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Trial of Atorvastatin in Rheumatoid Arthritis (TARA):
double-blind, randomised placebo-controlled trial

David W McCarey, Iain B McInnes, Rajan Madhok, Rosie Hampson, Olga Scherbakova, Ian Ford, Hilary A Capell, Naveed Sattar

Summary Introduction
HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A)
Background Rheumatoid arthritis is characterised by reductase inhibitors (statins) reduce cardiovascular
inflammatory synovitis, articular destruction, and morbidity and mortality.1–3 Although statins work in
accelerated atherogenesis. HMG-CoA (3-hydroxy-3- part via lipid modulation, findings of studies indicate
methylglutarylcoenzyme A) reductase inhibitors (statins) they have broader properties, including alteration of
mediate clinically significant vascular risk reduction in inflammatory pathways.4 Ex-vivo activities of statins
patients without inflammatory disease and might have include suppression of adhesion molecule expression,
immunomodulatory function. We postulated that statins leucocyte cytokine release, MHC class II expression,
might reduce inflammatory factors in rheumatoid arthritis lymphocyte and macrophage cognate interactions,
and modify surrogates for vascular risk. and effects on reactive oxygen and nitrogen intermediate
production.5 Statins also modify apoptosis in smooth
Methods 116 patients with rheumatoid arthritis were muscle and endothelial cells leading to altered
randomised in a double-blind placebo-controlled trial to vascular function and neovascularisation.5 These
receive 40 mg atorvastatin or placebo as an adjunct to properties offer the potential to modify chronic
existing disease-modifying antirheumatic drug therapy. inflammatory disease states with drugs that show
Patients were followed up over 6 months and disease minimal toxic effects in both the short and long term.
activity variables and circulating vascular risk factors were However, as yet, no clinical data clearly show that
measured. Coprimary outcomes were change in disease statins modulate autoimmune disease activity or indeed
activity score (DAS28) and proportion meeting EULAR modify vascular risk factors in the context of high-grade
(European League Against Rheumatism) response criteria. inflammation.
Analysis was by intention to treat. Rheumatoid arthritis is a chronic inflammatory
arthropathy associated with rapid onset of clinically
Findings At 6 months, DAS28 improved significantly on significant functional impairment. It is also associated
atorvastatin (–0·5, 95% CI –0·75 to –0·25) compared with with accelerated vascular risk with attendant early
placebo (0·03, –0·23 to 0·28; difference between groups mortality (pooled standardised mortality ratio 1·7)
–0·52, 95% CI –0·87 to –0·17, p=0·004). DAS28 EULAR and excess morbidity.6 We have proposed that
response was achieved in 18 of 58 (31%) patients cytokine-mediated inflammatory pathways can in part
allocated atorvastatin compared with six of 58 (10%) account for this increased vascular risk via accentuation
allocated placebo (odds ratio 3·9, 95% CI 1·42–10·72, of both classic (lipids) and novel (endothelial function
p=0·006). C-reactive protein and erythrocyte sedimentation or insulin resistance) pathways.7 Furthermore,
rate declined by 50% and 28%, respectively, relative to statins suppress articular inflammation in vivo in
placebo (p<0·0001, p=0·005, respectively). Swollen joint collagen-induced arthritis in mice.8 Moreover, in-vitro
count also fell (–2·69 vs –0·53; mean difference –2·16, cytokine release by rheumatoid arthritis synovial
95% CI –3·67 to –0·64, p=0·0058). Adverse events mononuclear cells and by synovial fibroblasts was
occurred with similar frequency in patients allocated also reduced by statins.8 Similar anti-inflammatory
atorvastatin and placebo. effects have been reported in neurological models
of inflammation.9 Statins therefore have a plausible
Interpretation These data show that statins can mediate bioactivity profile in vitro and in vivo that makes
modest but clinically apparent anti-inflammatory effects them possible therapeutic agents in rheumatoid
with modification of vascular risk factors in the context of arthritis to target both vascular risk and synovial
high-grade autoimmune inflammation. inflammation. We therefore undertook a randomised
Lancet 2004; 363: 2015–21 placebo-controlled study to test the clinical efficacy
and laboratory effects of these drugs in rheumatoid
See Commentary page 2011

Centre for Rheumatic Diseases (D W McCarey MRCP, Patients and methods
Prof I B McInnes FRCP, R Madhok MD, R Hampson BSc, H A Capell MD) Patients
and Department of Vascular Biochemistry (N Sattar MD), University We screened patients attending Glasgow Royal
of Glasgow, Glasgow Royal Infirmary, Glasgow, UK; and Robertson Infirmary and recruited those who gave informed
Centre for Biostatistics, University of Glasgow, Glasgow consent for a study approved by North Glasgow
(O Scherbakova PhD, I Ford PhD) University NHS Trust ethics committee. Recruitment
Correspondence to: Prof Iain McInnes, Centre for Rheumatic was from September, 2001, through November, 2002.
