Antifilaggrin antibodies in early rheumatoid arthritis may predict radiological progression

OBJECTIVE: To elucidate the possibility that autoantibodies to filaggrin, detected in patients with early RA (having a disease duration of not more than one year), may predict joint destruction assessed after five years of observation. METHODS: This is a 5 yr extension of a previous study (1) of 112 consecutive patients with early RA. Serum antifilaggrin autoantibodies were detected by immunoblotting (AFA) and by indirect immunofluorescence ("AKA"). DAS28, pain on a VAS. HAQ, and CRP were measured. Plain X-ray films were taken from hands and forefeet and a Larsen score was calculated. RESULTS: Ninety-two of the original 112 patients had baseline X-rays available and constituted the study material. At 5 year follow-up, 67 of these 92 have been assessed and for 63 of these X-rays were available. For the whole patient material, significant radiological progression, measured by Larsen scores, occurred while disease activity and function (pain VAS, DAS28, CRP, and HAQ) improved significantly over five years. The groups of patients having AFA or "AKA" at baseline had significantly (p=0.006 and p<0.001, respectively) higher Larsen scores five years later than the groups without these antibodies. No clear relation of these antibodies to disease activity or function was demonstrated, except that the group of patients with "AKA" had significantly higher median CRP (p=0,003) after five years. CONCLUSIONS: The present study shows that antifilaggrin autoantibodies may predict radiological progression. The prognostic value of these antibodies will be further evaluated in relation to other potential markers in a larger patient material.     

Does second-line therapy affect the radiological progression of rheumatoid arthritis?

The effect of 'second-line' drugs on radiological progression in rheumatoid arthritis is not clear, and previous studies have yielded contradictory results. Sixty-seven patients with rheumatoid arthritis have been followed up clinically and radiologically for approximately 2 years (26 patients were receiving intramuscular gold, 21 penicillamine, 10 levamisole, and there were 10 controls who had consistently refused second-line therapy). Patients on gold and penicillamine showed improvement in erythrocyte sedimentation rate and haemoglobin over 2 years which was not seen in levamisole and control patients, but hand radiograph scores in all 4 groups showed statistically significant deterioration. There was a trend towards slowing of the rate of erosion in the gold and penicillamine groups in comparison with controls, but healing of erosions was extremely unusual.     

Effect of sulphasalazine on the radiological progression of rheumatoid arthritis.

We have investigated the influence of sulphasalazine, a second line antirheumatic drug, on the radiological progression of erosions in rheumatoid arthritis over a two year period in 41 patients. Hand radiograph scores deteriorated significantly over this period, but in a group of 31 patients in whom one year films were also available this deterioration was limited to the first year. This slowing of radiological deterioration was not related to 'normalisation' of the erythrocyte sedimentation rate (ESR). Compared with a 'control' group of 10 patients who had refused offers of second line therapy, sulphasalazine treated patients showed less deterioration over the two year period, and this difference was more marked than in previous studies of gold or penicillamine. No significant change was seen in large joint radiographs in sulphasalazine treated patients over two years, but this probably represents the poor sensitivity of the method of assessment. No significant correlation was seen between changes in inflammatory indices and slowing of radiological deterioration in erosion score. Thus sulphasalazine appears to slow the progression of radiological disease of the hands over the second year of treatment in a representative sample of patients who continue to receive treatment for two years.     

Relation between body mass index and radiological progression in patients with rheumatoid arthritis

OBJECTIVE: To determine if there is an influence of body mass index (BMI) on the radiological progression in early and longer duration rheumatoid arthritis (RA). METHODS: Fifty-four patients with RA were observed in a progressive 2 year followup for radiological progression of joint damage. At the beginning of study, 27 (50%) patients had a duration of complaints less than 6 months, grouped as early RA. BMI at the beginning and end of the study were monitored, together with HLA-DRB1 alleles, initial joint erosions, duration of disease, age, sex, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Outcome was defined as radiographic damage according to yearly increase of Larsen score. RESULTS: Increased radiographic joint damage of patients was significantly correlated with lower BMI at the beginning of the study (r = 0.363, p < 0.05), the presence of initial joint erosions (r = 0.341, p < 0.01), ESR (r = 0.315, p < 0.05), and CRP at study entry (r = 0.427, p < 0.01). Patients with an increase of Larsen score > or = 5.8/year were found to have a lower weight at the beginning of their complaints (BMI 24.8 +/- 4.7 vs 27.8 +/- 3.8; p < 0.05) as well as after the time of observation (BMI 24.6 +/- 3.7 vs 27.6 +/- 4.9; p < 0.05). Stepwise logistic regression analysis revealed a BMI < 27 at the beginning of disease (beta = 2.04, p = 0.003, odds ratio = 7.69), the presence of HLA-DR4 shared epitope (beta = 1.76, p = 0.015, OR 5.82), and joint erosions at study entry (beta = 1.56, p = 0.044, OR 4.78) as significant predictors for rapid joint damage. CONCLUSION: Together with the presence of HLA-DR4 shared epitope and erosive disease at study entry, a low BMI at the beginning of RA was found in association with higher radiographic progression in RA. Accordingly, BMI could be of interest as a sensitive and inflammation-independent predictor for radiological outcome of RA.     

