Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study).

OBJECTIVE: Early treatment of patients with rheumatoid arthritis (RA) with combination treatment starting with methotrexate, sulfasalazine, hydroxychloroquine and prednisolone (FIN-RACo strategy) is superior to monotherapy. A study was undertaken to determine whether infliximab (INFL) added to intensified FIN-RACo treatment for the initial 6 months improves the 2-year outcome. METHODS: 99 patients with early untreated active RA were enrolled in an investigator-initiated, randomised, double-blind, multicentre, parallel-group trial. Primary outcomes were remission and radiological changes at 2 years. All patients started with FIN-RACo. In addition, they were randomised to receive INFL or placebo (Pla) from weeks 4 to 26. RESULTS: At 24 months, 66% and 53%, respectively, of the patients in the FIN-RACo+INFL and FIN-RACo+Pla groups were in remission according to the modified American College of Rheumatology (ACR) criteria (p=0.19), 26% and 10% were in sustained modified ACR remission (p=0.042) and 82% in both groups were in remission by 28-joint disease activity score (not significant). Mean changes in the total Sharp-van der Heijde score were 0.2 and 1.4, respectively (p=0.0058). CONCLUSIONS: Most patients with early active RA achieve clinical remission and develop negligible joint damage with the intensified FIN-RACo regimen. Adding INFL for the first 6 months delays radiological progression.

Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still's disease. An open, randomized, multicenter study.

OBJECTIVE: To study the efficacy of anakinra versus disease-modifying antirheumatic drugs (DMARD) in refractory adult-onset Still's disease (AOSD). METHODS: In a 24-week study, 22 patients with AOSD taking prednisolone ≥ 10 mg/day received anakinra (n = 12) or DMARD (n = 10). The primary endpoint was achievement of remission. RESULTS: At 8 and 24 weeks, 7/12 and 6/12 receiving anakinra and 5/10 and 2/10 receiving DMARD achieved remission. Anakinra induced greater improvement in physical health measured by Medical Outcomes Study Short-Form 36 (SF-36; p < 0.011). During an open-label extension (OLE) of 28 weeks, 7/14 patients taking anakinra and 2/3 taking DMARD were in remission. CONCLUSION: Anakinra induced more beneficial responses than DMARD in patients with AOSD and was favored in the OLE phase. (ClinicalTrials.gov Protocol Registration NCT01033656).

Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study.

INTRODUCTION: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. METHODS: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. RESULTS: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. CONCLUSIONS: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Rheumatoid atlantoaxial subluxation can be prevented by intensive use of traditional disease modifying antirheumatic drugs.

OBJECTIVE: To evaluate the 5-year incidence of cervical spine disorders in patients with early rheumatoid arthritis (RA) treated by 2 different disease modifying antirheumatic drug (DMARD) strategies. METHODS: In a national, multicenter, prospective FIN-RACo-trial, a cohort of 199 patients with early, clinically active RA was randomly assigned to treatment with a combination of 3 DMARD and prednisolone (Combi group) or with a single DMARD (Single group) with or without prednisolone, aiming to induce remission. After 2 years, the DMARD therapy was unrestricted. Lateral view cervical spine radiographs during full flexion and extension were taken at the 5-year followup visits. The presence of anterior atlantoaxial subluxation (aAAS), atlantoaxial impaction (AAI), and subaxial subluxation (SAS) was assessed in the 149 patients with radiographs available (80 Single and 69 Combi). RESULTS: At the 5-year visits, aAAS, AAI, and SAS were found in 13 (9%), 6 (4%), and 9 (6%) patients, respectively. The corresponding Single/Combi group ratios were 11/2, 5/1, and 5/4. Of the baseline data, only poor physical function [Health Assessment Questionnaire (HAQ); p = 0.024] and Single treatment strategy (p = 0.019) were significantly associated with aAAS. Worse HAQ scores and Disease Activity Score 28 values were found in patients who developed aAAS during the 5-year followup. CONCLUSION: RA patients with sustained clinical disease activity and poor HAQ are at increased risk of developing aAAS. The development of aAAS during the first 5 years of RA was rare among the patients treated with a combination of DMARD for at least 2 years from the diagnosis. Intensive treatment with traditional DMARD prevents or retards the development of aAAS in patients with recent-onset RA.

Remission and rheumatoid arthritis: data on patients receiving usual care in twenty-four countries.