Diseases, 3rd Floor Queen Elizabeth Building, Glasgow Royal Participants were 18–80 years of age, met 1987
Infirmary, Glasgow G31 2ER, UK American College of Rheumatology (ACR) criteria
(e-mail: (no limit on disease duration), and had active

THE LANCET • Vol 363 • June 19, 2004 • 2015

For personal use. Only reproduce with permission from The Lancet Publishing Group.

10. and swollen and 2 adverse event‡ 2 did not attend final tender joint counts (both 0–28). 2) early Age (years) 55·5 (11·8) 56·5 (10·0) morning stiffness for more than 30 min. patient-assessed global score. SDs calculated from log(natural)-transformed 177 assessed for eligibility distribution. and von Trial profile Willebrand factor. The same researcher (RH). and we asked them to maintain Haemostatic and endothelial factors their DMARD dose from study entry. LDL-cholesterol (mmol/L) 3·11 (0·76) 3·36 (0·89) steroidal anti-inflammatory drugs. British 30–41 6 (9%) 5 (7%) National Formulary). creatine kinase unchanged. We defined disease activity as six swollen Demographics joints plus two of: 1) six tender joints. or creatine Tender joint count 13·72 (8·14) 13·84 (8·61) kinase more than twice the upper limit of laboratory Early morning stiffness* 65·36 (3·32) 71·52 (3·52) normal range. We allowed Fibrinogen (g/L) 4·45 (1·00) 4·58 (1·24) and recorded intramuscular or intra-articular Plasma viscosity (mPa/s) 1·33 (0·10) 1·35 (0·11) corticosteroid injection during the study. and lipoproteins. Patients remained on all DMARDs. 0–100). The 58 received atorvastatin 58 received placebo primary outcome was change in DAS28. §Dry eyes and mouth and gastrointestinal After screening. Our analysis was by intention to treat. thrombotic variables.ARTICLES inflammatory rheumatoid arthritis despite ongoing Atorvastatin Placebo disease-modifying antirheumatic drug (DMARD) (n=58) (n=58) therapy. alanine aminotransferase. Only reproduce with permission from The Lancet Publishing Group. *Data are geometric means (SD).12 Components of DAS28 are erythrocyte 2 withdrew at 3-month assessment sedimentation rate. Computerised randomisation was done off-site (by independent study administrator) 116 randomised and both patients and doctors were unaware of drug allocation. and modified health assessment questionnaire. and Disease activity score 5·78 (1·10) 5·88 (0·97) Erythrocyte sedimentation rate* (mm/h) 19·11 (2·26) 19·89 (2·36) clinically significant renal disease or aspartate amino- C-reactive protein* (mg/L) 11·60 (2·95) 13·18 (3·62) For personal lipids. a validated composite disease activity score. study visits were scheduled for 0. †Creatine kinase raised at screening.11 and we used European League Against Rheumatism (EULAR) criteria to calculate response in DAS28 (details at 1 lost to follow-up 2 lost to follow-up http://www. and 3) Women 51 (88%) 49 (84%) erythrocyte sedimentation rate greater than 28 mm/h. endpoint C-reactive protein. and 6 months. Visual analogue score 58·62 (18·44) 66·33 (13·13) Swollen joint count 12·19 (4·41) 11·29 (3·70) Procedures Patient global assessment 58·67 (16·75) 67·44 (14·64) Health assessment questionnaire 1·84 (0·56) 1·89 (0·56) We recruited patients with active rheumatoid arthritis as defined above if they had been on an Lipid concentrations Cholesterol (mmol/L) 5·08 (0·81) 5·13 (0·99) adequate dose of DMARD therapy for at least Triglyceride (mmol/L) 1·34 (0·61) 1·39 (0·66) 3 months. Clinical outcome measures oral prednisolone greater than 10 mg/day. fibrinogen. Atorvastatin (40 mg) and identical placebo tablets were provided by Pfizer (NJ. patients who did not complete 6 months of active treatment 58 allocated atorvastatin 58 allocated placebo or placebo were categorised as non-responders. diabetes. 