A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial.

OBJECTIVES: To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. METHODS: In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. RESULTS: Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months' follow-up, with mean change scores of -3.7 (median -3.0), -2.2 (-1) and -5.3 (-4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann-Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001-0.002 and p=0.062-0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. CONCLUSIONS: A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.

CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients.

INTRODUCTION: Single-nucleotide polymorphisms (SNPs) in the CRP gene are implicated in the regulation of the constitutional C-reactive protein (CRP) expression and its response to proinflammatory stimuli. Previous reports suggest that these effects may have an impact on clinical decision-making tools based on CRP, such as the Disease Activity Score in 28 joints (DAS28). We aimed to investigate the possible association between seven CRP SNPs, their haplotypes and the serum levels of CRP, as well as DAS28 scores, in two cohorts of untreated active early rheumatoid arthritis (RA) patients followed during their initial treatment. METHODS: Overall, 315 patients with RA from two randomized controlled trials (the CIMESTRA and OPERA trials) who were naïve to disease-modifying antirheumatic drugs and steroids with disease durations less than 6 months were included. Seven CRP SNPs were investigated: rs11265257, rs1130864, rs1205, rs1800947, rs2808632, rs3093077 and rs876538. The genotype and haplotype associations with CRP and DAS28 levels were evaluated using linear regression analysis adjusted for age, sex and treatment. RESULTS: The minor allele of rs1205 C > T was associated with decreased CRP levels at baseline (P = 0.03), with the TT genotype having a 50% reduction in CRP from 16.7 to 8.4 mg/L (P = 0.005) compared to homozygosity of the major allele, but no association was observed at year 1 (P = 0.38). The common H2 haplotype, characterized by the T allele of rs1205, was associated with a 26% reduction in CRP at baseline (P = 0.043), although no effect was observed at year 1 (P = 0.466). No other SNP or haplotype was associated with CRP at baseline or at year 1 (P ≥ 0.09). We observed no associations between SNPs or haplotypes and DAS28 scores at baseline or at year 1 (P ≥ 0.10). CONCLUSION: CRP genotype and haplotype were only marginally associated with serum CRP levels and had no association with the DAS28 score. This study shows that DAS28, the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants. TRIAL REGISTRATION: The OPERA study is registered at Clinicaltrials.gov (NCT00660647). The CIMESTRA study is not listed in a clinical trials registry, because patients were included between October 1999 and October 2002.

Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial.

OBJECTIVES: An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months. METHODS: In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6-9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward. RESULTS: Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7-5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7-4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008

Three cases of severely disseminated Staphylococcus aureus infection in patients treated with tocilizumab.

We report three cases of severe disseminated Staphylococcus aureus infection in patients with rheumatoid arthritis (RA) treated with tocilizumab. Tocilizumab is a new drug, unknown to most internists, and injections given weeks before admission may not be considered by the patient as part of their 'current medical treatment', and the physician may not be aware that the patient is severely immunosuppressed. Severe infections in RA patients treated with tocilizumab may present with mild symptoms despite severe and disseminated infection and, as these patients are severely immunodeficient-intensive diagnostic work-up and early treatment should be performed. Systematic postmarketing studies are needed to clarify if there is a true increased risk of disseminated S aureus infections. We suggest caution when prescribing tocilizumab to patients with prosthetic joints and/or prior invasive S aureus infections and that patients are taught to inform health staff about their medication history and their increased risk of infection.

Short- and long-term efficacy of intra-articular injections with betamethasone as part of a treat-to-target strategy in early rheumatoid arthritis: impact of joint area, repeated injections, MRI findings, anti-CCP, IgM-RF and CRP.

OBJECTIVE: To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA). METHODS: During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan-Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested. RESULTS: 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not. CONCLUSION: In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Osteoporosis among Fallers without Concomitant Fracture Identified in an Emergency Department: Frequencies and Risk Factors.

We aimed to determine whether the Emergency Department (ED) is a suitable entrance point for osteoporosis screening among fallers without concomitant fracture compared to referral from general practice. Furthermore, to identify factors associated with osteoporosis among fallers. Methods. Patients aged 50-80 years sustaining a low-energy fall without fracture were identified from an ED (n = 199). Patients answered a questionnaire on risk factors and underwent osteodensitometry. Data was compared to a group of patients routinely referred to osteodensitometry from general practice (n = 201). Results. Among the 199 included fallers, 41 (21%) had osteoporosis. Among these, 35 (85%) reported either previous fracture or reduced body height (>3 cm). These two risk factors were more frequent among fallers with osteoporosis compared to fallers with normal bone mineral density or osteopenia (previous fracture P = .044, height reduction P = .0016). The osteoporosis frequency among fallers from ED did not differ from a similarly aged patient-group referred from general practice (P = .34). Conclusion. Osteodensitometry should be considered among fallers without fracture presenting in the ED, especially if the patient has a prior fracture or declined body height. Since fallers generally have higher fracture risk, the ED might serve as an additional entrance to osteodensitometry compared to referral from primary care.