OBJECTIVE: To compare the performance of different definitions of remission in a large multinational cross-sectional cohort of patients with rheumatoid arthritis (RA). METHODS: The Questionnaires in Standard Monitoring of Patients with RA (QUEST-RA) database, which (as of January 2008) included 5,848 patients receiving usual care at 67 sites in 24 countries, was used for this study. Patients were clinically assessed by rheumatologists and completed a 4-page self-report questionnaire. The database was analyzed according to the following definitions of remission: American College of Rheumatology (ACR) definition, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), clinical remission assessed using 42 and 28 joints (Clin42 and Clin28), patient self-report Routine Assessment of Patient Index Data 3 (RAPID3), and physician report of no disease activity (MD remission). RESULTS: The overall remission rate was lowest using the ACR definition of remission (8.6%), followed by the Clin42 (10.6%), Clin28 (12.6%), CDAI (13.8%), MD remission (14.2%), and RAPID3 (14.3%); the rate of remission was highest when remission was defined using the DAS28 (19.6%). The difference between the highest and lowest remission rates was >or=15% in 10 countries, 5-14% in 7 countries, and <5% in 7 countries (the latter of which had generally low remission rates [<5.5%]). Regardless of the definition of remission, male sex, higher education, shorter disease duration, smaller number of comorbidities, and regular exercise were statistically significantly associated with remission. CONCLUSION: The use of different definitions of RA remission leads to different results with regard to remission rates, with considerable variation among countries and between sexes. Reported remission rates in clinical trials and clinical studies have to be interpreted in light of the definition of remission that has been used.

Fecal microbiota in early rheumatoid arthritis.

OBJECTIVE: To compare the composition of intestinal microbiota of patients with early rheumatoid arthritis (RA) or fibromyalgia (FM), fecal samples were collected from 51 patients with RA and 50 with FM. METHODS: RA patients fulfilled the RA criteria of the American College of Rheumatology, and duration of their disease was < or = 6 months. Only nonhospitalized patients from outpatient care were included. Patients having extreme diets or previous disease modifying antirheumatic drug or glucocorticoid medication were excluded, as were those taking antibiotics or having gastroenteritis for at least 2 months prior to sampling. Fecal bacterial composition was analyzed with a method based on flow cytometry, 16S rRNA hybridization, and DNA-staining. A set of 8 oligonucleotide probes was used. RESULTS: In comparison to patients with FM, the RA patients had significantly less bifidobacteria and bacteria of the Bacteroides-Porphyromonas-Prevotella group, Bacteroides fragilis subgroup, and Eubacterium rectale--Clostridium coccoides group. Results from the 8 probes showed a significant overall difference between the 2 patient groups, indicating widespread microbial differences. CONCLUSION: These findings support the hypothesis that intestinal microbes participate in the etiopathogenesis of RA.

Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study.

INTRODUCTION: We analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care. METHODS: The study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models. RESULTS: Between January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries. CONCLUSION: In conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA.

Disease activity score 28 as an instrument to measure disease activity in patients with early rheumatoid arthritis.

OBJECTIVE: To examine the influence of components of the Disease Activity Score 28 (DAS28) [tender joint count (TJC), swollen joint count (SJC), patient's general health (GH), and erythrocyte sedimentation rate (ESR)] on the total DAS28 score, and overlapping of the 4 individual components in rheumatoid arthritis (RA) patients with low, moderate, or high disease activity. METHODS: The effect of each component was studied in the FIN-RACo trial patients at 6 months and in a "theoretical model," where each component of the DAS28 ranged as follows: TJC and SJC from 0 to 28, GH from 0 to 100, and ESR from 1 to 100, while the other 3 components were 0 (ESR1). Overlapping of the components was studied in the FIN-RACo trial patients at 6 months with low (DAS28 < or = 3.2), moderate (DAS28 > 3.2 and < or = 5.1), and high (DAS28 > 5.1) disease activity. The higher limit for overlapping was defined as the highest SJC in the low disease activity group, and the lower limit as the lowest SJC in the high disease activity group; the percentage of patients who fall between these limits represent overlapping in SJC. Overlapping was calculated similarly concerning TJC, ESR, and GH. RESULTS: ESR had the greatest effect on DAS28, followed by TJC, GH, and SJC, while in the "theoretical model" TJC had the greatest effect on the DAS28, followed by ESR, SJC, and GH. At 6 months, overlapping was present in 54%, 45%, 49%, and 31% of patients in SJC, TJC, GH, and ESR, respectively. CONCLUSION: In real-life patients, ESR had the greatest effect of the 4 components of DAS28 on the total DAS28 score. The values of the individual components of DAS28 overlap considerably among the 3 disease activity groups.