Can treatment with methotrexate influence the radiological progression of rheumatoid arthritis ?

Summary We have recently reported that methotrexate (MTX) is an effective treatment of patients with refractory rheumatoid arthritis (RA) to second line medication. We showed that 54% of our patients continued having clinical benefit after 24 months therapy with MTX. In this study we evaluated pairs of hand radiographs from 35 patients taken before and after 24 months treatment. We used a scale scoring similar to Larsen 's standard radiographs with minor modifications. No significant changes were observed in the overall scoring of the radiographs before (14.84 ± 13.05) and after treatment (18.77 ± 15.60) (p>0,5). Of these 35 patients, 23 had a clinical remission and 12 had a good response. Twenty patients have shown a stabilization of erosions in radiographs while 15 showed a deterioration. No correlation was found between clinical response and radiological changes. We conclude that MTX does not appear to be a disease modifying agent, but may inhibit joint damage progression.     

Predictors of radiological progression and changes in hand bone density in early rheumatoid arthritis

Objective. To identify predictors for radiological and functionaloutcome and bone loss in the hands in early rheumatoid arthritis(RA) during the first 2 yr of disease and to study the relationshipbetween these variables. Methods. An inception cohort of consecutively recruited patientswas examined at baseline and after 12 and 24 months using X-raysof hands and feet, clinical [28-joint count, Health AssessmentQuestionnaire (HAQ), global visual analogue scale (VAS), gripstrength] and laboratory (erythrocyte sedimentation rate, C-reactiveprotein, markers of bone formation and resorption) measurementsand dual-energy X-ray absorptiometry measurements of the hands. Results. Joint destruction increased significantly during thestudy, with the Larsen score at baseline as the strongest predictor.Radiological progression and bone loss over 24 months were significantlyretarded in patients responding to therapy. The effects of theshared epitope and initial high inflammatory activity on radiologicalprogression were overridden by the therapeutic response. Radiologicalprogression correlated significantly with bone loss. GlobalVAS, Larsen score and HAQ at inclusion significantly predictedchange in HAQ over time. Conclusions. Radiological progression and bone loss were retardedby early therapeutic response. Bone loss was related to radiologicalprogression. Correspondence to: S. Rantapää Dahlqvist, Departmentof Rheumatology, University Hospital, SE-901 85 Umeå,Sweden. E-mail: solbritt.rantapaa.dahlqvist{at}medicin.umu.se     

Serum soluble interleukin 2 receptor levels and radiological progression in early rheumatoid arthritis.

OBJECTIVE: To investigate the association between serum soluble interleukin 2 receptor (sIL-2R) levels and radiological changes in patients with early rheumatoid arthritis (RA). METHODS: sIL-2R levels from 155 patients with active RA were measured by immunoassay over a 2 year period and the associations with radiological change and other measures of disease activity were analyzed. RESULTS: The area under the curve for sIL-2R is weakly associated with the change in the modified Larsen score over a 2 year period; this is weaker than the association of radiological change with serum C-reactive protein. CONCLUSION: We found no significant association of sIL-2R levels with erosive change in early RA.     

