Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1) Very early rheumatoid arthritis as a predictor of remission: a multicentre real life prospective study The burden of musculoskeletal diseases in the general population of Spain: results from a national survey Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Safety of rituximab in rheumatoid arthritis: a long-term prospective single-center study of gammaglobulin concentrations and infections. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. 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Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Costs and predictors of costs in rheumatoid arthritis: a prevalence-based study. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Increased mortality in ankylosing spondylitis is related to disease activity A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis. The Pharmacokinetics of Etanercept in Healthy Volunteers Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial. Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumour necrosis factor α antibody infliximab Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort
Objective . To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA . Methods . Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches : ( i ) treatment to target ( TT ) : patients assessed 24 weeks after each course and retreated if not in remission [ DAS in 28 joints based on ESR ( DAS-28-ESR ) ≥ 2.6 ] ; ( ii ) treatment as needed ( PRN ) : patients retreated at the physician ’s discretion ≥24 weeks following the first course and ≥16 weeks following further courses , if both swollen and tender joint counts were ≥8 . All courses consisted of i.v . rituximab 2 × 1000 mg 2 weeks apart plus MTX . Observed data were analysed according to treatment strategy . Results . Multiple courses of rituximab maintained or improved responses irrespective of regimen . TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN . TT result ed in significantly more patients achieving major clinical response . PRN result ed in recurrence of disease symptoms between courses , with TT significantly reducing the incidence of RA flares . Despite more frequent retreatment with TT compared with PRN , the rates of serious adverse events and serious infections were comparable between regimens . Conclusions . Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile . TT may be the preferable rituximab treatment regimen for patients with RA Purpose To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis ( nr-axSpA ) . Methods Patients fulfilled Assessment of Spondyloarthritis international Society ( ASAS ) criteria for axial spondyloarthritis , had a Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) score of ≥ 4 , total back pain score of ≥ 4 ( 10 cm visual analogue scale ) and inadequate response , intolerance or contraindication to non-steroidal anti-inflammatory drugs ( NSAIDs ) ; patients fulfilling modified New York criteria for ankylosing spondylitis were excluded . Patients were r and omised to adalimumab ( N=91 ) or placebo ( N=94 ) . The primary endpoint was the percentage of patients achieving ASAS40 at week 12 . Efficacy assessment s included BASDAI and Ankylosing Spondylitis Disease Activity Score ( ASDAS ) . MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada ( SPARCC ) index . Results Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group ( 36 % vs 15 % , p<0.001 ) . Significant clinical improvements based on other ASAS responses , ASDAS and BASDAI were also detected at week 12 with adalimumab treatment , as were improvements in quality of life measures . Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment . Shorter disease duration , younger age , elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab . The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases . Conclusions In patients with nr-axSpA  , adalimumab treatment result ed in effective control of disease activity , decreased inflammation and improved quality of life  compared with placebo . Results from ABILITY-1 suggest that adalimumab has a positive benefit – risk profile in active nr-axSpA patients with inadequate response to NSAIDs Background To assess whether , in the real world of three early arthritis clinics , early referral could allow the best outcome , ie , remission , to be reached , and whether reaching the outcome was more dependent on therapy than on disease duration or vice versa . Methods 1795 patients with early arthritis ( symptom duration ≤12 months ) were entered into a prospect i ve follow-up study . 711 patients ( 39.6 % ) were diagnosed with rheumatoid arthritis ( RA ) . Each RA patient was treated according to the local algorithm , in three tertiary referral centres ( representing a small province , a medium sized province and a metropolitan area , respectively ) . Remission , defined using the disease activity score in 28 joints ( DAS28 < 2.6 ) and American College of Rheumatology ( ACR ) criteria , was the major outcome evaluated at the 12-month follow-up . Results DAS28 remission was achieved in 34.3 % ( range 19.5–49 % ) of RA patients and ACR remission in 15.2 % ( range 8.5–20.6 % ) . At the multivariate logistic regression analysis only two variables emerged as predictors of the major outcome : being in very early rheumatoid arthritis ( VERA ; less than 12 weeks symptom duration at the time of first treatment ) and being on disease-modifying antirheumatic drugs ( DMARD ) within 3 months from disease onset . Among RA patients in remission , only 10 % of VERA subjects received an anti-TNF blocker compared with 32.2 % of non-VERA patients ( p=0.002 , OR 0.23 , 95 % CI 0.09 to 0.64 ) . Conclusions In a real-world setting , the 12 weeks disease duration and an early intervention with DMARD represent the most significant opportunities to reach the major outcome , ie , remission of RA . Moreover , VERA represents a window of opportunity in terms of cost saving OBJECTIVE The objective of the EPISER study was to estimate the prevalence of rheumatoid arthritis ( RA ) , low back pain , h and and knee osteoarthritis ( OA ) , and fibromyalgia in the adult Spanish population , and to assess the impact of these diseases on function and quality of life , and use of health and social re sources . METHODS 2998 subjects aged 20 years or above were r and omly selected by stratified multistage cluster sampling from the censuses of 20 municipalities .  