Rheumatoid Arthritis: Torp-Pedersen S

Kubassova O, Boesen M, Peloschek P, Langs G, Cimmino MA, Bliddal H, Torp-Pedersen S. · Image Analysis Ltd., University of Leeds, 5-7 Cromer Terrace, Leeds, West Yorkshire, UK. · Ann N Y Acad Sci. · Pubmed #19250239 No free full text.

Abstract: Traditional imaging, represented by radiographs, provides a very concise description of anatomical pathology of bony structures. Both degenerative and inflammatory joint diseases are characterized by progressive joint destruction, and valid, reproducible measures of disease impact are available. Much effort has been expended to develop scoring systems for joint destruction in both osteoarthritis and rheumatoid arthritis, and the most common internationally accepted semiobjective scores are presented. The anatomical pathology mirrors the past activity of the disease, and advanced imaging gives an impression of the actual disease processes, which subsequently lead to the damage. Such information is required to facilitate the development of efficient therapy against arthritis. Newer technology, exemplified by MRI and ultrasound Doppler, supplements images of structural change with functional data of ongoing disease activity. This chapter focuses on the possibilities for quantification of images in MRI and ultrasound, in which postcontrast enhancement and Doppler information, respectively, are of special interest for the evaluation of the inflammatory changes of arthritis. To save time and eliminate human bias, automation is mandatory. In ultrasound, semiautomatic evaluations are coming that allow for a real-time, reproducible estimate of disease activity. With MRI fully automated algorithms have been developed for processing of data of bony structures, cartilage, and soft tissue, and are currently being implemented into everyday clinical practice.

Bliddal H, Boesen M, Christensen R, Kubassova O, Torp-Pedersen S. · The Parker Institute, Frederiksberg Hospital, 2000 Frederiksberg, Denmark. · Best Pract Res Clin Rheumatol. · Pubmed #19041080 No free full text.

Abstract: Imaging is key to the objective analysis of status in joint diseases. X-ray is the mainstay of imaging in both osteoarthritis (OA) and rheumatoid arthritis (RA) due to its accessibility, low cost and very good reproducibility. Also, considerable experience has been gathered in the evaluation of X-rays with the Sharp score in RA and the Kellgren-Lawrence score in OA. X-rays only show structural changes and, in comparison with magnetic resonance imaging (MRI), the detection of erosions on X-ray is delayed for more than 1 year. More advanced imaging by both MRI and ultrasound (US) may add to clinical examinations by showing signs of RA activity. US is by far the easiest modality to apply in a rheumatology outpatient setting, and is becoming an everyday diagnostic tool in many clinics. The definitions and standards for US are still being tested and need further work before application in longitudinal settings is possible. Reproducibility is better with MRI, but this examination is time-consuming, both in the acquisition phase with the patient and also for interpretation and scoring by the examiner. The latter issue seems to be overcome by computer-assisted diagnostics using algorithms for automatic evaluation. With technical developments and increasing knowledge regarding both MRI and US, both of these modalities may be of value in the evaluation of rheumatology patients.

Qvistgaard E, Terslev L, Bliddal H, Torp-Pedersen S. · H:S Frederiksberg Hospital, Parker Instituttet. · Ugeskr Laeger. · Pubmed #15017727 No free full text.

This publication has no abstract.

Terslev L, Torp-Pedersen S, Savnik A, von der Recke P, Qvistgaard E, Danneskiold-Samsøe B, Bliddal H. · The Parker Institute, Frederiksberg Hospital, Frederiksberg, Denmark. · Arthritis Rheum. · Pubmed #13130462 links to  free full text

