue, in the hope of achieving normal regeneration from underlying healthy synovium. As a local treatment it may be particularly appropriate for patients with mono- or oligo-arthritis.

Medical synovectomy is an attractive alternative to surgical synovectomy because it requires a comparatively short rehabilitation period, reduces the need for subsequent physiotherapy, and usually results in little or no scarring. In addition, if medical synovectomy fails to provide long-term remission, it does not preclude or prejudice subsequent surgical synovectomy.

Osmic acid was first used by von Reis and Swensson in 1951 for the treatment of knee effusion [1]. It is an aqueous solution of osmium tetroxide, which is a vigorous oxidizing agent that has a high affinity for lipids and coagulates proteins. It is deposited in inflamed synovial tissue and subsynovial fat. Necrosis of the inflamed synovial membrane is followed by regeneration from underlying undamaged tissues. Following contact with organic substances, osmic acid is very rapidly reduced to stable lower oxides and is thereafter entirely inert, causing no general toxic symptoms. A simultaneous injection of corticosteroid is required to decrease the incidence of reactive effusion and postinjection pain [2].

Radiation synovectomy, using agents such as yttrium-90 (90Y), has also been used to treat chronic joint synovitis successfully [3]. One advantage of osmic acid, however, is that it can be used in all age groups, whilst the use of radiation synovectomy is restricted in patients under 45 yr, due to the potential risk of carcinogenesis or teratogenicity [47]. In addition, the precautions necessary with radioisotopes are avoided, making osmic acid easier to administer. The volume of injection required in osmic acid synovectomy may, however, limit its use to the treatment of larger joints, especially the knee.

In a recent survey of consultant rheumatologists in the UK, only 33 out of 294 respondents had experience in the use of chemical synovectomy with osmic acid [8]. In contrast, 160 consultants were familiar with radiation synovectomy, and 175 indicated that they would refer patients for surgical synovectomy. This may reflect differences in training, and/or concerns over the effectiveness and safety of chemical synovectomy.

We chose to study the role of osmic acid injection in the treatment of chronic synovitis, aiming to assess its safety and efficacy. We also set out to identify any factors that could be used to predict the response to treatment. A retrospective analysis of 105 consecutive injections was performed, using a combination of hospital records and a telephone survey to obtain long-term follow-up information.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Sixty-five consecutive patients who underwent chemical synovectomy with osmium tetroxide (osmic acid) between 1992 and 1998 at Northwick Park Hospital (NPH), a tertiary referral centre for the medical treatment of chronic synovitis, were enrolled in this study. Patients were identified using the hospital's computerized patient administration system. The indication for treatment was chronic knee synovitis of more than 12 months duration that had failed to achieve a sustained response to intra-articular corticosteroid injection. In some cases the patient had also failed to benefit from systemic anti-inflammatory medication. No patient had received any other intra-articular treatment (e.g. radioactive yttrium). The presence of a Baker's cyst was considered a relative contraindication for osmic acid treatment because of the risk of osmic acid leakage. No treatment was carried out within 6 weeks of an intra-articular steroid injection. Repeat osmic acid injections were carried out after a minimum of 6 months, and no knee was injected more than twice. All treatments were carried out by one of three specialist registrars (RB, AS and SR), all of whom had been trained by a single consultant rheumatologist (MG).

Method of injection
The affected knee joint was initially aspirated to dryness to facilitate entry of osmic acid and to reduce the risk of extravasation due to high hydrostatic pressure. The joint was then injected with 10 ml of 2% lignocaine and left for at least 5 min for analgesia to take effect. One hundred milligrams of osmium tetroxide in 10 ml of 1% aqueous solution (Taab Laboratories, Aldermaston, Berkshire, UK) was then instilled, followed immediately by 20 mg triamcinolone hexacetonide (Lederspan; Wyeth Laboratories, Taplow, Berkshire, UK). This may serve to reduce local reaction due to the osmic acid injection, to provide temporary relief of symptoms prior to the onset of effect of the osmic acid, and to flush the needle. Each patient was then maintained on strict bed rest for 24 h, to prevent osmic acid leakage, and was subsequently mobilized gradually. Patients were maintained on their existing non-steroidal anti-inflammatory or second-line disease-modifying medication, where appropriate.

Data collection
For each patient, baseline data (including age, sex, diagnosis, duration of symptoms and X-ray grading of severity) were determined by a retrospective review of patient records held at NPH. Patients were offered routine review in the out-patient department at NPH 6 weeks after osmic acid injection, to assess the early response to the injection. The objective response to treatment was determined from these records. Objective responses were graded as ‘complete’ if there had been total remission, with no pain or swelling, ‘partial’ if there had been a definite improvement but some pain and/or swelling persisted, and ‘no change’ if there was no significant response to treatment.