小剂量糖皮质激素抑制类风湿关节炎放射学进展的系统评价

目的 系统评价小剂量糖皮质激素抑制类风湿关节炎(RA)放射学进展的疗效.方法 计算机检索Medline(1966年1月至2010年4月)、Embase(1966年至2010年4月)、Cochrane图书馆(2010年第2期)、中国生物医学数据库、中国期刊全文数据库(CNKI)、万方及维普数据库(1979年1月至2010年4月),并检索所纳入文献的参考文献.收集所有相关随机对照试验,采用Cochrane协作网提供的软件Revman5进行Meta分析,以获得小剂量糖皮质激素抑制RA放射学进展的相关证据.结果 经全面检索及筛查后,共纳入11个随机对照试验进行评价.Meta分析表明,在用药1年后,骨与关节侵蚀的标准化均数差(SMD)是-0.39[95％CI(0.50～-0.27)].2年时,侵蚀的SMD是-0.73[95％CI(- 1.29～-0.16)].结论 小剂量糖皮质激素能减缓RA放射学病损的进展.     

Immunogenetic markers and seropositivity predict radiological progression in early rheumatoid arthritis independent of disease activity

OBJECTIVE: A prospective clinical study of patients with recent onset rheumatoid arthritis (RA) to examine the relationship between inflammatory disease activity and joint destruction in a 4 year followup, and to evaluate prognostic markers for severe joint erosions early in the disease. METHODS: Eighty-seven patients with RA according to the American College of Rheumatology criteria and a disease duration < 2 years were followed for an observation time of 2 to 4 years (mean 3.1 yrs). Variables of clinical and laboratory disease activity were monitored, and HLA-DRB1 alleles were determined. Hand and foot radiographs were taken every 6 months. RESULTS: Multivariate analysis of independent contributions of covariates to progression of joint destruction resulted in a mixed effect regression model with significant influences for the presence of a shared epitope (SE) positive DR4 allele (SE+ DR4+; p = 0.007), rheumatoid factor (RF) IgA (p = 0.01), and sex (p = 0.059), but not for clinical variables or acute phase reactants. The odds ratio to reach a Larsen score above 32 during the observation period of 4 years was increased in patients positive for RF IgM (OR 2.7, p = 0.019), for the shared epitope on a DR4 allele (OR 8.6, p < 0.005), and in patients with erosions already at study entry (OR 11.9, p = 0.001). The highest sensitivity and specificity for the prediction of severe bone destruction (84% and 79%) were found when the presence of either a SE+ DR4 allele or of early erosions was used as a prognostic marker (OR 20.4, p < 0.0001). CONCLUSION: Our results show the pace of joint destruction in RA to be influenced by the presence of SE+ DR4 alleles, RF production, and sex and by the presence of erosive disease at presentation. Those prognostic markers exert their influence independently from the inflammatory disease activity.     

Circulating dickkopf-1 and radiological progression in patients with early rheumatoid arthritis treated with etanercept

OBJECTIVE: Dickkopf-1 (Dkk-1) regulates bone remodeling in animal models of inflammatory arthritis, but its role in patients with rheumatoid arthritis (RA) remains unclear. METHODS: Baseline circulating Dkk-1 was measured in 113 patients with RA (< 3 yrs) who received etanercept (10 or 25 mg twice/week, n = 63) or methotrexate alone (n = 40) for 1 year. Progression was assessed by changes in radiological Sharp score. RESULTS: Increased Dkk-1 was associated with a higher risk of progression of bone erosion, independently of age, sex, baseline radiological damage, C-reactive protein, and disease activity in patients treated with etanercept. CONCLUSION: Dkk-1 may be an important mediator of bone erosion in patients with RA.     

Comparison of radiological severity in psoriatic arthritis and rheumatoid arthritis

OBJECTIVE: To compare the radiological severity of patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). METHODS: Patients were identified from the University of Toronto PsA and RA databases. Using the earliest available radiographs, each RA patient was matched to a single PsA patient on the basis of sex, age, and disease duration. Two rheumatologists blinded to the patient's diagnosis scored the radiographs using the modified Steinbrocker method. RESULTS: PsA and RA groups were similar with respect to demographics as well as the use of disease modifying antirheumatic medications. No significant difference in Steinbrocker score for the hands and feet or the hands only was noted. Patients with RA had a higher radiological score in the feet. The 2 groups were similar in the number of joints with significant radiological damage (Steinbrocker 3 and 4). CONCLUSION; Overall the radiological severity in the hands and feet of patients with PsA was comparable to that of patients with RA.     

