Johan Bratt

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial

BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis. METHODS We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3-4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004. FINDINGS 487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10-2.30], p=0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group. INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs. FUNDING Swedish Rheumatism Association, Schering-Plough.

Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a genetically complex disease where the response to different treatments varies greatly between different patients. This is the case with the tumour necrosis factor (TNF) blocking agents, where 20–40% of patients have been described as non-responders. No predictive markers exist as yet for the prognosis of response. Objective: To analyse whether polymorphisms of several cytokine genes are associated with the responsiveness to TNF blockade with etanercept. Methods: 123 patients with active RA were treated with etanercept and response rates were determined after three months using American College of Rheumatology (ACR)20 and disease activity score (DAS)28 response criteria. Genotyping was done for TNF (−308 TNFA), interleukin (IL)10 (−1087 IL10), transforming growth factor (TGF)β1 (codon 25 TGFB1), and IL1 receptor antagonist (intron 2 IL1RN). Results: 24 patients (20%) were defined as non-responders owing to their failure to fulfil any of the ACR20 or DAS28 response criteria. None of the recorded alleles was alone significantly associated with responsiveness to treatment. However, a certain combination of alleles (−308 TNF1/TNF1 and −1087 G/G) was associated with good responsiveness to etanercept (p<0.05). In addition, a combination of alleles influencing interleukin 1 receptor antagonist (IL1Ra) and TGFβ1 production (A2 allele for IL1RN and rare C allele in codon 25 of TGFB1 gene) was associated with non-responsiveness (p<0.05). Conclusion: Genetic polymorphisms, which may influence the balance of pro- and anti-inflammatory cytokines of relevance for the course of RA, are associated with clinical responsiveness to etanercept treatment.

Adalimumab (Humira®) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade®) or etanercept (Enbrel®): results from the STURE registry at Karolinska University Hospital

Objectives: To determine whether the tumour necrosis factor‐α (TNF‐α) antagonist adalimumab (Humira®) can be efficacious after secondary loss of efficacy (i.e. loss of clinical response in patients who had initially demonstrated clinical response) to infliximab (Remicade®) or etanercept (Enbrel®). Patients and methods: We studied 36 patients from the Stockholm TNF‐α follow‐up registry (STURE) who received adalimumab after secondary loss of efficacy to infliximab (group A, n = 27) or etanercept (group B, n = 9), and 26 patients who were started on adalimumab as the first TNF‐α antagonist (group C). Results: In group A, the baseline disease activity score 28 (DAS28) at infliximab institution was 5.5±0.2. During infliximab treatment, the mean best DAS28 was 3.7±0.2 (p<0.001), but increased to 5.2±0.3 when infliximab was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.5±0.3 (p<0.003), and then to 4.2±0.2 at 6 months (p<0.001). In group B, the baseline DAS28 at etanercept institution was 6.6±0.5. During etanercept treatment, the mean best DAS28 was 4.6±0.5 (p<0.01), but increased to 5.7±0.4 by the time etanercept was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.8±0.3 (p<0.005), and to 4.1±0.2 at 6 months (p<0.001). In group C, the mean baseline DAS28 was 5.6±0.3. After 6 months of adalimumab therapy, the DAS28 decreased to 3.5±0.4 (p<0.001). ACR20 responses with adalimumab in groups A, B, and C were similar (70–78%). Conclusions: For patients with secondary loss of efficacy from infliximab or etanercept, switching to adalimumab can restore a good clinical response.

Predictors of response to methotrexate in early DMARD naïve rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial

Objective To identify predictors of response to methotrexate (MTX) in early rheumatoid arthritis (RA). Methods In the SWEFOT trial, patients with RA with symptom duration <1 year started MTX monotherapy (20 mg/weekly) and 405/487 continued until the 3–4- month visit. The primary outcome measure was the DAS28-based European League against Rheumatism (EULAR) response criteria. Multivariate logistic regression was used to study the association between response and the following baseline characteristics: gender, age, symptom duration, cigarette smoking habits, autoantibody status, Health Assessment Questionnaire (HAQ) score, concurrent prednisolone and treatment with non-steroidal anti-inflammatory drugs. Secondary response and remission measures were the American College of Rheumatology and the Simple Disease Activity Index and Clinical Disease Activity Index (SDAI/CDAI)-derived criteria. Results After 3–4 months of MTX treatment, the frequency of EULAR good/moderate/no response was 34%/41%/25%, respectively. Parameters associated with a decreased likelihood of EULAR response were female gender (adjusted OR (adj OR) 0.50, 95% CI 0.31 to 0.81), symptom duration (adj OR per month increase 0.93, 95% CI 0.88 to 0.99), current smoking (adj OR 0.35, 95% CI 0.20 to 0.63) and higher HAQ (adj OR 0.56, 95% CI 0.40 to 0.80). Parameters associated with an increased likelihood of EULAR response were higher age (adj OR per 10-year increase 1.30, 95% CI 1.11 to 1.51) and prednisolone treatment (adj OR 2.84, 95% CI 1.43 to 5.63). The findings were similar when patients on prednisolone were excluded and other response criteria tested, although current smoking was the only significant predictor using all response criteria, while HAQ was the only significant predictor of all the remission criteria used. A matrix showed up to ninefold differences between subgroups stratified by the main predictors. Conclusion Current smoking, female sex, longer symptom duration and younger age predict a worse response to MTX in patients with new-onset RA. TrialRegNo NCT00764725