A significant number of patients, however, elected to return to their original specialist for this first review appointment, and still more for long-term follow-up. We chose, therefore, to carry out a telephone survey, after a minimum of 12 months of follow-up (in January 2000), to determine the long-term efficacy of the treatment. The data collected from the telephone survey included: (i) a subjective initial response to treatment (graded by the patient as ‘excellent’, ‘good’, ‘minimal’ or ‘no response’); (ii) the duration of remission following the osmic acid injection (remission was defined as the absence of pain and swelling); (iii) any complications that occurred after osmic acid injection (the patients were questioned specifically regarding any immediate pain and about osmium-related skin burns); and (iv) any further treatment, including osmic acid injection, that was required. Data analysis was performed with the statistical software package SPSS, version 7.5.1 (SPSS Inc., Chicago, IL, USA). Results of bilateral and of repeated osmic acid injections were subjected to linear regression analysis.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Sixty-five patients underwent chemical synovectomy with osmic acid (Table 1Go). They consisted of 35 women (54%) and 30 men (46%), with a mean age of 48 yr (range 22–85 yr) at the time of synovectomy. The following disease groups were identified: rheumatoid arthritis (RA; n=33, 50.7%); psoriatic arthropathy (PsA; n=8, 12.3%); pigmented villonodular synovitis (PVNS; n=7, 10.8%); ankylosing spondylitis (AS; n =3, 4.6%); osteoarthritis (OA, n=2; 3.1%); and miscellaneous or unknown (other; n=12, 18.5%). This latter group included five patients with monoarthritis, one patient with juvenile chronic arthritis and one with synovial chondromatosis.


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TABLE 1. Indications for treatment and number of osmic acid injections administered

 
A total of 105 osmic acid injections were given to these 65 patients. RA was the commonest indication, accounting for 60 injections (57%). Ninety of these 105 osmic acid injections were first treatments. The remaining 15 were repeated osmic acid synovectomies, carried out on 10 patients. Five of these patients had two injections in each knee, making a total of four injections per patient. Repeat injections that took place after the study period were excluded. A total of 60 bilateral injections were performed on 25 subjects (38.4%), of whom 20 (80%) suffered from RA.

Sixty-three of the 65 patients were followed up by telephone survey, as two of the 65 patients had died prior to the survey. The response to 96 injections was monitored for a minimum of 3 yr, or until a relapse occurred. Seven knees were still in remission, at between 12 and 36 months of follow-up, at the time of the survey.

There was no significant difference between the responses to treatment obtained in patients originating from rheumatology clinics at NPH and those referred to NPH from other centres.

Joint characteristics
Due to the large number of tertiary referrals, pretreatment radiographs were only available for 31 knees. The radiological assessment of disease severity for 33 knees was therefore based on radiology reports, written by radiologists who had no knowledge of the study. In total, a radiological assessment of severity was available for 64 knees (61%).

Changes were graded as ‘mild’ (defined as no radiological changes seen) in 35 knees, ‘moderate’ (loss of joint space observed) in a further 23, and ‘severe’ (joint erosions present) in the remaining six. This simplified classification was employed due to the small numbers involved and the limited information contained in some radiology reports. It was not possible to use the more detailed Ahlbäck classification [9], which defines five radiological grades of severity, in the absence of the original radiographs.

The response to osmic acid injection was analysed in relation to these changes. The number of severely affected knees entered into this study may have been limited by a tendency for patients with severe disease to be referred for surgical management instead.

Complications
No complications were reported following osmic acid injection into 90 out of 105 joints (85%). Immediate pain was reported after 13 injections in nine patients. Despite this, these subjects subsequently stated that 10 of these injections went on to give ‘excellent’ relief of symptoms. Two patients, one of whom had also complained of immediate pain, suffered a skin burn following osmic acid injection. These ‘needle-track’ burns are a well-recognized, though uncommon, complication of osmic acid synovectomy [10]. One patient developed a reactive effusion, which required aspiration.

Response at six weeks after chemical synovectomy
Because some patients had returned to their referring hospital for the 6-week follow-up visit, an objective initial response could be determined from records held at NPH for only 82 injections. A subjective initial response to 103 injections was elicited during the telephone survey.