2004 • www. assessment 7 inefficacy visual analogue score (pain. ‡Dry eyes and exacerbation molecule 1.das-score. non. of irritable bowel symptoms. visual analogue score pain score. familial hypercholesterolaemia. 10–19 17 (29%) 19 (33%) risk of coronary heart disease event of more 20–29 11 (19%) 9 (16%) than 3% per year (joint British guidelines. previous adverse reaction to statins. USA). soluble intercellular adhesion study but withdrew at doctor’s and patient’s preference at week 2. and drugs for HDL-cholesterol (mmol/L) 1·36 (0·47) 1·32 (1·31) comorbid conditions. who was 2016 THE LANCET • Vol 363 • June 19. This score was assessment calculated as previously described. Rheumatoid factor positive 52 (90%) 50 (86%) Disease duration (years) Exclusion criteria included inability to give informed <10 24 (41%) 25 (43%) consent. Table 1: Baseline characteristics 61 excluded 26 refused to participate 35 exclusion criteria Patients were randomly allocated either atorvastatin 40 mg or placebo. Interleukin 6* (pg/mL) 14·67 (3·16) 13·42 (4·05) Data are mean (SD) or number of patients (%) unless otherwise indicated. These criteria consider both 2 did not continue 2 did not continue extent of DAS change and the final value achieved and intervention intervention 2 adverse event§ have been validated against ACR criteria in clinical 1 protocol violation* 1 adverse event† 9 withdrew at 3-month trials. . plasma viscosity. upset. 3. and the surrogate marker of *Pregnant. entered endothelial activation. Prespecified secondary endpoints 58 analysed for primary 58 analysed for primary endpoint included change in erythrocyte sedimentation rate. current lipid-lowering Smoker 20 (34%) 16 (28%) therapy. but this Von Willebrand factor (IU/dL) 150·55 (52·95) 166·59 (60·25) procedure was forbidden within 4 weeks of clinical Intercellular adhesion molecule 1* 314·19 (1·43) 323·76 (1·45) (ng/mL) assessment.11 Additional variables included early morning stiffness.

Denmark). erythrocyte other significant differences between groups. we accounted viscometer (Beckman Coulter. UK) by ELISA techniques. The assumptions of normality with rabbit antihuman C-reactive protein and needed for these analyses seemed to be approximately peroxidase conjugated rabbit antihuman C-reactive 2017 For personal use. measured all clinical variables was analysed on an intention-to-treat basis. We did haematology treatment effect. for dropouts by carrying their baseline value forward We measured fibrinogen by the Clauss assay and von to 6 months—ie. Oxon. High Wycombe. The EULAR DAS28 binary response (moderate or good vs otherwise) unaware of allocations. Copenhagen. ANCOVA was used for adjustment for with a sensitive double-antibody sandwich ELISA potential confounders.thelancet. We analysed results with logistic adverse events throughout the study and by specific regression to provide the estimated odds ratio for the request at assessment timepoints. . including change in DAS28. interleukin 6. Atorvastatin (n=58) Placebo (n=58) p Primary outcome measure Disease activity score –0·50 (–0·75 to –0·25) 0·03 (–0·23 to 0·28) 0·004 Secondary outcome measures Erythrocyte sedimentation rate (mm/h) –5·03 (–8·4 to –1·67) 1·91 (–1·61 to 5·44) 0·005 C-reactive protein (log mg/L) –0·46 (–0·64 to –0·28) 0·12 (–0·09 to 0·34) <0·0001 Clinical measures Tender joint count –1·21 (–3·28 to 0·86) 0·38 (–1·16 to 1·92) 0·22 Early morning stiffness (log) –0·47 (–0·82 to –0·12) –0·13 (–0·47 to 0·22) 0·17 Visual analogue score –5·07 (–10·5 to 0·36) 1·97 (–3·15 to 7·08) 0·06 Swollen joint count –2·69 (–3·81 to –1·57) –0·53 (–1·59 to 0·52) 0·0058 Patient global assessment –4·14 (–7·80 to –0·48) 0·15 (–4·25 to 4·56) 0·14 Health assessment questionnaire 0·02 (–0·12 to 0·16) 0·04 (–0·04 to 0·13) 0·75 Lipids Cholesterol (mmol/L) –1·48 (–1·73 to –1·23) –0·01 (–0·14 to 0·12) <0·0001 Triglyceride (mmol/L) –0·24 (–0·34 to –0·14) 0·07 (–0·04 to 0·18) <0·0001 LDL-cholesterol (mmol/L) –1·40 (–1·63 to –1·17) –0·07 (–0·23 to 0·10) <0·0001 HDL-cholesterol (mmol/L) 0·03 (–0·03 to 0·09) –0·04 (–0·10 to 0·02) 0·097 Other risk markers Fibrinogen (g/L) –0·38 (–0·69 to –0·07) 0·00 (0·19 to –0·20) 0·041 Plasma viscosity (mPa/s) –0·05 (–0·06 to –0·03) –0·00 (–0·02 to 0·01) 0·0004 Von Willebrand factor (IU/dL) –8·5 (–20·6 to 3·58) –4·53 (–16·7 to 7·6) 0·64 Intercellular adhesion molecule 1 (ng/mL) –22·6 (–41·6 to –3·7) 2·37 (–18·2 to 22·9) 0·076 Interleukin 6 (pg/mL) –6·6 (–13·2 to 0·01) 3·84 (–2·85 to 10·5) 0·028 Table 3: Differences after 6 months of treatment THE LANCET • Vol 363 • June 19. we calculated that 54 patients were Prednisolone (oral) 2 (3%) 0 needed per group to provide 80% power at the 5% Intra-articular triamcinolone 12 (21%) 17 (29%) significance level. no change assumed. IL. Total dose (mg) 530 760 we aimed to enrol 59 patients per group. 20 patients in the atorvastatin group and Distributions of C-reactive protein. ARTICLES Atorvastatin Placebo Willebrand factor (Dako. †Intramuscular sodium sedimentation rate. creatine p value from the Wald statistic. (lipids) and the remainder was stored at –70°C were done on the untransformed changes from until assay. Data are number of patients (%). administration according to study drug assignment Coprimary analyses were change in DAS28 and EULAR DAS28 binary response. Baseline data Intramuscular triamcinolone 6 (10%) 11 (19%) are summarised as mean (SD) for continuous variables Total dose (mg) 640 880 and number of patients (%) for categorical variables. as described previously. markedly skewed and hence geometric means are given Table 2: Concomitant DMARD therapy and corticosteroid as summary statistics. Concentrations less than 6 mg/L were associated 95% CIs to compare changes between subsequently measured by a high sensitivity assay groups. We recorded described above. the associated 95% CI.13 We analysed plasma with Spearman’s rank-correlation coefficient. We assessed associations between variables protein. UK). and the and biochemical screening for liver function. and renal function at baseline and 3 and groups of patients with respect to the proportion 6 months. as at study entry and at 3 and 6 months. 2004 • www. Abbott Park. and early morning stiffness were aurothiomalate.12 Anticipating about 10% dropout. we measured the ␹2 statistic We prepared plasma and serum samples immediately in those patients completing the study to 6 months. We fluorescence polarisation immunoassay with a used paired t tests and associated 95% CIs to examine TDX analyser (Abbott Laboratories. *More patients in the atorvastatin group received methotrexate (p=0·0074). Methotrexate* 29 (50%) 15 (26%) Sulfasalazine 35 (60%) 37 (64%) Statistical analysis Hydroxychloroquine 7 (12%) 13 (22%) Assuming a 10% reduction from baseline in mean Leflunomide 2 (3%) 5 (9%) Gold† 4 (7%) 5 (9%) DAS28 score on atorvastatin compared with no change Penicillamine 1 (2%) 0 on placebo (equivalent to a 0·6 unit mean difference) Minocycline 1 (2%) 0 and an underlying SD for the changes from baseline Corticosteroid therapy of 1·0 unit. no adhesion molecule 1. within-group differences and two-sample t tests and USA). A sample was assayed straightaway All other analyses. attending the 6-month visit. (n=58) (n=58) interleukin 6. after venepuncture. To compare the two kinase. Only reproduce with permission from The Lancet Publishing Group. and intercellular adhesion molecule 1 DMARD therapy (R&D systems. C-reactive protein was measured by baseline to 6 months in the outcome variable. For viscosity at 37°C in a Coulter-Harkness capillary change in laboratory variables. intercellular 15 in the placebo group received combination DMARD therapy.