Abstract: OBJECTIVE: To compare the quantitative and qualitative information obtained by Doppler ultrasound (US) measurements of the wrist joints and the small joints of the hand with the information obtained by postcontrast magnetic resonance imaging (MRI) and to correlate the imaging results with clinical observations in patients with rheumatoid arthritis (RA). METHODS: Twenty-nine consecutive RA patients were studied; 196 joints (29 wrist and 167 finger joints) were examined by both US and MRI. Parameters of inflammation were the color fraction and the resistance index (RI) obtained with color Doppler US and the thickness of enhanced synovium (in mm) and the MRI score obtained with postcontrast MRI. Clinical examination and measurements of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level were performed on the same day as the imaging studies. RESULTS: There was a highly significant association between US indices of inflammation and postcontrast MRI scores. The mean values for both the color fraction and the RI were significantly different in the group without joint swelling compared with the other groups. The mean RI values were significantly different in the group without joint tenderness compared with the other groups. The mean thickness of enhanced synovium on postcontrast MRI was significantly different between the group without joint swelling and the other groups, but this difference was statistically significant only for the comparison of the group without joint tenderness versus the group with maximum tenderness. No association between the MRI or US estimates of inflammation and values on the visual analog scale for pain, Health Assessment Questionnaire, duration of morning stiffness, ESR, or CRP was found. CONCLUSION: Estimates of synovial inflammatory activity by Doppler US and postcontrast MRI were comparable. Estimation of synovial inflammatory activity by the RI and color fraction parameters of US appears to be a promising method of detecting and monitoring inflammatory activity in patients with RA.

Terslev L, Torp-Pedersen S, Qvistgaard E, Kristoffersen H, Røgind H, Danneskiold-Samsøe B, Bliddal H. · The Parker Institute, Department of Rheumatology, Frederiksberg Hospital, DK 2000 Frederiksberg, Denmark. · Ann Rheum Dis. · Pubmed #12525391 links to  free full text

Abstract: OBJECTIVE: to estimate and visualise the efficacy of treatment with etanercept (Enbrel) in patients with rheumatoid arthritis (RA) using colour Doppler and spectral Doppler ultrasonography to determine the possible changes in synovial perfusion during a one year observation period. METHODS: Eleven patients from the European multicentre trial of the efficacy and safety of etanercept were included in this study when transferred into the open label, long term safety, and efficacy study. Before a scheduled dosage increase to 50 mg/week they were examined clinically, serologically, and by ultrasonography using the colour Doppler pixels and the spectral Doppler resistance index (RI) as indicators of inflammation. The patients were re-examined at two weeks and at one year follow up RESULTS: The clinical activity decreased significantly from baseline to week 2, but no significant changes were seen from baseline to one year. The number of coloured pixels in each region of interest decreased from baseline to week 2 with a median reduction of 60% (p=0.005). This effect on the perfusion in the synovium could not be found after one year of treatment. During the initial treatment we detected an increase in synovial RI by spectral Doppler. The median increase in peripheral resistance from baseline to week 2 as estimated by the mean RI was 22.6% (p=0.005). The increase in peripheral resistance was maintained to some extent after one year (mean RI increased by 18.8% p=0.074). CONCLUSION: Ultrasonography seems to be a promising tool for the detection of treatment response using spectral Doppler and pixel estimation.

Ellegaard K, Torp-Pedersen S, Terslev L, Danneskiold-Samsøe B, Henriksen M, Bliddal H. · The Parker Institute, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000, Frederiksberg, Denmark. · Rheumatology (Oxford). · Pubmed #19129350 No free full text.

Abstract: OBJECTIVE: Colour Doppler ultrasound (CDU) displays blood flow in the tissues and is able to detect hyperaemia. Because hyperaemia is part of the inflammatory response, the amount of CDU activity in the inflamed synovium may be used to quantify the inflammatory activity in RA. It has never been investigated if the amount of CDU activity in a single joint can be used to quantify disease activity in RA. METHODS: A total of 109 patients with RA and affection of the wrist joint underwent a standardized CDU examination assessing three positions in their most affected wrist at start up in biological treatment. On the same day the following measures of disease activity were collected: assessment of the number of tender and swollen joints, CRP, ESR and 28-joint disease activity score (DAS28). The amount of CDU activity was quantified by measuring the percentage of colour in the synovium--the colour fraction (CF). Correlation between CF and other measures of disease activity was calculated. RESULTS: There was a significant correlation between CF and DAS28 (r = 0.29; P < 0.001), swollen joint count (r = 0.35; P < 0.001), CRP (r = 0.5; P < 0.001) and ESR (r = 0.5; P < 0.001). No other significant correlations were found. CONCLUSION: A standardized ultrasound examination of a single affected wrist joint in patients with RA may be used as a measure of disease activity. More studies are needed to identify the number of joints needed to examine by CDU to obtain the best validity of Doppler measurements.