Patients reported an ‘excellent’ response to 74 injections (71.8%), a ‘good’ response to 15 treatments (14.6%), a ‘minimal’ response in 2 cases (1.9%), and ‘no response’ on 12 occasions (11.7%). The clinicians' objective grading of the response was: ‘complete’ remission following 47 injections (57.3%); a ‘partial response’ to a further 20 (24.4%); and ‘no change’ in the remaining 15 (18.3%). In total, therefore, an initial response to osmic acid synovectomy occurred subjectively in 91 knees (88.3%) and objectively in 67 knees (81.7%).

Long-term follow-up
Twenty-two knees (21.4%) were still in full remission at the time of the telephone survey (Table 2Go). Fifteen of these joints had more than 36 months of follow-up, and may have achieved a permanent benefit from treatment. These 15 included eight knees with RA, one each with PsA, PVNS, AS and OA, and three with other diseases. The longer-term outcome for the seven knees that were in remission at between 12 and 36 months of follow-up at the time of the survey is not known.


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TABLE 2. Time to relapse of synovitis according to diagnosis

 
The number of joints still in remission at 6 months was 69 (67.0%), falling to 52 (50.5%) at 12 months, 32 (31.1%) at 24 months and 19 (18.4%) at 36 months. When these data were plotted on a survival curve, an exponential trend line, as seen in Fig. 1Go, provided the closest fit. Of the 52 knees that remained in remission at 12 months, the final outcome was known for 45 (seven were still in remission between 12 and 36 months), and 15 of these were still in remission at over 36 months. This suggests that approximately one-third of patients who are in remission at 12 months may gain long-term (greater than 3 yr) remission.



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FIG. 1. Survival curve indicating duration of remission following osmic acid injection. Data points indicate the number of patients remaining in remission at specified times following osmic acid injection. Also shown is an exponential line of best fit (broken line) corresponding to these data points.

 
The duration of remission according to diagnosis is presented in Table 2Go. The proportion of treatments resulting in 12 months and 36 months of remission was similar for all diagnoses, and at least one joint from each category was still in remission at 36 months.

Effect on outcome of radiological grading
The effect of radiological disease severity on long-term response to osmic acid injection is evaluated in Table 3Go. At 12 months, 26 out of 35 joints (74.3%) classified as mildly affected were still in remission. This compares with 9 out of 23 (39.1%) for moderately affected knees and 2 out of 6 (33.3%) severely affected knees. The 12-month data were analysed with the {chi}2 test to compare the number of knees in remission in each group. Significant differences were observed between mild and moderate (P=0.006) and between mild and severe (P=0.046), but not between moderate and severe disease (P=00.78). The most significant difference was obtained when joints with mild disease were compared with a category that combined the moderate and severely affected knees (P=0.0005).


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TABLE 3. Time to relapse vs X-ray severity

 
At 36 months, only five knees (14.3%) with mild disease, three with moderate changes (13.0%) and none of the severely affected joints were still in remission. The small numbers involved preclude further analysis of the 36-month data.

Results of bilateral synovectomies
We wished to determine whether, in patients who had undergone bilateral osmic acid injection, the response to the first injection could act as an accurate predictor of the response that would be obtained from a subsequent injection into the contralateral joint. Thus, in patients who had undergone one or more bilateral synovectomies (n=30), the duration of remission achieved for the left knee was compared with that for the fellow right knee. These data are plotted in the form of a scatterplot in Fig. 2Go. A significant correlation between left and right knees was obtained using the Pearson bivariate correlation method (r=0.83, P < 0.01), indicating that the length of remission achieved in one joint can be used to predict the outcome of second procedure on the contralateral knee.



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FIG. 2. Scatterplot comparing results of bilateral synovectomies. The time to relapse following osmic acid injection into the right knee (x axis) is plotted against the time to relapse for the fellow, left knee (y axis). Each point represents one pair of injections (n=30). Knees affected by RA (n=23) are represented by a black circle and other diagnoses (see text) by a white circle.

 

Results of repeated osmic acid injections of the same joint
A similar analysis was performed in patients (n=15) in whom a single joint had undergone two separate osmic acid injections (n=30), to determine whether the response achieved with the first synovectomy could be used to predict whether a repeat treatment would be worthwhile. The lengths of remission achieved after the first and second treatments were compared and are shown as a scatterplot in Fig. 3Go. Once again a significant correlation was obtained, although at a lower level of significance (r=0.62, P < 0.05).



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FIG. 3. Scatterplot comparing results of repeat synovectomies. The time to relapse following the first osmic acid injection (x axis) is plotted against the time to relapse following the second injection (y axis). Each point represents two consecutive injections (n=15). Knees affected by RA (n=7) are indicated by a black circle and other diagnoses (see text) by a white circle.