Prognosis of 5-year radiographic erosions of the wrist according to early, late, and persistent wrist swelling or tenderness in patients with early rheumatoid arthritis.

OBJECTIVE: To determine whether early inflammatory activity in the first year of disease compared to persistent or later occurrence of swelling or tenderness in the wrist joints is associated with 5-year erosions in the same joint in patients with early rheumatoid arthritis (RA). METHODS: A cohort of 195 patients with early active RA was enrolled in the Finnish RA Combination Trial. Swelling and tenderness of wrists were assessed at baseline and at 3, 6, 12, 24, 36, and 48 months. Radiographs of the wrists were taken at the baseline and at 5 years. The 237 wrist joints of 125 patients without erosions at baseline were classified according to wrist swelling, i.e., I: never swollen; II: swollen during first year only; III: swollen during the second to fourth year only; and IV: swollen during the first year and followup, and similarly according to tenderness. RESULTS: Thirty percent of the wrists were never swollen in all clinical examinations; 43% were swollen only during the first year; 11% were not swollen in the first year, but were swollen at some time during 24-48 months; and 16% of wrists were swollen during the first year and at some time during 24-48 months. At 5 years, 64% of 237 wrists remained free of erosions. Erosions developed in 82% of wrists that were swollen during both the first year and 24-48 months, versus 56% of wrists that were not swollen at first year but were swollen during 24-48 months, 31% of wrists that were swollen during the first year only, and 11% of wrists that were never swollen. Similar results were seen for joint tenderness. CONCLUSION: Wrist swelling during the first year only is associated with less future wrist radiographic damage than persistent swelling or swelling only during the followup. Our results emphasize the value of early and continuous suppression of inflammatory activity in early RA.

Trypsin-2 degrades human type II collagen and is expressed and activated in mesenchymally transformed rheumatoid arthritis synovitis tissue.

It has traditionally been believed that only the human collagenases (matrix metalloproteinase-1, -8, and -13) are capable of initiating the degradation of collagens. Here, we show that human trypsin-2 is also capable of cleaving the triple helix of human cartilage collagen type II. We purified human trypsin-2 and tumor-associated trypsin inhibitor by affinity chromatography whereas collagen type II was purified from cartilage extracts using pepsin digestion and salt precipitation. Degradation of type II collagen and gelatin by trypsin-2 was demonstrated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis, zymography, and mass spectrometry, and tumor-associated trypsin inhibitor specifically inhibited this degradation. Although human trypsin-2 efficiently digested type II collagen, bovine trypsin did not. Furthermore, immunohistochemical staining detected trypsin-2 in the fibroblast-like synovial lining and in stromal cells of human rheumatoid arthritis synovial membrane. These findings were confirmed by reverse transcriptase-polymerase chain reaction and nucleotide sequencing. Trypsin-2 alone and complexed with alpha(1)-proteinase inhibitor were also detected in the synovial fluid of affected joints by time-resolved immunofluorometric assay, suggesting that trypsin-2 is activated locally. These results are the first to assess the ability of human trypsin to cleave human type II collagen. Thus, trypsin-2 and its regulators should be further studied for use as markers of prognosis and disease activity in rheumatoid arthritis.

Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial.

OBJECTIVE: To compare the efficacy of therapy with a combination of disease-modifying antirheumatic drugs (DMARDs) versus therapy with a single DMARD in the prevention of work disability in patients with early rheumatoid arthritis (RA). METHODS: In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomly assigned to receive either combination therapy with DMARDs (sulfasalazine, methotrexate, hydroxychloroquine) plus prednisolone or single therapy with a DMARD with or without prednisolone. After 2 years, the drug treatment strategy was no longer restricted. At baseline, 162 patients (80 in the combination-treatment group and 82 in the single-treatment group) were still working or at least available for work. After 5 years of followup, data on all sick leave and retirement were obtained from social insurance registers or case records. The main outcome for each patient was the cumulative duration of all sick leaves and RA-related disability pensions, divided by the observation period during which the patient was not retired because of another disease or because of age. RESULTS: The cumulative duration of work disability per patient-observation year was significantly lower in those randomized to combination therapy than in those randomized to single therapy: median 12.4 days (interquartile range [IQR] 0-54) versus 32.2 days (IQR 6-293) (P = 0.008, sex- and age-adjusted P = 0.009). This was mainly due to the difference in sick leaves (i.e., work disability periods

Assay for cross-linked carboxyterminal telopeptide of type I collagen (ICTP) unlike CrossLaps assay reflects increased pathological degradation of type I collagen in rheumatoid arthritis.