Trained rheumatologists carried out structured visits at which subjects were asked about rheumatic symptoms and sociodemographic characteristics , completed vali date d instruments for measuring function ( HAQ ) and  quality of life  ( SF-12 ) , and underwent a st and ardised physical examination . Cases were defined by previously vali date d criteria . RESULTS The estimated prevalences with 95 % confidence intervals were as follows : RA lifetime cumulative : 0.5 % ( 0.3 to 0.9 ) ; low back pain : 14.8 % ( 12.2 to 17.4 ) ; symptomatic knee OA : 10.2 % ( 8.5 to 11.9 ) ; h and OA : 6.2 % ( 5.9 to 6.5 ) ; fibromyalgia : 2.4 % ( 1.5 to 3.2 ) . Most conditions significantly impaired function and quality of life . CONCLUSIONS The EPISER study has internal and external validity for application of the results to the adult Spanish population . The diseases studied affect a significant proportion of the population , with various degrees of impact on disability and quality of life result ing in a significant number of physician visits , work disability , and medication use We analyzed the clinical response and the time to relapse after discontinuation of continuous long-term infliximab therapy in patients with ankylosing spondylitis ( AS ) . After 3 years of infliximab therapy , all AS patients ( n = 42 ) discontinued treatment ( time point (TP)1 ) and were visited regularly for 1 year in order to assess the time to relapse ( TP2 ) . Relapse was defined as an increase to a value ≥ 4 on the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) and a physician 's global assessment ≥ 4 according to the recommendations of the Assessment s in Ankylosing Spondylitis ( ASAS ) working group . After 52 weeks , 41 of the 42 patients ( 97.6 % ) had to be reinfused because of relapse . The mean change in the BASDAI between TP1 and TP2 was 3.6 ± 1.7 and that in the physician 's global assessment was 4.4 ± 1.8 ( both P < 0.001 ) . The mean time to relapse was 17.5 weeks ( ± 7.9 weeks , range 7 to 45 ) . Ten patients ( 24 % ) showed a relapse within 12 weeks and 38 patients ( 90.5 % ) , within 36 weeks . After 52 weeks , only one patient had remained in ongoing remission without further treatment with anti-tumor-necrosis factor . Patients who were in partial remission according to the ASAS criteria and those with normal C-reactive protein levels at the time point of withdrawal had longer times to relapse after discontinuation of the treatment . Retreatment with infliximab was safe and result ed in clinical improvement in all patients to a state similar to that before the treatment was stopped . Discontinuation of long-term therapy with infliximab eventually led to relapse of disease activity in all patients but one Background : To investigate whether intensive treatment with methotrexate ( MTX ) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis . Methods : In a two-year multicentre open label strategy trial , 299 patients with early rheumatoid arthritis were r and omly assigned to the intensive strategy group or the conventional strategy group . Patients in both groups received MTX , the aim of treatment being remission . Patients in the intensive treatment group came to the outpatient clinic once every month ; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria , using a computerised decision program . Patients of the conventional strategy group came to the outpatient clinic once every three months ; they were treated according to common practice . Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses . Results : Seventy six ( 50 % ) patients in the intensive strategy group achieved at least one period of remission during the two year trial , versus 55 patients ( 37 % ) in the conventional strategy group ( p = 0.03 ) . Areas under the curve for nearly all clinical variables were significantly lower — that is , there was a better clinical effect for the intensive treatment group compared with the conventional treatment group . Conclusion : The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX , aim ing for remission , tailored to the individual patient . Furthermore , participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice OBJECTIVE To evaluate the efficacy , pharmacokinetics , immunogenicity , and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody ( cA2 ) ( infliximab ; Remicade , Centocor , Malvern , PA ) given alone or in combination with low-dose methotrexate ( MTX ) in rheumatoid arthritis ( RA ) patients . METHODS In a 26-week , double-blind , placebo-controlled , multicenter trial , 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were r and omized to 1 of 7 groups of 14 - 15 patients each . The patients received either intravenous cA2 at 1 , 3 , or 10 mg/kg , with or without MTX 7.5 mg/week , or intravenous placebo plus MTX 7.5 mg/week at weeks 0 , 2 , 6 , 10 , and 14 and were followed up through week 26 . RESULTS Approximately 60 % of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20 % Paulus criteria for response to treatment , for a median duration of 10.4 to > 18.1 weeks ( P < 0.001 versus placebo ) . Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 ( median duration 2.6 weeks ; P=0.126 versus placebo ) . However , coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic , prolonging the duration of the 20 % response in > 60 % of patients to a median of 16.5 weeks ( P < 0.001 versus placebo ; P=0.006 versus no MTX ) and the 50 % response to 12.2 weeks ( P < 0.001 versus placebo ; P=0.002 versus no MTX ) . Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease , with a Paulus response lasting a median of 0 weeks . A 70 - 90 % reduction in the swollen joint count , tender joint count , and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX . In general , treatment was well tolerated and stable blood levels of cA2 were achieved in all groups , except for the group receiving 1 mg/kg of cA2 alone , at which dosage antibodies to cA2 were observed in approximately 50 % of the patients . CONCLUSION Multiple infusions of cA2 were effective and well tolerated , with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60 % of patients with active RA despite therapy with low-dose MTX . When cA2 at 1 mg/kg was given with low-dose MTX , synergy was observed . The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2 OBJECTIVE Rituximab seems well tolerated in patients with rheumatoid arthritis ( RA ) . However , variations in the gammaglobulin profile that might increase the infection risk have been reported . Here , our objective was to evaluate gammaglobulin concentrations and the infection risk in patients receiving rituximab therapy for RA in everyday practice . METHODS Prospect i ve single-center observational study of 65 patients with refractory RA ( median age , 59 years ; range , 26 - 83 ) treated with rituximab 1 g twice 15 days apart , with or without a further 1-g dose at least 6 months later  depending on the clinical response . Gammaglobulins were assayed before each rituximab dose . RESULTS The median cumulative rituximab dose was 4 g ( 1 - 16 ) and the median time to retreatment was 8 months ( 6 - 16 ) . Rituximab therapy significantly improved the DAS-28 score . The gammaglobulin concentration decreased significantly between the first and last rituximab dose ( from 11.6 g/L [ 5 - 26 ] to 8.2 g/L [ 3 - 20 ] , a -2.6 g/L difference ; P<0.05 ) . The decrease was larger in the 24 patients with cumulative rituximab doses greater than 5 g than in the 41 other patients ( difference of -4 vs. -2.7 g/L ; P<0.05 ) . Three patients experienced severe infections , two in the high-dose group and one in the other group ( P=0.5 ) . CONCLUSION These data obtained in everyday practice constitute further evidence that rituximab is well-tolerated in patients with RA .  