Patterns of magnetic resonance imaging bone erosion in rheumatoid arthritis--which bones are most frequently involved and show the most change?

OBJECTIVE: To investigate by magnetic resonance imaging (MRI) which bones in wrists and metacarpophalangeal (MCP) joints most frequently show bone erosions, and which most frequently demonstrate erosive progression, in early and established rheumatoid arthritis (RA). METHODS: MRI datasets from 258 RA patients [126 with early RA (disease duration < 6 months)] were analyzed, of whom 223, including 126 with early RA, had 1-year followup MRI. All patients had MRI of one wrist, whereas 86 patients had additional images of 2nd-5th MCP joints, and 46 patients additional images of the contralateral wrist. MRI were evaluated blinded by one reader, according to the OMERACT RA MRI scoring system (RAMRIS) for erosions, and presence/absence of erosions was noted in each bone, as was presence/absence of erosive progression. RESULTS: The capitate, ulna, lunate, triquetrum, and scaphoid were the 5 bones with both most frequent baseline erosions and most frequently demonstrated erosive progression. No bones were without erosions. Patterns of erosions and progression were similar in early and established RA. No major difference between dominant and nondominant wrists was detected. In the fingers, the 2nd-3rd MCP joint most frequently displayed erosions and erosive progression. CONCLUSION: The distribution and frequency of bone erosion and erosive progression as detected by MRI in RA wrists and MCP joints were identified. No pattern differences between early versus established disease and dominant versus nondominant sides were detected. No bones showed erosive progression. Thus, no self-evident simplification of the RAMRIS erosion score was identified. Bone involvement patterns may be considered, when joints are selected for MRI protocols for clinical trials and practice.

Cartilage oligomeric matrix protein associates differentially with erosions and synovitis and has a different temporal course in cyclic citrullinated peptide antibody (anti-CCP)-positive versus anti-CCP-negative early rheumatoid arthritis.

OBJECTIVE: Cyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative rheumatoid arthritis (RA) have been suggested as 2 distinctive disease subsets with respect to disease activity and prognosis. Previously, we proposed that anti-CCP antibodies might have a chondrocyte-suppressive effect. We aimed to compare circulating cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in untreated anti-CCP-positive and anti-CCP-negative RA, and to study the temporal pattern of COMP through 4 years of treatment, including the relationship to imaging and clinical findings. METHODS: A total of 160 patients with newly diagnosed RA who were naive to disease-modifying antirheumatic drugs were included in the CIMESTRA trial. Ninety healthy blood donors served as controls. Demographic and disease measures including Disease Activity Score in 28 joints, IgM rheumatoid factor, anti-CCP, Health Assessment Questionnaire, visual analog scale scores for pain and global and physician assessment, and magnetic resonance imaging (MRI) of the nondominant hand were recorded at baseline. COMP in serum was measured by ELISA at inclusion and serially through 4 years. RESULTS: Median baseline COMP was higher in patients with RA [9.8 U/l (interquartile range 8.96, 10.5)] compared with controls [8.3 U/l (IQR 7.84, 8.9); p < 0.001] and remained elevated at 4 years [10.8 U/l (IQR 10.2, 11.7); p < 0.001]. At baseline, anti-CCP-positive patients had lower COMP than anti-CCP-negative patients (p = 0.048). In anti-CCP-positive patients, COMP exhibited a parabolic course over 4 years, while COMP in anti-CCP-negative patients had an almost linear course. In anti-CCP-positive patients, COMP was associated with MRI edema and erosion score, while COMP was correlated with synovitis score in anti-CCP-negative individuals. CONCLUSION: Our study provides additional evidence for the existence of different disease pathways in anti-CCP-positive and anti-CCP-negative subsets of RA, and evidence that anti-CCP antibodies may be implicated in the disease process by modifying cartilage metabolism.

Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial.