Ellegaard K, Torp-Pedersen S, Lund H, Henriksen M, Terslev L, Jensen PS, Danneskiold-Samsøe B, Bliddal H. · The Parker Institute, Frederiksberg Hospital. · Ultraschall Med. · Pubmed #18709606 No free full text.

Abstract: PURPOSE: The amount of colour Doppler activity in the inflamed synovium is used to quantify inflammatory activity. The measurements may vary due to image selection, quantification method, and point in cardiac cycle. This study investigated the test-retest reliability of ultrasound colour Doppler measurements in the wrist of patients with rheumatoid arthritis (RA) using different selection and quantification methods. MATERIALS AND METHODS: 14 patients with RA had their wrist scanned twice by the same investigator with an interval of 30 minutes. The images for analysis were selected either by the anatomical position only or by the anatomical position with maximum colour Doppler activity. Subsequently, the amount of colour Doppler was measured in an area defined by either the synovial tissue or by specific anatomical structures surrounding the synovial tissue. RESULTS: The best test-retest reliability was obtained when the images were selected guided by colour Doppler and the subsequent quantification was done in an area defined by anatomical structures. With this method, the intra-class coefficient ICC (2.1) was 0.95 and the within-subject SD (SW) was 0.017, indicating good reliability. In contrast, poor test-retest reliability was found if the images were selected by anatomical position only and the quantification was done in an area defined by the synovial tissue (ICC [2.1] = 0.48 and SW = 0.049). CONCLUSION: The study showed that colour Doppler measurements are reliable if the images for analysis are selected by anatomical position in combination with colour Doppler activity and the subsequent analysis is performed in an area defined by anatomical structures.

Boesen M, Boesen L, Jensen KE, Cimmino MA, Torp-Pedersen S, Terslev L, Koenig M, Danneskiold-Samsøe B, Røgind H, Bliddal H. · The Parker Institute Frederiksberg Hospital, Copenhagen, Denmark; · J Rheumatol. · Pubmed #18322991 No free full text.

Abstract: OBJECTIVE: To assess the magnetic resonance imaging (MRI) and ultrasound (US) changes in the wrist of patients with rheumatoid arthritis (RA) 4 weeks after an US guided intraarticular (IA) injection. METHODS: Contrast enhanced MRI and US-Doppler were performed at baseline and 4 weeks after IA injection of either 40 mg methylprednisolone (n = 12) or 25 mg etanercept (n = 13) in 25 patients with RA taking disease modifying antirheumatic drugs with a therapy-resistant wrist joint. All injections were US guided. RESULTS: There was an improvement in swollen target joint score (p < 0.001), tender target joint score (p < 0.002), and physician visual analog scale score (p < 0.001) after 4 weeks. Baseline MRI synovitis score was mean 5.08 (range 3-9) and was unchanged at followup in the whole group (p = 0.52) and between treatment groups (p = 0.43). MRI edema score (mean 4.46, range 0-29) in the total group was unchanged after 4 weeks (p = 0.13), whereas MRI erosion score increased in the total group from baseline, 17.88 (range 7-40), to 4 weeks, 18.25 (range 7-40) (p < 0.001). Neither US-Doppler color fraction (0.07) nor Resistive Index (RI) (p = 0.36) changed from baseline to 4 week followup. CONCLUSION: In contrast to the clinical evaluation, imaging measures of relevance for the estimation of inflammation, US-Doppler, US RI, MRI synovitis, and bone-marrow edema did not change 4 weeks after a single IA injection of either methylprednisolone or etanercept in the wrist. Within the same period, erosive progression in some patients suggested that joints with active disease may deteriorate within as little as 1 month, and that this development is not arrested by 1 injection. Given the small sample size of our study further studies are required to confirm our results.

Terslev L, von der Recke P, Torp-Pedersen S, Koenig MJ, Bliddal H. · The Parker Institute, Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark. · J Rheumatol. · Pubmed #18172922 No free full text.