Rituximab therapy was associated with a decrease in gammaglobulin concentrations that was greater in patients receiving higher cumulative doses Objectives Evaluation of long-term safety of rituximab in rheumatoid arthritis ( RA ) . Methods Pooled observed case analysis of data from patients with moderate-to-severe , active RA treated with rituximab in a global clinical trial programme . Results As of September 2010 , 3194 patients had received up to 17 rituximab courses over 9.5 years ( 11 962 patient-years ) . Of these , 627 had > 5 years ’ follow-up ( 4418 patient-years ) . A pooled placebo  population ( n=818 )  ( placebo+methotrexate ( MTX ) ) was also analysed . Serious adverse event and infection rates generally remained stable over time and multiple courses . The overall serious infection event ( SIE ) rate was 3.94/100 patient-years ( 3.26/100 patient-years in patients observed for > 5 years ) and was comparable with placebo+MTX ( 3.79/100 patient-years ) . Serious opportunistic infections were rare . Overall , 22.4 % ( n=717 ) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5 % ( n=112 ) low IgG levels for ≥4 months after ≥1 course . SIE rates were similar before and during/after development of low Ig levels ; however , in patients with low IgG , rates were higher than in patients who never developed low IgG. Rates of myocardial infa rct ion and stroke were consistent with rates in the general RA population . No increased risk of malignancy over time was observed . Conclusions This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses , with a safety profile consistent with published data and clinical trial experience . Overall , the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation Background In the IMAGE study , rituximab plus methotrexate ( MTX ) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis . Objective The aim of this study was to assess joint damage progression and clinical outcomes over 2 years . Methods Patients ( n=755 ) were r and omised to receive rituximab 2 × 500 mg+MTX , 2 × 1000 mg+MTX or placebo+MTX . The placebo-controlled period continued to week 104 . Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score ( mTSS ) , total erosion score and joint space narrowing score from baseline to week 104 . Clinical efficacy and physical function end points were also assessed . Results At 2 years , rituximab 2 × 1000 mg+MTX maintained inhibition of progressive joint damage  versus MTX alone ( mTSS change 0.41 vs 1.95 ; p<0.0001 ( 79 % inhibition ) ) , and a higher proportion of patients receiving rituximab 2 × 1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone ( 57 % vs 37 % ; p<0.0001 ) . Contrary to 1-year results , exploratory analysis of rituximab 2 × 500 mg+MTX at 2 years showed that progressive joint damage was slowed by ∼61 % versus placebo+MTX ( mTSS , exploratory p=0.0041 ) . Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2 . Safety profiles were similar between groups . Conclusions Treatment with rituximab 2 × 1000 mg+MTX was associated with sustained improvements in radiographic , clinical and functional outcomes over 2 years . Clinical trials.gov identifier NCT00299104 OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy OBJECTIVE To establish the safety and efficacy of repeat infusions of tocilizumab ( previously known as MRA ) , a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , alone and in combination with methotrexate ( MTX ) , for the treatment of rheumatoid arthritis ( RA ) . METHODS The study group comprised 359 patients with active RA in whom the response to MTX was inadequate . During a stabilization period , these patients received their current dose of MTX for at least 4 weeks . Following stabilization , they were r and omized to 1 of 7 treatment arms , as follows : tocilizumab at doses of 2 mg/kg , 4 mg/kg , or 8 mg/kg either as monotherapy or in combination with MTX , or MTX plus placebo . RESULTS A 20 % response ( improvement ) according to the American College of Rheumatology criteria ( ACR20 response ) was achieved by 61 % and 63 % of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy , respectively , and by 63 % and 74 % of patients receiving those doses of tocilizumab plus MTX , respectively , compared with 41 % of patients receiving placebo plus MTX . Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX ( P < 0.05 ) . A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward , in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab . In the majority of patients who received 8 mg/kg of tocilizumab , the C-reactive protein level/erythrocyte sedimentation rate normalized , while placebo plus MTX had little effect on these laboratory parameters . Tocilizumab was mostly well tolerated , with a safety profile similar to that of other biologic and immunosuppressive therapies . Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern ( rising and falling between infusions ) . There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels . There were 2 cases of sepsis , both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX . CONCLUSION These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA OBJECTIVE To evaluate a magnetic resonance imaging ( MRI ) scoring system for the assessment of spinal inflammation in patients with ankylosing spondylitis ( AS ) who participated in a r and omized , placebo-controlled trial of infliximab  , and to examine whether infliximab is also effective for the reduction of MRI-proven spinal inflammation . METHODS Twenty patients with AS ( 9 women and 11 men , mean age 40.9 years ) were examined at baseline and after 3 months . Nine patients had received infusions of infliximab ( 5 mg/kg body weight ) at weeks 0 , 2 , and 6 , and 11 patients had received placebo . Three MRI sequences and 2 scoring systems were used . Chronic lesions were evaluated by T1-weighted turbo spin-echo ( TSE ) sequences and were assigned a chronicity score . Active lesions were evaluated either by repetition of T1-weighted TSE sequences after infusion of gadolinium-diethylenetriaminepentaacetic acid ( Gd-DTPA ) or by short tau inversion recovery ( STIR ) sequences , and were assigned an activity score . The 40 images were evaluated twice by 2 readers who were blinded to the names of the patients and the date s of the examinations , and were analyzed in relation to the clinical results . RESULTS Active spinal lesions were detected in 15 of 20 patients ( 75 % ) ; the frequency as determined by STIR was equal in the 2 groups . At baseline , the total MRI scores determined using Gd-DTPA , STIR , and T1 were 112.5 , 156 , and 253.5 , respectively . The interrater variance and intrarater variance were , respectively , 6.4 and 7.7 for the active lesion score as determined by Gd-DTPA , 15.7 and 5.3 for the active lesion score as determined by STIR sequence , and 167.3 and 75.5 for the chronic lesion score as determined by T1 sequence . Based on the means of the scores assigned by the 2 readers , the active lesion score as determined by Gd-DTPA improved by 40 % in the infliximab group compared with 6 % in the placebo group , the active lesion score as determined by STIR improved by 60 % in the infliximab group but deteriorated by 21 % in the placebo group , and the chronic lesion score as determined by T1 improved by 7 % in the infliximab group but worsened by 35 % in the placebo group . Five patients in the infliximab group and 2 in the placebo group were clinical responders . The acute MRI changes correlated with clinical improvement as assessed by the Bath Ankylosing Spondylitis Disease Activity Index . CONCLUSION This novel MRI scoring system performed well in assessing acute inflammation by using STIR and post-Gd-DTPA sequences . In correlation with clinical improvement in patients with active AS who