Michael T. Nurmohamed

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis

Objectives: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR’s “standardised operating procedures”, the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. Results: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. Conclusions: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up

CONTEXT Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up. OBJECTIVE To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA). DESIGN, SETTING, AND PATIENTS Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic. MAIN OUTCOME MEASURES Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies. RESULTS After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies--51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, -4.5; 95% CI, -6.0 to -2.9; P < .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, -7.1; 95% CI, -8.4 to -5.8; P < .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P < .001) compared with antiadalimumab antibody-negative ones (n = 28 [14%]). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (< 3.2; HR, 3.6; 95% CI, 1.8-7.2; P < .001) compared with antiadalimumab antibody-negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody-negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 < 2.6; HR, 7.1; 95% CI, 2.1-23.4; P < .001) compared with antiadalimumab antibody-negative ones. CONCLUSION Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.

Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis

Background: A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to adalimumab treatment. One explanation for non-response is that patients develop anti-adalimumab antibodies. Objectives: To evaluate the incidence of formation of antibody against adalimumab and the association with serum adalimumab concentrations and clinical response. Methods: In a cohort of 121 consecutive patients with RA treated with adalimumab, serum adalimumab concentrations and antibodies against adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Results: Anti-adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/l, range 2.0–33.0, respectively; p<0.001). Good responders had higher serum adalimumab concentrations than moderate responders (p = 0.021) and non-responders (p = 0.001). Concomitant methotrexate use was lower in the group with anti-adalimumab antibodies (52%) than in the group without antibodies (84%) (p = 0.003). Conclusions: Serum antibodies against adalimumab are associated with lower serum adalimumab concentrations and non-response to adalimumab treatment.

Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study

OBJECTIVE Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD), but longitudinal observations are limited and the precise magnitude is unknown. We prospectively assessed the incidence of CVD in patients with RA compared with patients with type 2 diabetes mellitus (DM) and the general population. METHODS The 3-year incidence rate of CVD was determined in a prospective cohort (the Cardiovascular Research and Rheumatoid Arthritis Study) of 353 outpatients with RA, and was compared with that in 1,852 population-based cohort study participants (155 had type 2 DM). We investigated fatal and nonfatal CVD (according to International Classification of Diseases, Ninth Revision criteria) and used Cox proportional hazards models to assess the incidence of CVD in RA, type 2 DM, and the general population. RESULTS The 3-year incidence of CVD was 9.0% in patients with RA and 4.3% in the general population, corresponding with an incidence rate of 3.30 per 100 patient-years (95% confidence interval [95% CI] 2.08-4.25) and 1.51 per 100 person-years (95% CI 1.18-1.84), respectively. Compared with the general population, the age- and sex-adjusted hazard ratio (HR) for RA was 1.94 (95% CI 1.24-3.05, P = 0.004). Neither exclusion of patients with prior CVD at baseline nor adjustment for cardiovascular risk factors significantly influenced this. Compared with the nondiabetic population, nondiabetic patients with RA and those with type 2 DM had comparable HRs, 2.16 (95% CI 1.28-3.63, P = 0.004) and 2.04 (95% CI 1.12-3.67, P = 0.019), respectively. CONCLUSION The risk of CVD in RA was significantly elevated compared with the general population, and comparable with the magnitude of risk in type 2 DM.

Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study

Objective To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to adalimumab in rheumatoid arthritis (RA). Methods This cohort study consisted of 235 patients with RA, all treated with adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab (‘switchers’), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and adalimumab were assessed. Clinical response to adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-adalimumab antibody status. Results After 28 weeks of adalimumab treatment the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-adalimumab and 0.6±1.3 in patients with anti-adalimumab (p<0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). ΔDAS28 was greater for anti-TNF naive patients (1.7±1.5) than for switchers without anti-infliximab antibodies (ΔDAS28=0.9±1.4) (p=0.009). ΔDAS28 for switchers with anti-infliximab was 1.2±1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against adalimumab than anti-TNF naive patients. Response to adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.

The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept

Objective The aim of this study was to test the hypothesis that the reason for non-response (caused by immunogenicity or not) to a first tumour necrosis factor (TNF) inhibitor defines whether a second TNF inhibitor will be effective. Methods This cohort study consisted of 292 consecutive patients with rheumatoid arthritis (RA), all treated with etanercept. A total of 89 patients (30%) were treated previously with infliximab or adalimumab (‘switchers’), and the remaining 203 (70%) were anti-TNF naive. All switchers were divided into two groups: with and without antibodies against the previous biological. Differences in clinical response to etanercept between switchers with and without antibodies and patients who were anti-TNF naive were assessed after 28 weeks of treatment using changes in Disease Activity Score in 28 joints (DAS28). Results After 28 weeks of treatment, response to etanercept did not differ between patients who were anti-TNF naive and switchers with anti-drug antibodies (ΔDAS28=2.1±1.3 vs ΔDAS28=2.0±1.3; p=0.743). In contrast, switchers without anti-drug antibodies had a diminished response to etanercept treatment compared to patients who were TNF naive (ΔDAS28=1.2±1.3 vs ΔDAS28=2.1±1.3; p=0.001) and switchers with antibodies (ΔDAS28=1.2±1.3 vs ΔDAS28=2.0±1.3; p=0.017). Conclusion Patients with RA with an immunogenic response against a first TNF-blocking agent had a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence, determining immunogenicity can be helpful in deciding in which patient switching could be beneficial and can be part of a personalised treatment regimen.

Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review

Objective Data regarding cardiovascular comorbidity and cardiovascular risk factors in patients with psoriatic arthritis (PsA) are limited. To evaluate the cardiovascular risk profile, a systematic literature search was performed to provide an extensive summary of all studies available on cardiovascular risk in PsA. Methods Medline, EMBASE and the Cochrane library were searched from January 1966 to April 2011 for English language articles on data concerning cardiovascular diseases and cardiovascular risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded. Results Twenty-eight articles were included in this review. Studies on all-cause mortality revealed mixed results. Available data on cardiovascular disease appeared more consistent, indicating an increased cardiovascular mortality and morbidity in PsA. Commensurate with this, surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls. Suppression of inflammation was linked with a favourable effect on cardiovascular surrogate markers, for example carotid intima media thickness and endothelial dysfunction, in several (un)controlled studies. Conclusion Most studies point towards an increased cardiovascular risk in PsA, broadly on a par with the risk level in rheumatoid arthritis, emphasising the need for similar cardiovascular risk management in both conditions. Further studies are needed to indicate whether inflammatory suppression or modification of traditional cardiovascular risk factors, or both, will reduce cardiovascular risk.

Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner

Immunogenicity of adalimumab could impair important treatment outcome parameters in patients with rheumatoid arthritis (RA). Patients who developed antiadalimumab antibodies (AAA) during a 3 year time period achieved less often minimal disease activity or remission and treatment failure occurred more often compared with patients without AAA.1 There were remarkable baseline differences: patients developing AAA had more long-standing, severe disease and less often used concomitant medication including lower doses of methotrexate (MTX), compared with patients not developing AAA. In literature, a favourable effect of concomitant MTX use on the immunogenicity of adalimumab for several inflammatory conditions is suggested.2 To investigate which MTX dose is sufficient to reduce immunogenicity, patients of …

A comparative trial of a low molecular weight heparin (enoxaparin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery

BACKGROUND Various studies have been performed in general surgery patients comparing low molecular weight heparin (LMWH) with standard heparin (SH) for the prevention of postoperative deep vein thrombosis (DVT), revealing contradicting results. Therefore, we have compared the efficacy and safety of a LMWH for the prevention of DVT after major general surgery. PATIENTS AND METHODS Patients received either 20 mg LMWH (enoxaparin) once daily, or 5,000 IU SH TID, starting preoperatively in a prospective, randomized, double-blind international multicenter trial. DVT was diagnosed using fibrinogen I 125 leg scanning. Major and minor bleeding were assessed clinically. RESULTS A total of 718 patients were randomized to LMWH, and 709 patients to SH. DVT was detected in 58 LMWH-treated patients (8.1%, 95% confidence interval [CI] 6.2% to 10.3%) and in 45 patients allocated to SH (6.3%, 95% CI 4.7% to 8.4%, P > 0.05). Major bleeding complications occurred in 11 LMWH-treated patients (1.5%, 95% CI 0.8% to 2.7%) and in 18 patients to whom standard heparin was administered (2.5%, 95% CI 1.5% to 3.9%, P > 0.05). Four LMWH-treated patients (0.6%) required reoperation for bleeding as compared to 13 patients in the SH group (1.8%, P = 0.03). CONCLUSION This LMWH appeared as effective and safe as SH. In view of its more convenient way of administration, this LMWH might be preferred for thromboprophylaxis.

Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment

Risk of cardiovascular (CV) disease is increased among RA patients. High inflammatory burden associated with RA appears to be a key driver of the increased cardiovascular risk. Inflammation is linked with accelerated atherosclerosis and associated with a paradoxical inversion of the relationship between CV risk and lipid levels in patients with untreated RA, recently coined the lipid paradox. Furthermore, the inflammatory burden is also associated with qualitative as well as quantitative changes in lipoproteins, with the anti-inflammatory and atheroprotective roles associated with high-density lipoprotein cholesterol significantly altered. RA therapies can increase lipid levels, which may reflect the normalization of lipids due to their inflammatory-dampening effects. However, these confounding influences of inflammation and RA therapies on lipid profiles pose challenges for assessing CV risk in RA patients and interpretation of traditional CV risk scores. In this review we examine the relationship between the increased inflammatory burden in RA and CV risk, exploring how inflammation influences lipid profiles, the impact of RA therapies and strategies for identifying and monitoring CV risk in RA patients aimed at improving CV outcomes.