Abstract: OBJECTIVE: To evaluate the sensitivity and specificity of Doppler ultrasound (DUS) in diagnosing arthritis in the wrist and hands, and, if possible, to define a cutoff level for our ultrasound measures for inflammation, resistive index (RI), and color fraction. METHODS: Using DUS, 88 patients with active RA were selected for study and 27 healthy controls. A total of 419 joints were examined. The synovial vascularization was determined by color Doppler and spectral Doppler estimating the color fraction (the percentage of color pixels inside the synovium was the region of interest) and RI in wrist, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints. Receiver-operator characteristic (ROC) curves were made for both US measures. Cutoff levels were selected from the ROC curves as the values with the optimum sensitivity and specificity. RESULTS: Analyses were carried out for small joints (MCP and PIP), wrists, and for all joints (pooled). Pooled joint analysis showed the area under the curve for both RI and color fraction was 0.84. The cutoff level for the color fraction was 0.01 and for RI 0.83. With these cutoff levels, the sensitivity and specificity for the color fraction were 0.92 and 0.73, respectively. For RI a sensitivity of 0.72 and specificity of 0.70 were found. Analysis of small joints and wrist gave very similar results. CONCLUSION: DUS may detect vascularization of the inflamed synovium with a high sensitivity and a moderate specificity with selected cutoff levels.

Boesen M, Jensen KE, Torp-Pedersen S, Cimmino MA, Danneskiold-Samsøe B, Bliddal H. · The Parker Institute, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Copenhagen, Denmark. · Eur J Radiol. · Pubmed #17935920 No free full text.

Abstract: OBJECTIVE: To investigate the distribution of an ultrasound-guided intra-articular (IA) injection in the wrist joint of patients with rheumatoid arthritis (RA). METHODS: An ultrasound-guided IA drug injection into the wrist joint was performed in 17 patients with 1 ml methylprednisolone (40 mg/ml), 0.5 ml Lidocaine (5mg/ml) and 0.15 ml gadolinium (Omniscan 0.5 mmol/ml). The drug solution was placed in the central proximal part of the wrist between the distal radius and the lunate bone. Coronal and axial MRI sequences were performed after the injection to visualize the distribution. Carpal distribution (radio-carpal, inter-carpal, and carpo-metacarpal) as well as radio-ulnar distribution was recorded. Full distribution in one compartment was given the value 1, partial distribution 0.5 and no distribution 0. A sum of the total distribution for all four compartments was calculated and correlated to the clinical parameters and the MRI OMERACT scores. RESULTS: No uniform pattern was seen in the distribution of the contrast. Only two patients had full contrast distribution to all four compartments, and the mean distribution count for all patients was 2.4 (range 0.5-4). The distribution count correlated with the MRI OMERACT synovitis score (r=0.60, p=0.014), but not with the erosions, bonemarrow oedema scores or any clinical parameters. CONCLUSION: The distribution of contrast on MRI showed patient specific and random patterns after IA injections in active RA wrist joints. The degree of distribution increased with the MRI synovitis score, while no association was found with the erosion- and bonemarrow oedema score. These results indicate that a single injection into a standard injection site in the proximal part of the wrist cannot be assumed to distribute--and treat--the whole joint.

Ellegaard K, Torp-Pedersen S, Holm CC, Danneskiold-Samsøe B, Bliddal H. · The Parker Institute, Frederiksberg Hospital, Denmark. · Ultraschall Med. · Pubmed #17680518 No free full text.

Abstract: PURPOSE: Grey-scale ultrasound may be used to visualise the amount of synovial tissue in patients with rheumatoid arthritis (RA). Different scoring systems have been developed. None of the scoring systems have been tested on a larger group of healthy joints, and it is therefore unknown to what extent synovial tissue is seen on grey-scale ultrasound in healthy joints. The objective of this study was to test two scoring systems on healthy volunteers. MATERIALS AND METHODS: 24 healthy men and women between 30 and 54 years underwent scanning of the MCP, PIP and DIP joints of their dominant hand. Each person was scanned in 69 positions. The images were graded on a scale from 0 to 4 with two scoring systems (I and II). Scores 0 - 1 were defined as normal and 2 - 4 as pathological. With scoring system I, only markedly hypoechoic synovium was graded. With scoring system II, marked hypoechogenicity was not a criterion. RESULTS: With system I, 89 % of the joints obtained at least one pathological score. With system II, 95 % of the joints obtained at least one pathological score. With both systems, women obtained higher scores than men, and the number of high scores increased with increasing age. CONCLUSION: An unacceptably high number of joints obtained pathological scores with both scoring systems in healthy volunteers. This indicates that many of the scores interpreted as pathological in patients with RA may just be normal findings, with increasing numbers in older patients.