 
Eight of these 15 knees achieved less than 12 months of remission following the first injection. In five of these eight, the duration of remission following the second injection was less than 1 month. In contrast, of the seven knees in which the first injection resulted in greater than 12 months' benefit, three knees achieved more than 36 months of remission.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study has shown osmic acid synovectomy to be a fundamentally safe and effective treatment for chronic synovitis. It has also identified several factors that may predict a good response to treatment.

Safety of osmic acid synovectomy
In this study the great majority of osmic acid injections (85%) were uncomplicated.

Postinjection pain
Despite intra-articular administration of local anaesthetic immediately prior to osmic acid injection, postinjection pain was described following 13 out of 103 injections (12.6%). The pain was described as an intense local burning pain which either set in within a couple of minutes of the injection and was short-lived (a matter of seconds or a few minutes) or occurred 3–4 h after the injection, when the effect of the local anaesthetic began to wear off. In the latter situation the pain usually subsided completely after about 3 days and was well controlled with simple analgesics.

Skin burn
Skin burns at the point of entry, presumably due to reflux of osmic acid along the needle track, occurred in just two patients; in both patients the burns healed spontaneously. These burns are usually superficial pinpoint burns, which heal spontaneously, although depigmentation may occur. As with radiosynovectomies, a meticulous injection technique is recommended to minimize the risk of osmic acid reflux.

Reactive effusion
Despite concomitant intra-articular steroid injection, a reactive effusion occurred in one patient. Aspiration of the joint followed by repeat intra-articular steroid injection provided relief of this complication.

Efficacy of osmic acid synovectomy
Studies have shown that patients suffering from chronic, painful rheumatological conditions, such as persistent synovitis, are able to provide relatively reliable information regarding the response obtained from radiation or surgical synovectomy [1113].

The response following osmic acid synovectomy is usually defined in terms of pain, stiffness and swelling. In previous studies, most authors have defined the complete absence of pain and swelling as an ‘excellent’ response, and a significant reduction in symptoms and signs as a ‘good’ response. Overall success was then defined as the combination of ‘excellent’ and ‘good’ responses. In the present study, however, long-term remission was defined as the total absence of both pain and swelling, which would be equivalent to an ‘excellent’ result in other studies. The results of previous investigations are summarized in Table 4Go [10, 1421].


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TABLE 4. Efficacy of osmic acid synovectomy in previous studies

 
Amongst our patients, a good or excellent initial response was reported following osmic acid synovectomy in 91 knees (88.3%) and an objective improvement was recorded by clinicians in 67 knees (81.7%). This initial response may in part have resulted from the simultaneous administration of intra-articular steroids.

Previous studies have demonstrated a success rate (combination of excellent and good responses) of between 52 and 78% (median 64%) at 6 months and between 44 and 76% (median 49%) at 12 months, following osmic acid treatment [10, 1421] (Table 4Go).

Despite using more stringent criteria for success, including the total absence of pain, the present study has comparable results, with 67% of joints in remission at 6 months and 50.5% in remission at 12 months. Pain following synovectomy may not be attributable solely to continuing inflammation, but in some patients may be due to degenerative changes within the knee joint. For these reasons, the strictness of our criteria may have led us to underestimate the potential benefit of chemical synovectomy.

Although most studies describe only 12 months of follow-up, some authors have reported a prolonged benefit from osmic acid synovectomy [10]. In our study 15 injections (14.6%) resulted in greater than 3 yr remission, and a further seven (6.8%) were still in remission, at between 12 and 36 months, at the time of the survey. These results are comparable to those of a recent study employing radiation synovectomy, which demonstrated 22% of patients achieving prolonged remission [3]. One study of osmic acid synovectomy reported ‘good’ or ‘very good’ pain relief in 63% of knees at 3 yr [10]. It should be noted, however, that the authors of this study enrolled only knees of patients with RA which had either no or minimal radiological changes.

Factors predicting a favourable response
Factors that might be predicted to affect the outcome of osmic acid synovectomy include: (i) the underlying diagnosis; (ii) disease duration; (iii) radiological assessment of disease severity; and (iv) response to previous treatments.

One study, carried out in patients with juvenile idiopathic arthritis, demonstrated better results in subjects with disease duration of less than 1 yr [18]. As the inclusion criteria for the present study required a knee to have had synovitis of duration greater than 1 yr, we were not able to assess this factor. We considered it unlikely that a comparison of longer disease durations would produce significant results, and did not analyse this aspect further.