were treated with infliximab , significant regression of spinal inflammation was shown by using the MRI activity scores OBJECTIVE To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone OBJECTIVE To investigate prognostic factors associated with mortality in patients with psoriatic arthritis ( PsA ) . METHODS Patients followed up at the Toronto PsA Clinic between 1978 and 1994 were included . Patients were review ed at initial clinic entry and at 6-month intervals using a st and ard protocol . Data on deaths were collected in a prospect i ve manner , and death certificates were used to identify the primary and antecedent cause(s ) of death . All death information was recorded in the clinic 's computerized data base . Only factors that represented st and ard clinical measures of disease activity and progression were studied . The relationship between potential prognostic factors recorded at the time of the first clinic visit and the mortality rate was determined using the Cox relative risk regression model . RESULTS There were 428 patients ( 234 men and 194 women ) , of whom 68 % were known to be alive on September 1 , 1994 , 20 % were lost to followup but assumed to be alive , and 12 % had died . Multivariate analysis revealed that an erythrocyte sedimentation rate ( ESR ) > 15 mm/hour , medications used prior to initial clinic visit , radiologic damage , and the absence of nail lesions were associated with an increased overall mortality rate . There is some suggestion that prior medication use was least important for deaths associated with the circulatory system , while radiologic damage was particularly important for such deaths . A marked sex-associated effect was noted among deaths caused by injuries/poisoning , since 6 of the deaths occurred in men and only 1 was in a woman . CONCLUSION Patients with PsA are at an increased risk of death compared with the general population . Evidence of previously active and severe disease , as manifested by the prior use of medications and by radiologic changes as well as an elevated ESR at presentation , are prognostic indicators for death . The presence of nail lesions appears to be a protective factor that has the most clinical importance in the context of previously active and severe disease OBJECTIVE A 2-year r and omized controlled trial was performed to test the hypothesis that long-term , continuous treatment with nonsteroidal antiinflammatory drugs ( NSAIDs ) , in comparison with NSAID treatment on dem and only , influences radiographic progression in patients with ankylosing spondylitis ( AS ) . METHODS Patients with AS ( n = 215 ) , who had previously participated in a 6-week , r and omized , double-blind clinical trial that compared  celecoxib , ketoprofen , and placebo , were r and omly allocated to receive either continuous treatment with NSAIDs or on-dem and treatment with NSAIDs for a period of 2 years . All patients began treatment with celecoxib , at a starting dosage of 100 mg twice daily ; patients could increase this dosage to 200 mg twice daily or could switch to another NSAID while maintaining the same treatment strategy . Structural changes were assessed by radiographs of the lumbar and cervical spine and scored according to the modified Stoke Ankylosing Spondylitis Spine Score by one observer who was blinded to the treatment strategy and temporal order of the radiographs . Statistical analyses included a between-group comparison of 1 ) radiographic progression scores ( by Mann-Whitney U test ) , 2 ) time-averaged values of variables reflecting signs and symptoms of AS ( by linear regression analysis ) , and 3 ) the frequency of reported site-specific adverse events ( by chi-square test or Fisher 's exact test , as appropriate ) . RESULTS Complete sets of radiographs were available for 76 of the 111 patients in the continuous-treatment group and for 74 of the 104 patients in the on-dem and group . The mean + /- SD scores for radiographic progression were 0.4 + /- 1.7 in the continuous-treatment group and 1.5 + /- 2.5 in the on-dem and treatment group ( P = 0.002 ) . Parameters reflecting signs and symptoms were not statistically significantly different between groups . The between-group difference in radiographic progression did not disappear after adjusting for baseline values of radiographic damage or disease activity variables and for time-averaged values of disease activity variables , nor after input of missing data . Relevant adverse events tended to occur more frequently in the continuous-treatment group than in the on-dem and group ( for hypertension , 9 % versus 3 % ; for abdominal pain , 11 % versus 6 % ; for dyspepsia , 41 % versus 38 % ) , but the differences were not statistically significant . CONCLUSION A strategy of continuous use of NSAIDs reduces radiographic progression in symptomatic patients with AS , without increasing toxicity substantially BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the  single-therapy  group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis OBJECTIVE To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate ( MTX ) over a 2-year period in patients with rheumatoid arthritis ( RA ) who previously experienced an incomplete response to MTX .  METHODS Four hundred twenty-eight patients were r and omly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks , with an additional year of followup . The protocol was later amended to allow for continued treatment during the second year . Of 259 patients who entered the second year of treatment , 216 continued to receive infliximab plus MTX for 102 weeks . Ninety-four of these 259 patients experienced a gap in therapy of > 8 weeks before continuing therapy . Infusions were administered at weeks 0 , 2 , and 6 , followed by treatment every 4 weeks or every 8 weeks ( alternating with placebo infusions in the interim 4-week visits ) at a dose of 3 or 10 mg/kg for a total of 102 weeks ( including the gap in therapy ) . For safety and efficacy assessment s , data on the patients who were r and omized to receive treatment , irrespective of whether treatment was administered for 102 weeks , were evaluated using all actual observations available . The efficacy measures included the Health Assessment Question naire ( HAQ ) ( physical function ) , Short Form 36 health survey ( SF-36 ) ( health-related quality of life ) , total radiographic scores ( structural damage ) , and the American College of Rheumatology 20 % improvement criteria ( ACR20 ) ( signs and symptoms ) . RESULTS The infliximab plus MTX regimens result ed in significantly greater improvement in HAQ scores ( P < or = 0.006 ) and SF-36 physical component summary scores ( P < or = 0.011 ) compared with the MTX-only group . There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens . Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen . The proportion of patients achieving an ACR20 response at week 102 varied from 40 % to 48 % for the infliximab plus MTX groups compared with 16 % for the MTX-only group . CONCLUSION Throughout 102 weeks of therapy , infliximab plus MTX provided significant , clinical ly relevant improvement in physical function and quality of life , accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone OBJECTIVE To evaluate the effects of golimumab on radiographic progression in patients with rheumatoid arthritis ( RA ) . METHODS  Methotrexate (MTX)-naive patients ( in the Golimumab Before Employing Methotrexate as theFirst-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset [ GO-BEFORE ] study ; n = 637 ) and patients with active RA despite MTX therapy ( in the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy [ GO-FORWARD ] study ; n = 444 ) were r and omly assigned to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Golimumab orplacebo was administered subcutaneously every 4 weeks . Radiographs of the h and s and feet were taken at baseline , week 28 , and week 52 in the GO-BEFORE study and at baseline , week 24 ( week 16 for patients who entered early escape ) , and week 52 in the GO-FORWARD study . Radiographs were scored by 2 independent readers in each study using the van der Heijde modification of the Sharp score . RESULTS In the GO-BEFORE study , the mean ± SD changes in the modified Sharp score from base line to week 52 ( control period ) were 1.4 ± 4.6 in group 1 , 1.3 ± 6.2 in group 2 ( P = 0.266 ) , 0.7 ± 5.2 in group 3 ( P = 0.015 ) , and 0.1 ± 1.8 in group 4 ( P = 0.025 ) . In the GO-FORWARD study , changes from baseline to week 24 ( control period ) were 0.6 ± 2.4 in group 1 , 0.3 ± 1.6 in group 2 ( P = 0.361 ) , 0.6 ± 2.7 in group 3 ( P = 0.953 ) , and 0.2 ± 1.3 in group 4 ( P = 0.293 ) . CONCLUSION Golimumab in combination with MTX  inhibited radiographic progression significantly better than did MTX alone in the GO-BEFORE study . Radiographic progression in the GO-FORWARD study was minimal in all treatment arms , precluding an adequate assessment of the effect of golimumab on radiographic progression in this study OBJECTIVE To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept ( ETN ) ( 25 mg/week ) compared with st and ard-dose ETN ( 50 mg/week ) in RA . METHODS In this prospect i ve , r and omized , open-label study , 70 patients were assigned to receive  ETN at either 50 or 25 mg/week for 52 weeks . The primary endpoint was the variation in modified total Sharp score ( mTSS ) , and secondary endpoints were variations in disease activity score in 28 joints ( DAS-28 ) , modified HAQ and adverse event rate . Values of mTSS were calculated at baseline and after 52 weeks . Non-progression was estimated as ΔmTSS ≤0.5 , and the non-progression rate was compared between groups . RESULTS Mean values at baseline were as follows : disease duration 9.2 years ; DAS-28 5.45 ; and annual progression of mTSS 26.1 . No significant differences in background were seen between groups . At 52 weeks , the non-progression rate was significantly less in the 25 mg/week group ( 36.7 % ) than in the 50 mg/week group ( 67.7 % ) ( P = 0.041 ) . Mean ΔmTSS was higher at 25 mg/week ( 1.03 ) than at 50 mg/week ( -0.13 ) . DAS-28 was significantly improved at 4 weeks , and the effect of treatment lasted for 52 weeks in both groups . No differences in adverse event rates were seen between groups . CONCLUSION Low-dose ETN is not inferior to st and ard-dose ETN in terms of effects on clinical manifestations . However , in terms of the radiographic non-progression rate , the effects of low-dose ETN may be inferior to the effects of st and ard-dose ETN . TRIAL REGISTRATION UMIN Clinical Trials Registry , http://www.umin.ac.jp/ctr/ , UMIN000001798 OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA Objectives : To characterise RA in a sample of Spanish patients by estimating mean clinical activity , functional ability , and radiological damage , and current and cumulative prevalence of extra-articular manifestations . Methods : Cross sectional analysis of a cohort of patients with RA r and omly selected from the clinical data bases of 34 centres . St and ard definitions and measurements were used , and radiographs read central ly . Estimates and confidence intervals were adjusted to sampling . Results : Data were available for 788 patients . Extra-articular RA was present in 285 ( 36.2 % ) patients . Cumulative prevalence and 95 % confidence intervals of extra-articular manifestations were estimated : nodules 24.5 % ( 21.5 to 27.5 ) , Sjögren ’s syndrome 17.0 % ( 14.4 to 19.6 ) , atlantoaxial subluxation 12.1 % ( 9.8 to 14.4 ) , carpal tunnel syndrome 10.7 % ( 7.8 to 13.6 ) , interstitial lung disease 3.7 % ( 2.4 to 5.0 ) , serositis 2.5 % ( 1.4 to 3.5 ) , eye disease 2.5 % ( 1.1 to 3.9 ) , vasculitis 1.3 % ( 0.5 to 2.1 ) , amyloidosis 0.6 % ( 0.1 to 1.2 ) , and Felty ’s syndrome 0.3 % ( < 0.6 ) . Mean ( SD ) activity/progression indexes were : DAS28 - 3 3.4 ( 1.2 ) , HAQ 1.6 ( 0.4 ) , Larsen score 54.7 ( 26.4 ) . Less than 5 % of the patients were in remission . 205 ( 72 % ) patients were receiving disease modifying antirheumatic drugs ( DMARDs ) . Conclusion : Spanish patients with RA ever seen by a rheumatologist have , on average , a moderate degree of activity , despite widespread use of DMARDs . Measures of the degree of progression do not show a benign disease . The proportion of extra-articular manifestations in Spanish patients with RA is similar to that found in other Mediterranean population s , and lower than that reported in Anglo Saxon countries OBJECTIVE To investigate the relationship between serum concentrations of infliximab , a monoclonal anti-tumor necrosis factor alpha antibody , and clinical improvement from infliximab therapy for rheumatoid arthritis ( RA ) . METHODS Multiple blood sample s were obtained from each of 428 subjects with active RA who were enrolled in a multicenter , r and omized , double-blind , placebo-controlled trial ( ATTRACT [ Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy ] ) evaluating the clinical efficacy and safety of infliximab therapy .  Serum levels of infliximab  were measured by enzyme-linked immunosorbent assay . Dose-response trends were analyzed using generalized logistic regression techniques . Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial . RESULTS At week 54 , 26 % of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab  , a significantly greater proportion than in the other 3 treatment groups ( P < 0.001 ) . Increased magnitude of American College of Rheumatology ( ACR ) response ( measured by the ACR-N , a continuous measure of clinical improvement derived from the ACR 20 % response criteria ) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab  ( P < 0.001 ) , as was less progression of radiographic joint damage ( P = 0.004 ) , providing support for a dose-response relationship . Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab  than increasing the dose by 100 mg . CONCLUSION These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks BACKGROUND Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis . Although moderately active rheumatoid arthritis is common , treatment effects in moderate disease have not been well studied . Additionally , optimum use of biologics needs further investigation , including the use of induction , maintenance , and withdrawal treatment strategies . The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease . METHODS In a r and omised controlled trial , patients aged between 18 and 70 years with moderately active rheumatoid arthritis ( disease activity score in 28 joints [ DAS28 ] > 3.2 and ≤5.1 ) despite treatment with methotrexate were enrolled at 80 centres in Europe , Latin America , Asia , and Australia between March 6 , 2008 , and Sept 9 , 2009 . To be eligible , patients had to have been receiving 15 - 25 mg of methotrexate every week for at least 8 weeks . In an open-label period of 36 weeks , all patients were given 50 mg etanercept plus methotrexate every week . To be eligible for a subsequent double-blind period of 52 weeks , participants had to have achieved sustained low disease activity . These patients were r and omly assigned ( 1:1:1 ) by an interactive voice-response system to one of three treatment groups : 50 mg etanercept plus methotrexate , 25 mg etanercept plus methotrexate , or placebo plus methotrexate . Patients were stratified in blocks of three by DAS28 response ( low disease activity or remission ) at week 36 . Patients , investigators , data analysts , and study staff were all masked to treatment allocation . The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period . A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity . Modified intention-to-treat population s were used for analyses . This trial is registered with Clinical Trials.gov , number NCT00565409 . FINDINGS 604 ( 72.4 % ) of 834 enrolled patients were eligible for the double-blind period , of whom 202 were assigned to 50 mg etanercept plus methotrexate , 202 to 25 mg etanercept plus methotrexate , and 200 to placebo plus methotrexate . At week 88 , 166 ( 82.6 % ) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity , compared with 84 ( 42.6 % ) of 197 who had received placebo ( mean difference 40.8 % , 95 % CI 32.5 - 49.1 % ; p<0.0001 ) . Additionally , 159 ( 79.1 % ) of 201 patients given 25 mg etanercept had low disease activity at week 88 ( mean difference from placebo 35.9 % , 27.0 - 44.8 % ; p<0.0001 ) . INTERPRETATION Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept . FUNDING Pfizer OBJECTIVE To assess the efficacy and safety of tocilizumab plus methotrexate ( MTX ) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX .  METHODS A total of 1,196 patients were enrolled in a 2-year , r and omized , double-blind , placebo-controlled trial . Patients received tocilizumab ( 8 mg/kg or 4 mg/kg ) or placebo every 4 weeks plus MTX . Rescue treatment was available from week 16 . Results from year 1 are presented . RESULTS Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX , respectively , versus 1.13 with placebo plus MTX ( P < 0.0001 for both comparisons ) . Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Question naire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg ( -144.1 and -128.4 units , respectively ) than with placebo ( -58.1 units ; P < 0.0001 for both comparisons ) . Proportions of patients with American College of Rheumatology 20 % , 50 % , and 70 % improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo ( P < 0.0001 for all comparisons ) . The safety profile of tocilizumab was consistent with the profiles in previous studies . Infections were the most common adverse and serious adverse events . CONCLUSION The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone . Tocilizumab has a well-characterized safety profile OBJECTIVE To analyze the annual cost of rheumatoid arthritis ( RA ) and its predictive factors . METHODS Data were obtained from a 12-month retrospective cohort of 201 RA patients , r and omly selected from a rheumatology registry , through a structured interview and records of the Central Information System of the hospital . Results were divided into direct , indirect , and total costs in 2001 US dollars . A sensitivity analysis was performed . Multiple linear regression models for the different types of costs were carried out . RESULTS The total cost was US dollars 2.2 million per year , with a cost attributable to RA of US dollars 2.07 million per year . The average cost per patient was US dollars 10419 per year ( ranging from US dollars 7914 per patient per year in the best scenario to US dollars 12922 per patient per year in the worst case ) . Direct costs represent nearly 70 % of total costs . We found an average increment in total costs of US dollars 11184 per year per unit of Health Assessment Question naire ( HAQ ) score ( P < 0.0001 ) and an average annual increment of US dollars 621 per year of disease ( P < 0.0001 ) . After adjustment , the HAQ score , inability to perform housework tasks , and being permanently disabled for work were the only predictors of high costs . CONCLUSION Our data show a remarkable economic impact of RA over society and link the costs of the disease to its consequences in terms of functional disability , work disability , and housework disability BACKGROUND Neutralization of tumor necrosis factor a ( TNF-alpha ) for three to six months reduces the symptoms and signs of rheumatoid arthritis . However , the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known . METHODS We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab , a chimeric monoclonal antibody against TNF-alpha  , in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks . We assessed clinical responses with use of the criteria of the American College of Rheumatology , the quality of life with a health-status question naire , and the effect on joint damage radiographically . RESULTS The combination of infliximab and methotrexate was well tolerated and result ed in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone ( clinical response , 51.8 percent vs. 17.0 percent ; P<0.001 ) . The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone . Radiographic evidence of joint damage increased in the group given methotrexate , but not in the groups given infliximab and methotrexate ( mean change in radiographic score , 7.0 vs. 0.6 , P<0.001 ) . Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response . CONCLUSIONS In patients with persistently active rheumatoid arthritis despite methotrexate therapy , repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage Background The onset of disease in ankylosing spondylitis ( AS ) is generally earlier than in other joint diseases , exposing patients to a prolonged burden of disease . Whether this is associated with excess mortality is still uncertain . Radiation therapy for AS has previously been shown to increase mortality . The present study investigated st and ardised mortality ratios , causes of death and survival predictors in a large regional cohort of patients with AS . Method A total of 677 patients with AS followed at our hospital since 1977 were matched by gender , age and postal area to three controls from the general population and st and ardised mortality rates ( SMRs ) were calculated . Cause of death was established using patients ' hospital records . In a subset of 360 patients , clinical and demographic data collected during an earlier research visit ( 1998–2000 ) were used in a prospect i ve multivariate analysis of predictors for mortality in AS . Results The crude mortality among patients with AS in this study was 14.5 % ( 98 patients ) ; SMR was only significantly increased among male patients compared with female patients ( 1.63 vs 1.38 , p<0.001 ) . Circulatory disease was the most frequent cause of death ( 40.0 % ) , followed by malignant ( 26.8 % ) and infectious ( 23.2 % ) diseases . Factors independently associated with reduced survival were diagnostic delay ( OR 1.05 ) , increasing levels of C-reactive protein ( OR 2.68 ) , work disability ( OR 3.65 ) and not using any non-steroidal anti-inflammatory drugs ( OR 4.35 ) . Conclusions Mortality is increased in patients with AS and circulatory disease is the most frequent cause of death . Parameters reflecting the duration and intensity of inflammation are associated with reduced survival . These results indicate that , to improve long-term survival in AS , there is a need for early detection and anti-inflammatory treatment as well as a vigilant approach for cardiovascular risk factors OBJECTIVE To assess the pharmacokinetics , safety profile , and efficacy of the fully human anti-tumor necrosis factor-alpha ( anti-TNF-alpha ) monoclonal antibody adalimumab ( D2E7 ) in patients with long-st and ing , active rheumatoid arthritis ( RA ) . METHODS This was a r and omized , double blind , placebo controlled study of single intravenous injections of ascending doses ( 0.5 to 10 mg/kg ) of adalimumab in 5 cohorts of 24 patients each ( 18 adalimumab and 6 placebo in all cohorts except the 0.5 mg/kg cohort of 17 adalimumab , 7 placebo ) . A total of 120 patients participated ( adalimumab 89 , placebo 31 ) . The clinical response was measured by changes in composite scores defined by the criteria of the European League Against Rheumatism ( EULAR ) and the American College of Rheumatology . RESULTS Single doses of adalimumab showed a rapid onset of clinical effect ( 24 hours to 1 week ) , with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks and for as long as 3 months in some patients . EULAR response was seen at least once during the 4 week period after drug injection in 29 % of patients in the placebo group as well as in 41 % , 78 % , 72 % , 89 % , and 100 % in the 0.5 , 1 , 3 , 5 , and 10 mg/kg groups , respectively . No dose related increases in adverse events were observed in the adalimumab patients compared with the placebo group . Adalimumab systemic drug exposure ( AUC0- ( ) ) increased linearly with an increase in dose . The mean total serum clearance was 0.012 to 0.017 l/h , and the steady-state volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half-life ranged from 10.0 to 13.6 days for the 5 cohorts , with an overall mean half-life of 12 days . CONCLUSION Treatment with the fully human Mab adalimumab was safe and well tolerated when administered as a single intravenous injection at doses up to 10 mg/kg , and was associated with a clinical ly significant improvement in the signs and symptoms of active RA OBJECTIVE To evaluate the safety and pharmacokinetics of multiple infusions of a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , MRA , in patients with rheumatoid arthritis ( RA ) . METHODS In an open label trial , 15 patients with active RA were intravenously administered 3 doses ( 2 , 4 , or 8 mg/kg ) of MRA biweekly for 6 weeks , and pharmacokinetics were assessed . Patients continued on MRA treatment for 24 weeks , and were then assessed for safety and efficacy . RESULTS The treatment was well tolerated at all doses with no severe adverse event . Increased total serum cholesterol was detected as an MRA related reaction in 10/15 ( 66 % ) patients . There was no statistically significant difference in the frequency of adverse events among the 3 dose groups . There were no new observations of antinuclear antibody or anti-DNA antibody , and no anti-MRA antibody was detected . The T1/2 increased with repeated doses and as the dose increased . T1/2 after the 3rd dose of 8 mg/kg reached 241.8 + /- 71.4 h. In 12/15 ( 80 % ) patients whose serum MRA was detectable during the treatment period , objective inflammatory indicators such as C-reactive protein , erythrocyte sedimentation rate , and serum amyloid A were completely normalized at 6 weeks , although there was no statistically significant difference in efficacy among the 3 dose groups . Nine of 15 patients achieved ACR 20 at 6 weeks . At 24 weeks , 13 patients achieved ACR 20 and 5 achieved ACR 50 . CONCLUSION Repetitive treatment with MRA was safe and normalized acute phase response in patients with RA . Optimal dosing schedule was not defined in this small study , but maintenance of serum MRA concentration seemed important to achieve efficacy Tocilizumab is a humanized anti-interleukin-6 ( IL-6 ) receptor monoclonal antibody that has demonstrated efficacy in the treatment of rheumatoid arthritis ( RA ) . A population pharmacokinetic ( PK ) model was developed using nonlinear mixed effect modeling to describe the PK profile of tocilizumab and used to estimate interindividual variability and assess the influence of covariates on PK parameters . The model was constructed based on data collected from 1793 patients with moderate to severe RA who received tocilizumab ( 4 or 8 mg/kg ) , via intravenous infusion every 4 weeks , during 4 phase III clinical trials .  Serum concentration-time profiles of tocilizumab were adequately described by a 2-compartment disposition model with parallel linear and nonlinear elimination kinetics . The 8-mg/kg dose of tocilizumab , compared with the 4-mg/kg dose , result ed in a more pronounced saturation of the nonlinear clearance pathway over the dosing interval , and this nonlinear clearance was representative of target-mediated elimination due to tocilizumab binding to the IL-6 receptor OBJECTIVE : To describe the pharmacokinetics of etanercept when administered by subcutaneous injection in single doses to healthy volunteers . METHODS : Twenty-six healthy volunteers between 19 and 50 years of age received single doses of etanercept 25 mg by subcutaneous injection into the abdomen . Serial serum sample s were collected for 21 days . An enzyme-linked immunosorbent assay with a quantitation limit of 0.3 ng/mL was used to measure the drug concentrations . RESULTS : Etanercept was well tolerated by healthy volunteers . A one-compartment model was found to best describe the concentration – time data and was used to determine the pharmacokinetic parameters . Etanercept is slowly absorbed from the site of injection with a time of peak concentration ( ± SD ) of 51 ± 14 hours ; peak concentration was 1.46 ± 0.72 mg/L. The AUC was 235 ± 98 mg•h/L , apparent clearance was 132 ± 85 mL/h , apparent volume of distribution was 12 ± 6 L , and the half-life was 68 ± 19 hours . CONCLUSIONS : Etanercept was slowly absorbed and slowly eliminated after subcutaneous administration . Dosing at the recommended rate of 25 mg twice weekly would be expected to result in concentrations of approximately 3 mg/L. Intersubject variability for apparent clearance in healthy volunteers was 64 % OBJECTIVE To determine the effects of treatment on the radiologic manifestations of joint damage in patients with rheumatoid arthritis ( RA ) who participated in a 24-week extension study of a r and omized , placebo-controlled clinical trial of anakinra  , a recombinant human interleukin 1 receptor antagonist . METHODS The patients had entered a 24-week , r and omized , double-blind , placebo-controlled study . Anakinra was self-administered by subcutaneous injection of 30 , 75 , or 150 mg/day . Upon completion of the placebo-controlled phase , the patients entering the extension study who had received placebo were r and omized to one of the 3 treatment dosages for a further 24 weeks , and the patients who had been initially r and omized to one of the 3 anakinra dosages continued