We compared the ability of assay for cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and CrossLaps assay to reflect increased pathological degradation of type I collagen in serum and synovial fluid samples of patients with rheumatoid arthritis (RA; n = 40). ICTP and CrossLaps concentrations were correlated with each other and with markers of collagen synthesis (PINP and PIIINP, amino terminal propeptides of type I and type III procollagens, respectively) and with markers of inflammation, i.e., C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Serum ICTP was increased in half of the RA patients, whereas CrossLaps assays were increased only occasionally. Serum ICTP correlated with the other markers of collagen metabolism as well as with CRP and ESR. Serum CrossLaps correlated only with PINP and ICTP, but not with serum PIIINP, CRP or ESR. Two patients had false-positive reactions in the CrossLaps assay due to the rheumatoid factor. The ICTP and CrossLaps antigens were clearly separate peaks in gel filtration analysis. The CrossLaps assay is able to detect the same ICTP antigen, but not vice versa. The ICTP assay reflects increased matrix metalloproteinase-mediated collagen degradation in joints in RA. In contrast, the physiological cathepsin K-mediated bone resorption measured by the CrossLaps assay was only occasionally increased.

Bacterial components in the synovial tissue of patients with advanced rheumatoid arthritis or osteoarthritis: analysis with gas chromatography-mass spectrometry and pan-bacterial polymerase chain reaction.

OBJECTIVE: To study the presence of bacterial components in the synovial tissue (ST) of patients with advanced rheumatoid arthritis (RA). METHODS: ST was collected during joint surgery from 41 RA patients. Tissue from 39 patients with osteoarthritis (OA), 4 patients with undifferentiated inflammatory arthritis (UA), and 3 cases of accidental deaths served as controls. The pan-bacterial polymerase chain reaction (PCR) with primers for the 23S ribosomal RNA (rRNA) and 16S rRNA genes was used to detect bacterial DNA. In addition, synovial fluid (SF) samples from patients with chlamydial reactive arthritis (ReA) were also examined by the same method. The positive controls, bacterial DNA or ST spiked with different living bacteria, were analyzed alongside clinical samples. Most of the ST samples were also analyzed by gas chromatography-mass spectrometry (GC-MS) for determining the presence of bacteria-derived muramic acid. Strict precautions were followed in the clinics and the laboratory to prevent contamination. RESULTS: In GC-MS analysis, muramic acid was observed in the ST from 4 of 35 RA patients and from 2 of 14 OA patients, but not in ST from 2 patients with UA and 3 cadavers. Bacterial DNA was not detected by either one of the PCR primers used in ST from 42 patients with RA and 39 patients with OA. However, 5 of 15 SF samples from ReA patients were PCR positive. The sensitivity of GC-MS to detect muramic acid was 2 pg/injected amount (227 pg muramic acid/mg ST), and that of the pan-bacterial PCR was 2-20 bacteria colony forming units/reaction. CONCLUSION: These results indicate that a bacterial component, muramic acid, is detectable by GC-MS in ST from a few patients with advanced RA or OA. However, no bacterial DNA was detectable by PCR.

Regulation of CD154-induced interleukin-12 production in synovial fluid macrophages.

Interleukin (IL)-12, being a major cytokine that induces T helper (Th) 1 differentiation and inflammatory response, has been postulated to be an important mediator of synovial inflammation in rheumatoid arthritis (RA). However, the regulation of IL-12 production in RA has not been elucidated. Our knowledge is mainly based on studies of the production of IL-12p40 and not the functional IL-12p70 heterodimer. We have studied the CD154-induced IL-12p40 and IL-12p70 production by synovial fluid (SF) macrophages from patients with RA. CD40 ligation induced the secretion of IL-12p40 but not IL-12p70. The observed increase in IL-10 and tumor necrosis factor (TNF)-alpha production indicated that SF macrophages responded to CD40 ligation. The expression of p40 mRNA was increased significantly and remained upregulated after CD40 ligation, whereas the increase of p35 transcript expression was observed only transiently and at a lower level. We further observed that dendritic cells (DCs) derived in vitro from SF macrophages produced IL-12p70. Most importantly, IL-4 and IL-13 primed SF macrophages to produce IL-12p70, whereas IFN-gamma was not observed to activate IL-12p70 production in these cells, in contrast with normal peripheral blood monocytes. These results provide novel information about the regulation of IL-12p70 production and the function of the cytokine network in RA.