Bliddal H, Terslev L, Qvistgaard E, Konig M, Holm CC, Rogind H, Boesen M, Danneskiold-Samsøe B, Torp-Pedersen S. · The Parker Institute, Frederiksberg Hospital, Copenhagen, Denmark. · Scand J Rheumatol. · Pubmed #17062431 No free full text.

Abstract: OBJECTIVE: Glucocorticosteroids are used successfully for both systemic and intra-articular treatment of arthritis. Inhibitors of tumour necrosis factor alpha (TNF-alpha) are effective when administered systemically and this study was performed to compare the effect of intra-articular injection of these two substances. DESIGN: A randomized, parallel-group, double-blind study with an independent observer. Thirty-eight patients with flare of arthritis in a single joint (wrist, elbow, or knee) were given intra-articular 25 mg etanercept or 40 mg methylprednisolone guided by ultrasound. The primary end-point was the 4-week change in pain in the target joint. The study complied with Good Clinical Practice (GCP) and the Consolidated Standards for Reporting of Trials (CONSORT) statement. RESULTS: At 4 weeks no difference in pain outcome between treatment groups was demonstrated by analysis of covariance (ANCOVA). Pain on the Visual Analogue Scale (VAS) for etanercept was baseline mean 40.9 (SD 19.6) mm, follow-up 32.7 (29.1) mm (p = 0.29), methylprednisolone baseline mean 47.1 (29.6) mm, follow-up 25.3 (24.7) mm (p<0.001). The investigator's evaluation was for etanercept baseline 30.6 (21.2) mm, follow-up 17.1 (15.5) mm (p = 0.054) and for methylprednisolone baseline 35.4 (26.4) mm, follow-up 11.9 (14.6) mm (p = 0.012). Joint swelling was for etanercept baseline 1.78 (0.73), follow-up 1.25 (0.77) (p = 0.015) and for methylprednisolone baseline 1.74 (0.73), follow-up 0.71 (0.77) (p<0.001). One serious adverse event was seen in a patient treated with methylprednisolone injection. CONCLUSION: Although no difference between groups was demonstrated, the within-group effect of methylprednisolone was more marked than that of etanercept. Injections with 25 mg etanercept were well tolerated. However, the cost of etanercept will presumably limit its use to patients with adverse reactions to steroid.

Qvistgaard E, Torp-Pedersen S, Bliddal H. · H:S Frederiksberg Hospital, Parker Instituttet. · Ugeskr Laeger. · Pubmed #15017733 No free full text.

This publication has no abstract.

Terslev L, Qvistgaard E, Kristoffersen H, Torp-Pedersen S, Bliddal H. · H:S Frederiksberg Hospital, Parker Instituttet. · Ugeskr Laeger. · Pubmed #15017732 No free full text.

This publication has no abstract.

Terslev L, Torp-Pedersen S, Qvistgaard E, Bliddal H. · The Parker Institute, Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark. · Acta Radiol. · Pubmed #14616209 No free full text.

Abstract: PURPOSE: To evaluate the use of spectral Doppler in the longitudinal follow-up of inflammatory joint involvement in rheumatoid arthritis (RA) by comparing resistive index (RI) findings with color fraction and pain on a visual analog scale (VAS). MATERIAL AND METHODS: Five patients on unchanged disease modifying anti-rheumatic drugs (DMARD) treatment were followed after an intra-articular corticosteroids injection and received no further injections in the observation period. They were followed clinically and by ultrasound using color Doppler pixels and the spectral Doppler RI as indicators of inflammation. At 1, 6 and 12 months the measurements were repeated on the same joint. RESULTS: At 1-month follow-up after the corticosteroids injection, a marked decrease in the color fraction was seen in 4 out of 5 patients, while the fifth patient had a moderate decrease (Wilcoxon p < 0.05). The changes in RI showed correspondingly a marked increase in 4 out of 5 patients indicating a diminished flow to the synovium (Wilcoxon p < 0.05). The effect of the corticosteroid injection could still be seen after 1 year in 4 out of 5 patients. In RI, pixel fraction and VAS there was improvement compared with the baseline values; however, only the pixel fraction was statistically significant (Wilcoxon p < 0.05). CONCLUSION: RI seems to be an objective alternative to pixel estimation of the degree of inflammation and treatment response in RA.