In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial

Objective To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis (RA; symptom duration <1 year) who had initially responded well to methotrexate monotherapy. Methods In the SWEFOT trial, all 487 patients started methotrexate (target dose 20 mg/week). After 3–4 months, 147 had low disease activity, 28-joint based disease activity score (DAS28) ≤3.2. These patients were not randomly selected but were followed in regular care for 2 years. Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp (SvdH) score were analysed. Results The majority of the 147 patients continued on methotrexate monotherapy. After 1 and 2 years, DAS28 remission was achieved in 59.6% and 71.8% and mean observed DAS28 values were 2.53 and 2.25, respectively. Despite the favourable clinical course, a proportion of the patients progressed radiographically with a mean (SD) increase in the SvdH score after 2 years of 3.90 (6.84). There was no significant difference in progression between patients in DAS28 remission versus not in remission (p=0.73). At baseline, approximately half the patients had no radiographic damage, while after 2 years the proportion was approximately 20%. Conclusion Most early RA patients who achieve low disease activity after 3–4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up, and additional treatment is needed infrequently. Some radiological progression occurs in most patients, and may be marked or severe in some, even despite sustained DAS28 remission. Close monitoring for radiological progression is thus warranted.

Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious

Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFα Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone.

Anti-apoA-1 IgG and oxidized LDL are raised in rheumatoid arthritis (RA): potential associations with cardiovascular disease and RA disease activity

Objective: To determine whether emerging cardiovascular risk factors such as anti-apolipoprotein A-1 (anti-apoA-1) immunoglobulin (Ig)G and oxidized low density lipoprotein (oxLDL) are associated with cardiovascular disease (CVD), carotid intima–media thickness (IMT), and disease activity in rheumatoid arthritis (RA). Method: We determined the aforementioned associations in 69 RA patients with disease duration of 5 years and 46 controls matched by age, sex, and smoking status. Anti-apoA-1 IgG and oxLDL were measured by enzyme-linked immunosorbent assay (ELISA). Carotid arteries were examined by ultrasound. Disease Activity Score calculated on 28 joints (DAS28) was used to assess disease activity. Results: CVD prevalence was higher among RA patients than controls (17% vs. 2%, p = 0.01) but there was no difference in IMT (median: 0.67 vs. 0.66, p = 0.33). RA patients had a higher anti-apoA-1 IgG prevalence than controls (20% vs. 0%, p = 0.001). Anti-apoA-1 IgG and oxLDL levels were higher in cases than controls [median: 0.33 vs. 0.175 optical density (OD), p = 0.03; and 121 vs. 37.2 U/L, p = 0.0001, respectively]. Anti-apoA-1 IgG-positive patients had higher levels of oxLDL (median: 140.5 vs. 112 U/L, p = 0.01) than those tested negative. Receiver operating characteristic (ROC) curve analysis showed that only anti-apoA-1 IgG was a modest but significant predictor of CVD [area under the curve (AUC) = 0.65, p = 0.03] in RA patients. oxLDL was significantly associated with RA disease activity, whereas anti-apoA-1 IgG was not. Conclusions: Anti-apoA-1 IgG could be a marker of CVD in RA, whereas oxLDL levels seem to reflect RA disease activity. Other causes of CVD than a general increase in atherosclerosis (as determined by IMT measurements) including plaque stability may therefore be of importance to explain the increased incidence of CVD in RA.

Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial

Objective To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21 months in patients with methotrexate-refractory early rheumatoid arthritis. Methods In this multicentre, two-arm, parallel, randomised, active-controlled, open-label trial, rheumatoid arthritis patients with <1 year symptom duration were recruited from 15 rheumatology clinics in Sweden between October 2002 and December 2005. After 3–4 months of methotrexate monotherapy, patients not achieving low disease activity were randomised to addition of infliximab or sulfasalazine+hydroxychloroquine (conventional treatment group). Costs of drugs, healthcare use, and productivity losses were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. Results Of 487 patients initially enrolled, 128 and 130 were randomised to infliximab and conventional treatment, respectively. The infliximab group accumulated higher drug and healthcare costs (€27 487 vs €10 364; adjusted mean difference €16 956 (95% CI 14 647 to 19 162)), while productivity losses did not differ (€33 804 vs €29 220; €3961 (95% CI −3986 to 11 850)), resulting in higher societal cost compared to the conventional group (€61 291 vs €39 584; €20 916 (95% CI 12 800 to 28 660)). Mean accumulated quality-adjusted life-years (QALYs) did not differ (1.10 vs 1.12; adjusted mean difference favouring infliximab treatment 0.01 (95% CI −0.07 to 0.08)). The incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2 404 197/QALY from the societal perspective and €1 948 919/QALY from the healthcare perspective. Conclusions In early, methotrexate-refractory rheumatoid arthritis, a treatment strategy commencing with addition of infliximab, as compared to sulfasalazine+hydroxychloroquine, was not cost-effective over 21 months at willingness to pay levels generally considered acceptable. Trial registration number: NCT00764725.

Biological vs Conventional Combination Treatment and Work Loss in Early Rheumatoid Arthritis A Randomized Trial

IMPORTANCE The introduction of biological tumor necrosis factor inhibitors has improved the treatment of rheumatoid arthritis (RA) but at a substantial cost. These drugs have been shown to lead to superior radiological outcomes compared with a combination of conventional disease-modifying antirheumatic drugs over 2 years. OBJECTIVE To investigate whether radiological superiority translates into better work loss outcomes. DESIGN, SETTING, AND PARTICIPANTS Multicenter, 2-arm, parallel, randomized, active-controlled, open-label trial. Patients with early RA (symptom duration <1 year) were recruited from 15 rheumatology clinics in Sweden from October 1, 2002, through December 31, 2005. The study population was restricted to working-age patients (aged <63 years). INTERVENTIONS Patients who did not achieve low disease activity after 3 to 4 months of methotrexate therapy were randomized to receive additional biological treatment with infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. MAIN OUTCOMES AND MEASURES Monthly sick leave and disability pension days 21 months after randomization retrieved from the nationwide Swedish Social Insurance Office register. Main analyses were by intention to treat, including all patients, and adjusted for baseline sick leave and disability pension. RESULTS Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, -3.0 to 3.9). The mean changes in work loss at 21 months were -4.9 d/mo in the biological and -6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, -1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, -1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, -2.8 to 3.8). CONCLUSIONS AND RELEVANCE The radiological superiority of biological compared with conventional combination therapy did not translate into better work loss outcomes in patients with early RA who had experienced an insufficient response to methotrexate. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00764725.

Endogenous glutamate in association with inflammatory and hormonal factors modulates bone tissue resorption of the temporomandibular joint in patients with early rheumatoid arthritis.

PURPOSE The aim of this study was to investigate the relation between plasma level of glutamate and extent of radiographic bone erosion of the temporomandibular joint (TMJ) in patients with early rheumatoid arthritis (RA) in relation to inflammatory disease activity as well as estradiol and testosterone. MATERIALS AND METHODS A total of 47 patients (29 women and 18 men) of whom 24 were seropositive were included shortly after being diagnosed with RA. Radiographic signs of bone tissue resorption (erosions) in the TMJ were recorded by cone-beam CT images, and an erosion score (0 to 24) was calculated for each patient. Venous blood was analyzed for rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate, leukocyte particle count, glutamate, estradiol, and testosterone. Nonparametric statistical methods were used in the analysis. RESULTS Resorptive changes of the TMJ were found in a major part of the patients. There was a significant positive correlation between plasma level of glutamate and extension of radiographic erosions that was strongest in the patients with low levels of C-reactive protein, estradiol, or testosterone. By contrast, erosions were correlated with C-reactive protein in patients with high levels of estradiol. The highest levels of glutamate were found in patients with low levels of C-reactive protein and estradiol. CONCLUSIONS This study shows that a majority of patients with early RA presents radiographic signs of bone tissue resorption of the TMJ and that circulating glutamate is associated with the extent of these changes. The relationship between glutamate and bone resorption seems to be influenced by systemic inflammatory activity as well as estradiol and testosterone levels.