Serum matrix metalloproteinase 3 in early rheumatoid arthritis is correlated with disease activity and radiological progression

OBJECTIVE: To analyze the clinical significance of serial measurements of serum matrix metalloproteinase 3 (MMP-3) levels in relation to markers of disease activity and radiological progression in early rheumatoid arthritis (RA). METHODS: In a 3 year prospective study of 33 patients with early RA (symptoms < 1 year at entry) monthly measurements of serum MMP-3 were transformed into time integrated values for 6 month periods for comparison with other markers of disease activity like swollen joint count (SJC), tender joint count (TJC), Ritchie articular index (RAI), the disease activity score (DAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and radiological progression, scored according to Sharp's method, in which erosions and joint space narrowing are scored separately and combined to a total Sharp score. RESULTS: Significant correlations were found between serum MMP-3 and SJC, ESR, and CRP during all periods and between 6 and 30 months with the DAS. There were no correlations between serum MMP-3 and TJC or the RAI. During the first 12 months serum MMP-3 was correlated only with the item joint space narrowing of the Sharp score. After 12 months of followup it was also correlated with the total Sharp score and after 18 months it was correlated with all 3 items of the Sharp score. There was a wide interindividual variation in the relation between serum MMP-3 and radiological progression but intraindividually this relation seemed to be rather constant. CONCLUSION: Time integrated values of serum MMP-3 are correlated with time integrated values of other markers of disease activity such as joint swelling, ESR, CRP, and the DAS. Of the radiological scores, as outcome measures, especially joint space narrowing correlated closely with cumulative serum MMP-3.     

Progression of radiological changes in rheumatoid arthritis.

A prospective study over one year of patients who had active rheumatoid arthritis discovered 64 who had received treatment for an adequate time with second-line drugs. In these patients there was evidence of continuing joint destruction as shown by radiological progression. During the year there were highly significant correlations between improvements in clinical and laboratory measurements, but neither group of tests was related to the degree of radiological change. However, in the second 6 months of treatment there was evidence that radiological progression was reduced. In a second prospective study of 88 patients with rheumatoid arthritis given prolonged, intensive therapy with second-line drugs and followed up for 10 years two-thirds showed radiological progression. However, the number of joints damaged per year fell significantly during the study period. There was a divergence between deterioration in radiological features and improvements in the ESR and functional capacity, though patients with a persistently low ESR had less radiological progression. These studies provide evidence that treatment may be associated with a reduced rate of radiological progression but suggest that changes in radiological progression and clinical and laboratory measurements may result from different mechanisms.     

Relationship between serum RANTES levels and radiological progression in rheumatoid arthritis patients treated with methotrexate.

OBJECTIVE: The aim of this study was to evaluate the relationship between serum chemokines and the clinical and radiological response to a one-year course of methotrexate (MTX) in patients suffering from rheumatoid arthritis (RA). METHODS: Twenty out-patients suffering from active RA entered a one-year open prospective study on the effects of low dose MTX therapy. Plain radiographs of the hands and feet were taken at study entry and at the end of the follow-up, and were compared for the number of eroded joints. Serum levels of both C-X-C and C-C chemokines were obtained before the initation of MTX and after 6 and 12 months of treatment. RESULTS: The levels of serum RANTES before treatment were significantly higher in RA patients than in the controls and returned to normal levels after one year of treatment. Serum levels of the other chemokines were either in the normal range or undetectable. Twelve patients (60%) did not show any new eroded joints at the end of the follow-up period and were considered as radiological responders (RR). Serum levels of GRO-alpha and RANTES after 6 months of treatment were significantly higher among the patients with radiological progression than in RR patients. CONCLUSIONS: We observed high levels of serum RANTES in a series of RA patients during the active stage of the disease. MTX treatment significantly lowered the serum levels of RANTES, GRO-alpha and MCP-1. High levels of serum RANTES or GRO-alpha after 6 months of MTX treatment seem to be predictive of radiological erosions after one year.     