to receive the same dosage . Radiographs of the h and s were obtained at baseline and at 24 and 48 weeks . The radiographs were evaluated using a modified Sharp method . RESULTS A total of 472 patients were recruited . The mean change in the total modified Sharp score of 178 patients who completed 48 weeks treatment , including all dosages , was significantly less than the change observed in 58 patients who received placebo for 24 weeks and anakinra for 24 weeks ( p = 0.015 ) . A significant reduction in the change of the total modified Sharp score was observed in the patients who received anakinra 75 and 150 mg/day . The total modified Sharp score was reduced significantly more during the second 24-week treatment period , compared to the first ( p < 0.001 ) . Significant reductions in the second 24-week period were observed following anakinra 75 mg/day ( p = 0.006 ) and 150 mg/day ( p = 0.008 ) . CONCLUSION Patients with RA who received anakinra for 48 weeks demonstrated significant slowing of radiographic joint damage . The treatment effect observed after the first 24-week period appeared to increase when anakinra was continued for 48 weeks Background : Anti-tumour necrosis factor ( TNF ) treatment is clinical ly efficacious in patients with active ankylosing spondylitis ( AS ) and leads to improvement of spinal inflammation , as assessed by magnetic resonance imaging . It is unclear whether anti-TNF treatment affects chronic spinal changes in AS . Objectives : To analyse the effect of infliximab on the radiographic course of AS over 2 years . Methods : Complete sets of lateral radiographs of the cervical spine and lumbar spine were available from 82 patients from two sources : 41 patients ( group 1 ) had been treated with infliximab ( 5 mg/kg/6 weeks ) as part of a recent r and omised controlled trial and 41 patients ( group 2 ) were part of the early German AS cohort ( GESPIC ) , without controlled interventions . Radiographs were obtained at baseline and after 2 years and scored by the modified Stokes AS Spinal Score ( mSASSS ) . Results : Patients in the infliximab group were older , had a longer disease duration , and more radiographic damage  at baseline . The mean ( SD ) mSASSS change was 0.4 ( 2.7 ) and 0.7 ( 2.8 ) for groups 1 and 2 , respectively ( p = NS ) . Radiographic damage at baseline was a predictor for more radiographic progression .  Patients with baseline damage who were treated with infliximab showed a trend for less radiographic progression . No correlations between clinical parameters and radiographic progression were found . Conclusions : Patients with AS treated with infliximab  had less radiographic progression after 2 years . Patients with prevalent radiographic damage are prone to develop more damage over time . Infliximab may decelerate radiographic progression in such patients . Larger studies are needed to prove that anti-TNF treatment inhibits structural damage BACKGROUND Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs , but a minority of patients achieve a good response . We aim ed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis -- for sustained , tight control of disease activity -- compared with routine outpatient care . METHODS We design ed a single-blind , r and omised controlled trial in two teaching hospitals . We screened 183 patients for inclusion . 111 were r and omly allocated either intensive management or routine care . Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response ( defined as a disease activity score < 2.4 and a fall in this score from baseline by > 1.2 ) . Analysis was by intention-to-treat . FINDINGS One patient withdrew after r and omisation and seven dropped out during the study . Mean fall in disease activity score was greater in the intensive group than in the routine group ( -3.5 vs -1.9 , difference 1.6 [ 95 % CI 1.1 - 2.1 ] , p<0.0001 ) . Compared with routine care , patients treated intensively were more likely to have a good response ( definition , 45/55 [ 82 % ] vs 24/55 [ 44 % ] , odds ratio 5.8 [ 95 % CI 2.4 - 13.9 ] , p<0.0001 ) or be in remission ( disease activity score < 1.6 ; 36/55 [ 65 % ] vs 9/55 [ 16 % ] , 9.7 [ 3.9 - 23.9 ] , p<0.0001 ) . Three patients assigned routine care and one allocated intensive management died during the study ; none was judged attributable to treatment . INTERPRETATION A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity , radiographic disease progression , physical function , and quality of life at no additional cost Objective To assess the association between a single nucleotide polymorphism in the gene of FCGR3A and the response to treatment with rituximab ( RTX )  in rheumatoid arthritis ( RA ) . Methods SMART is a r and omised open trial assessing two strategies of re-treatment in patients responding to 1 g infusion of RTX with methotrexate on days 1 and 15 after failure , intolerance or contraindication to tumour necrosis factor ( TNF ) blockers . Among the 224 patients included , 111 could be genotyped and were included in an ancillary study of SMART . Univariate and multivariate analyses adjusted on disease activity score on 28 joints were performed to assess whether FCGR3A-158V/F polymorphism was associated with European League Against Rheumatism response at week 24 . Results Among the 111 patients , 90 ( 81 % ) were responders of whom 30 ( 27 % ) were good responders . V allele carriage was significantly associated with a higher response rate ( 91 % of responders vs 70 % , OR 4.6 ( 95 % CI 1.5 to 13.6 ) , p=0.006 ) . These results were also confirmed in rheumatoid factor-positive patients ( 93 % vs 74 % , p=0.025 ) . In multivariate analysis , V allele carriage was independently associated with response to RTX  ( OR 3.8 ( 95 % CI 1.2 to 11.7 ) , p=0.023 ) . Conclusion The 158V/F polymorphism of FCGR3A seems to influence the response to RTX  in patients with RA after failure , intolerance or contraindication to TNF blockers Objective To investigate the influence of non-steroidal anti-inflammatory drugs ( NSAIDs ) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis ( AS ) and non-radiographic axial spondyloarthritis ( SpA ) . Methods 164 patients with axial SpA ( 88 with AS and 76 with non-radiographic axial SpA ) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake . Spinal radiographs  were scored by two trained readers in a concealed r and omly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score ( mSASSS ) system . An index of the NSAID intake counting both dose and duration of drug intake was calculated . Results High NSAIDs intake ( NSAID index≥50 ) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units : OR=0.15 , 95 % CI 0.02 to 0.96 , p=0.045 ( adjusted for baseline structural damage , elevated C reactive protein ( CRP ) and smoking status ) in comparison with patients with low NSAIDs intake ( NSAID index<50 ) . This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP : mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake , p=0.02 . In non-radiographic axial SpA , no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found . Conclusion A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS . In non-radiographic axial SpA this effect is less evident , probably due to a low grade of new bone formation in the spine at this stage
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