Terslev L, Torp-Pedersen S, Qvistgaard E, Danneskiold-Samsoe B, Bliddal H. · The Parker Institute, Department of Rheumatology, Frederiksberg Hospital, DK 2000 Frederiksberg, Denmark. · Ann Rheum Dis. · Pubmed #14583566 links to  free full text

Abstract: OBJECTIVE: To evaluate the use of ultrasound, including quantitative Doppler analysis of synovial vascularisation, before and after intra-articular treatment with glucocorticosteroids in patients with rheumatoid arthritis (RA). METHODS: 51 patients with RA were followed prospectively after an intra-articular glucocorticosteroid injection. Disease modifying antirheumatic drug treatment was kept unchanged and no further injections given in this observation period. At baseline, disease activity was estimated clinically by target join pain on a 100 mm visual analogue scale, on which the target joint was scored 0-3 for swelling and tenderness, and by ultrasound measurements of grey scale pixels, colour Doppler pixels, and the spectral Doppler resistive index (RI) as indicators of synovial swelling and inflammation. After four weeks, the measurements were repeated on the same joint. An observer unaware of the sequence and patient number evaluated the ultrasound images. RESULTS: At one month follow up after the glucocorticosteroid injection, a marked decrease in the fraction of colour pixels was seen in 41/51 patients (Student's t test p<0.001). Correspondingly, the RI increased indicating a diminished flow to the synovium (Student's t test p<0.01). Both the fraction of colour pixels and the RI values corresponded with the clinical evaluation and with the subjective effect of the treatment. The synovial membrane volume estimated by total amount of pixels showed a significant decrease by 31% after treatment. CONCLUSION: Ultrasound-Doppler seems to be a promising tool for the estimation of synovial activity in arthritis. After intra-articular glucocorticosteroid, changes in RI and fraction of colour pixels may both be used as quantitative measurements of the blood flow.

Qvistgaard E, Røgind H, Torp-Pedersen S, Terslev L, Danneskiold-Samsøe B, Bliddal H. · The Parker Institute, Department of Rheumatology, Frederiksberg Hospital, DK 2000 Frederiksberg, Denmark. · Ann Rheum Dis. · Pubmed #11406524 links to  free full text

Abstract: OBJECTIVE: To evaluate ultrasonographic methods, including the Doppler technique, as measures of synovial inflammation in finger joints of patients with rheumatoid arthritis. METHODS: Ultrasonography was performed with a high frequency transducer (13 MHz). Evaluation of the sonographic data was conducted by two independent observers and included measurement of synovial area and thickness (grey tone ultrasound), vascularisation (power/colour Doppler), and indices of the intra- and extrasynovial arterial flow (spectral Doppler). The flow pattern was estimated by the indices of pulsatility (PI) and resistance (RI). RESULTS: The sonographic measurements of joint space were reproducible with intraobserver, intraclass correlation coefficients (ICC) 0.82-0.97 (p<0.0001) and interobserver ICC 0.81 (p<0.0001). The mean (SD) fraction of the synovium vascularised in the patients was 0.15 (0.15). The synovial blood flow was characterised by a diastolic flow-that is, the flow persisting during the diastole. The mean (SD) PI was 1.92 (1.18) and RI 0.70 (0.13). The estimated vascular fraction correlated with the erythrocyte sedimentation rate (ESR) (r(s)=0.53, p=0.03). The relative Pi (rPi), an estimate of an abnormally low resistance to vascularisation, correlated with both ESR (r(s)=-0.557, p<0.05) and Health Assessment Questionnaire score (r(s)=-0.584, p<0.05). After an injection of contrast Levovist the vascular fraction increased, while no difference in PI and RI was observed. CONCLUSION: Ultrasonography is a reliable tool for estimating the size of the joint space and the synovial activity measured by the degree of vascularisation and pattern of flow. Ultrasonography may be useful in monitoring the synovial inflammation in rheumatoid arthritis.