Whilst developed initially for the treatment of chronic synovitis in patients with RA, both chemical and radiation synovectomy are now used in cases of seronegative spondyloarthropathy, OA, PVNS and haemophilic arthropathy.

In this study the underlying diagnosis did not predict the response to osmic acid injection. At least one joint from each diagnostic category was still in remission at 36 months, indicating that osmic acid synovectomy should be considered as a potential therapeutic option whatever the underlying cause of the persistent synovitis.

Effect of radiological assessment of disease severity
Previous studies have shown that joints with less advanced radiological changes respond better to osmic acid treatment than those with existing destructive changes [1518, 2022]. This effect might be predicted, as joints that are severely damaged prior to synovectomy will remain severely damaged afterwards.

Whilst we used a simplified radiological grading system and had data on only 64 knees, we also observed a statistically significant difference in the number of joints still in remission at 12 months. Of the joints classified as mildly affected, 74.3% were still in remission at one year, compared with 39.1% of moderately and 33.3% of severely affected knees (P=0.006 and P=0.046 respectively). At 3 yr, however, there was no significant difference between mildly and moderately affected knees, suggesting that this difference may be relatively short-lived.

None of the six severely affected knees remained in remission at 2 yr, and if osmic acid is considered for use in such joints, any treatment should probably be preceded by advising the patient that the benefit is unlikely to be prolonged.

Predictive value of response to previous osmic acid synovectomy
This study has demonstrated that the length of remission achieved following osmic acid synovectomy in one joint can be used to predict the outcome of a second procedure on the contralateral knee.

It has also shown that patients who obtain a prolonged response to a first osmic acid synovectomy are more likely to achieve a long-lasting response to any subsequent injection. This suggests that a second procedure may only be justified if the first injection resulted in a substantial period of remission.

This is the first time that these correlations have been demonstrated for chemical synovectomy with osmic acid, though similar findings have been reported with radiation synovectomy using 90Y [23]. Our findings indicate that the response to a first osmic acid injection should be recognized as having a strong predictive value when considering further treatment of the same or the contralateral joint.

Comparison with radiation and arthroscopic synovectomy
Radiation synovectomy of the knee with 90Y is associated with success rates of between 48 and 69% at 12 months after injection [10, 23, 24]. Similar results have been reported in persistent knee synovitis with dysprosium-165 (61%) [25] and with samarium-153 (46% success at 12 months) [26]. Of three studies that compared osmic acid directly with radiation synovectomy [10, 27, 28], the largest reported a significantly larger percentage of knees remaining satisfactory with osmic acid (63 vs 48%) 3 yr after synovectomy [10]. At 1 yr, however, the difference (76 vs 69%) was not significant.

In the treatment of knee synovitis, therefore, the efficacies of chemical synovectomy with osmic acid and of radiation synovectomy are similar, and the choice of agent may therefore be left to the discretion of the individual clinician.

Some studies report excellent success rates for arthroscopic synovectomy in persistent knee synovitis [2931]. We have not, however, encountered any trials in which this technique has been directly compared with chemical synovectomy. The potential disadvantages of arthroscopic synovectomy include the risks associated with general or local anaesthesia and the use of multiple portals of entry. As the use of chemical synovectomy does not preclude subsequent arthroscopic synovectomy, we feel that osmic acid treatment should be considered prior to surgical intervention.

Conclusions
Chemical synovectomy with osmic acid is a relatively safe, efficacious and convenient alternative to both radiation and surgical synovectomy in the management of persistent knee synovitis in joints that have not responded adequately to previous intra-articular steroid injection. This study has confirmed that complete remission may be achieved in roughly half of the injected knees at 1 yr, and demonstrated long-term remission in approximately 20%. Subjects may gain prolonged benefit from treatment irrespective of the underlying rheumatological diagnosis. Radiological evidence of severe disease prior to the time of injection is predictive of a poorer outcome, indicating that osmic acid synovectomy may be best reserved for joints with less severe radiological changes.

The findings of this study, in subjects undergoing bilateral and repeated injections, indicate that the response to a first osmic acid injection has a strong predictive value when considering further treatment of the same or the contralateral joint.


    Acknowledgments
 
The authors would like to thank the patients who took part in the study and Dr Bharti Shah, consultant radiologist at Northwick Park Hospital, for her indispensable assistance with the process of grading the knee radiographs.


    Notes
 
Correspondence to: R. Bessant, Centre for Rheumatology, University College London Hospitals, London W1P 9PG, UK. E-mail: r.bessant{at}ucl.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 13 July 2002; Accepted 16 January 2003





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