Comparison of functional disability scales and their relevance to radiological progression in patients with rheumatoid arthritis in remission

OBJECTIVE: To look for any correlations between radiological scores and hand functions evaluated with two different methods in patients with rheumatoid arthritis in remission. METHODS: Forty-two patients diagnosed with rheumatoid arthritis (RA) in remission according to ACR criteria were assessed for their hand functions with Duru?z's Hand Index (DHI), and with Sollerman Function Test (SHFT) as well as with Health Assessment Questionnaire (HAQ). Hand X-rays were evaluated according to Modified Sharp Index; joint space narrowing score (JSNS), erosion score (ES), and total score (TS) were calculated. The X-rays were assessed by the same rheumatologist three times. RESULTS: Mean HAQ score, mean DHI score and mean SHFT scores were 0.88+/-0.68, 17.74+/-17.81, 72.24+/-9.23 respectively. Radiologic scores were as follows: JSN 35.04+/-28.14, ES 25.19+/-36.23, TS 60.26+/-66.21. Intraobserver reliability was high (r=0,98). There was a positive correlation between HAQ and DHI (p<0.001), a negative correlation between SHFT. There was also a negative correlation between DHI and SHFT. The correlations between JSNS, ES and TS with respect to HAQ and SHFT were strong (p<0.0001) along with DHI (p<0.05). CONCLUSION: HAQ was found correlated with DHI and SHFT. Modified Sharp scores were found correlated with the general disability and hand functions. SHFT, with respect to DHI, takes a longer period of time, depends on equipment and needs an observer. On the contrary, DHI offers a more practical and economical way of assessment.     

Aspects of the radiological evaluation of rheumatoid arthritis

This paper gives an overview of several aspects of the radiographic evaluation of rheumatoid arthritis (RA). Radiographs give important information about the structural damage caused by RA. On a group level, the natural progression follows a rather linear cause, but on an individual patient level, this can vary widely. Feet are often affected earlier and to a larger extent than hands. Both hands and feet give a good overall impression of the damage in the large joints and are sufficient to monitor the patient. It is recommended to take annual films of hands and feet to monitor patients. Several scoring methods are available for application in clinical trials. Most widely used are the Sharp and Larsen methods with their modifications. For use in clinical practice the SENS method is more feasible. Several drugs are capable of retarding radiographic progression. However, it is difficult to compare results across trials and these difficulties are elaborated.     

The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials

OBJECTIVE: To undertake a systematic review of randomized placebo-controlled trials to assess and rank the efficacy of pharmacological interventions in preventing radiological progression of rheumatoid arthritis. METHODS: The two outcome measures were the weighted standardized mean difference and the odds of progression of X-ray scores pooled as close to 12 months as possible to minimize heterogeneity. RESULTS: A total of 38 trials were identified. Of these, 13 were excluded, leaving data on 3907 subjects. Infliximab, cyclosporin, sulphasalazine, leflunomide, methotrexate, parenteral gold, corticosteroids, auranofin and interleukin 1 receptor antagonist were statistically better than placebo in terms of change in erosion scores. All agents were equivalent statistically, with the exception of infliximab (which was superior to the last five agents). There were similar findings for the odds of progression, with the exception of auranofin (P=0.06) and the infliximab-methotrexate comparison (P=0.07). Other agents did not reach statistical significance in either outcome measure. With the exception of the antimalarials, the magnitude of the effect was consistent with the effect seen in short-term disease activity trials. CONCLUSION: There is published evidence which supports the efficacy of nine agents in decreasing radiological progression in rheumatoid arthritis.     

Influence of cyclosporin A on radiological progression in early rheumatoid arthritis patients: a 42-month prospective study

The aim of this study was to evaluate whether cyclosporin A (CsA) influences the radiological disease progression in early rheumatoid arthritis (RA) patients in comparison with other disease-modifying drugs (DMARDs). A total of 103 early RA patients, without prior use of DMARDs, were randomized to receive CsA (3 mg/kg per day) or methotrexate (MTX) (0.15 mg/kg per week). In addition, all patients received prednisone (7.5 mg/day). After 42 months of treatment, pairs of hand and wrist radiographs of 41 patients treated with CsA and 42 treated with MTX were evaluated blindly and separately by two investigators, using reference radiographs for scoring. A scale scoring similar to Larsen's standard radiographs with minor modifications was used. The studied radiographs were obtained at the beginning and 42 months after therapy in both groups. Patients in both groups responded beneficially to the above treatment regimens. In the CsA group, 37 patients (71%) remained radiographically stable and 4 worsened, while in the MTX group 39 patients (76%) remained stable and 3 deteriorated. No significant radiological worsening was found in the CsA-treated patients as compared to those treated with MTX. Early immunointervention in RA patients appears to be crucial for the future development of joint damage. CsA can delay radiological disease progression and may inhibit joint damage deterioration in early RA patients. Received: 28 August 1999 / Accepted: 3 December 1999