OBJECTIVE: At 5 years' follow-up of early (<6 months) rheumatoid arthritis patients to (1) investigate whether initial combination therapy with methotrexate (MTX) and ciclosporin (CSA) (n=80) is superior to initial monotherapy with MTX (n=80) with respect to prevention of radiographic progression, (2) investigate whether the favourable clinical and radiographic response reported at 2 years in the CIMESTRA trial can be maintained and (3) identify predictors of radiographic outcome. METHODS: 139 patients completed 5 years' follow-up with maintained double-blinding and a strict synovitis suppressive treatment strategy with intra-articular betamethasone injections (intra-articular glucocorticosteroid (GC)) and escalation of disease-modifying anti-rheumatic drug treatment. Disease activity, total Sharp-van der Heijde Score (TSS) of hands, wrists and forefeet were assessed at baseline and after 3, 4 and 5 years. MRI of the wrist and anti-cyclic citrullinated peptide (anti-CCP) were assessed at baseline. RESULTS: At 5 years, TSS progression rate was <1 unit/year and 47% had not progressed radiographically since baseline. 78% were in Disease Activity Score remission, 56% in American College of Rheumatology remission and 17% withdrawn from treatment due to remission. There were no differences between initial treatment groups. MRI-bone marrow oedema, TSS and anti-CCP predicted radiographic progression at 5 years. CONCLUSION: Early and strict synovitis suppressive treatment with MTX and intra-articular GC lead to high remission rates and halting of erosive progression at 5 years. No additional effect of initial combination therapy with CSA was found. The results parallel those reported for tumour necrosis factor α antagonists. Baseline MRI-bone oedema, TSS and anti-CCP predicted radiographic progression.

Uncoupling of collagen II metabolism in newly diagnosed, untreated rheumatoid arthritis is linked to inflammation and antibodies against cyclic citrullinated peptides.

OBJECTIVE: To investigate the relationship between markers of collagen II synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naïve to disease-modifying antirheumatic drugs. METHODS: One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PIIANP and CTX-II measurements. RESULTS: PIIANP was low at diagnosis and 4 years on (p < 0.001), irrespective of treatment and disease activity. PIIANP was lowest in anti-CCP positive patients (p = 0.006), and there was a negative correlation between PIIANP and anti-CCP titers (rho = -0.25, p 0.002). CTX-II was increased (p < 0.001) and correlated positively with disease activity and radiographic progression, but not with anti-CCP (p = 0.93). The uncoupling index was not superior to CTX-II in predicting radiographic changes. CONCLUSION: These results suggest that cartilage collagen formation and degradation are unbalanced when RA is diagnosed. The different associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration by inhibiting collagen IIA formation. Trial registration j.nr NCT00209859.

Circulating surfactant protein -D is low and correlates negatively with systemic inflammation in early, untreated rheumatoid arthritis.

INTRODUCTION: Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA. METHODS: One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed. RESULTS: Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings. CONCLUSIONS: This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation. TRIAL REGISTRATION: (j.nr NCT00209859).

Mannose-binding lectin gene polymorphisms are associated with disease activity and physical disability in untreated, anti-cyclic citrullinated peptide-positive patients with early rheumatoid arthritis.

OBJECTIVE: To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). RESULTS: Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. CONCLUSION: The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

Do rheumatoid arthritis patients in clinical practice benefit from switching from infliximab to a second tumor necrosis factor alpha inhibitor?

OBJECTIVE: To investigate the efficacy of switching to a second biological drug in rheumatoid arthritis (RA) patients. METHODS: Since 2000, Danish RA patients (n = 1021) receiving biological therapy have been registered in the nationwide DANBIO database. The first and second treatment series of patients, who switched therapy before 2005 (n = 235), were analysed for their reasons for switching, Disease Activity Score 28 (DAS28), DAS28 improvement, European League against Rheumatology (EULAR) response and drug survival. Most patients switched from infliximab to etanercept or adalimumab. RESULTS: Median survivals for switchers' first/second treatment were 37/92 weeks (all patients' first treatment 119 weeks). Reasons for switching were lack of efficacy (LOE; 109 patients), adverse events (AE; 72), other reasons (54). If patients experienced AE to the first drug, 15% had AE to the second. Median DAS28 improvements in first/second treatment at 3 months were: LOE switchers 1.1/1.6; AE switchers 1.5/0.8. In LOE switchers, a good/moderate EULAR response was more prevalent during the second treatment course than during the first (63% versus 54%, p = 0.02). AE switchers achieved similar EULAR responses to both treatments (59% versus 50%, p = 0.38). CONCLUSION: LOE switchers had a better clinical response to the second treatment. AE switchers responded equally well to both treatments, with a low risk of discontinuing the second drug as a result of AE. Drug survival of the switchers' second biological therapy was higher than of the first, but lower than that of non-switchers. No difference between various sequences of drugs were found. Danish post-marketing data thus support that RA patients may benefit from switching biological therapy.

Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study.

OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. METHODS: Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group. CONCLUSION: Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.