plasma viscosity. erythrocyte sedimentation rate. and interleukin 6 (10%) given placebo at 6 months (odds ratio for concentrations all declined significantly in the DAS28 response 3·9. No (table 2). relative to placebo. 40 mg atorvastatin or placebo (figure). patient received parenteral steroid within 4 weeks of Table 3 documents outcomes for each study DAS28 assessment. data collection. reduction in C-reactive protein and erythrocyte sedimentation rate remained significant (p=0·0002 and Discussion p=0·003. although visual analogue score In particular. After adjustment (by cholesterol did not correlate with alteration in any other ANCOVA) for potential confounders that were study variable including disease activity score. Adjustment for methotrexate cholesterol. . generally comparable. figure). soluble allocated atorvastatin compared with six of 58 intercellular adhesion molecule 1. suggesting that the change in disease 177 patients with rheumatoid arthritis were screened.ARTICLES Methotrexate status at baseline Difference p Not taking (n=29) p Taking (n=29) p DAS28 –0·40 (–0·74 to –0·06) 0·02 –0·59 (–0·97 to –0·21) 0·004 0·19 (–0·31 to 0·69) 0·46 Erythrocyte sedimentation rate (mm/h) –4·17 (–6·88 to –1·47) 0·004 –5·90 (–12·28 to 0·49) 0·069 1·72 (–5·06 to 8·51) 0·61 C-reactive protein (log mg/L) –0·40 (–0·67 to –0·13) 0·006 –0·52 (–0·77 to –0·27) 0·0002 0·12 (–0·24 to 0·49) 0·51 Table 4: Changes in key study variables in the atorvastatin group according to baseline methotrexate status Role of the funding source response to methotrexate was unlikely to account for our Pfizer provided an educational grant and the findings. erythrocyte sedimentation rate. Events leading to withdrawal are shown with median disease duration of 11·5 years in the figure. placebo groups (table 3). study to 6 months compared with those on placebo fibrinogen. 95% CI Significant reductions in total cholesterol. respectively). and visual analogue pain interleukin 6. placebo (difference between groups –0·52. A similar result was recorded in the atorvastatin group remained on treatment when data for individuals taking or not taking to completion. C-reactive protein (including C-reactive protein reduction correlated with reduction detection by the high sensitivity assay) and erythrocyte in interleukin 6 (r=0·31. At 6 For personal use. Although the magnitude of change sulfasalazine were compared (data not shown). More patients in the placebo group than in methotrexate compared with placebo (p=0·007). C-reactive protein. 95% CI 1·42–10·72. By Frequency of corticosteroid administration is shown chance. the data analysis. We examined correlations with change over time in Acute-phase reactants improved significantly in patients allocated atorvastatin. reduction in LDL- respectively. suggesting that a delayed disease. LDL- –0·87 to –0·17. By intention criteria) were achieved in 18 of 58 (31%) patients to treat. Adverse events arose with similar (5–20). Atorvastatin and placebo groups were frequency in patients allocated atorvastatin and placebo. fibrinogen. and VLDL-cholesterol use did not change the significance of observed concentrations were recorded in atorvastatin versus reduction in this primary outcome measure (p=0·007). atorvastatin (–2·69 joints) compared with placebo (–0·53 joints. or patient global assessment. 95% CI –3·67 to Results –0·64. namely methotrexate use. Reductions in plasma viscosity. Significantly more patients responses (table 4). Only reproduce with permission from The Lancet Publishing Group. In particular. the atorvastatin group received intra-articular or whereas other drugs were equally represented intramuscular administration of triamcinolone. further indicating change in patients allocated atorvastatin was compared the beneficial effect of statin use and tolerability of with that in placebo recipients (table 3). HDL-cholesterol was Moderate or good DAS28 responses (EULAR slightly raised in atorvastatin recipients. When change over patients allocated atorvastatin versus placebo 6 months was examined in these individuals (n=53). in patients given atorvastatin (table 3). more patients allocated atorvastatin received in table 2. all Several individual disease activity variables improved sponsors had no role in study design. score. no effect was seen on other 2018 THE LANCET • Vol 363 • June 19. Otherwise. The median Atorvastatin was well tolerated in the study age of the study group was 56 years (IQR 47–66) population. and interleukin 6 remained significant when (53 vs 45. However. DAS28 was significantly reduced in patients prednisolone at baseline—neither were clinical who were allocated atorvastatin compared with responders (table 2). p=0·004). the significant reduction in DAS28 difference in response was seen in individuals allocated provides proof of concept that pathways targeted placebo and taking methotrexate compared with by statins offer therapeutic opportunity in inflammatory those not taking this drug. therapy. activity score indicated not only a laboratory change but of whom 116 were randomised to receive either also a true articular response. (r=0·51. p=0·04. No is modest. no significant liver function or muscle and patient global assessment were slightly lower abnormality was detected in those given atorvastatin. unbalanced at baseline. 2004 • www. p=0·006). triglyceride. p=0·0058). mean difference –2·16. or writing of the swollen joint count declined in individuals allocated report. of acute-phase variables and a significant reduction and C-reactive protein in patients allocated atorvastatin in swollen joint count in patients with rheumatoid and who were taking or not taking methotrexate we arthritis presenting with active disease despite noted that both groups showed similar significant existing DMARD therapy. p=0·0009). (table 3). By contrast. When we compared change in We have shown marked suppression with atorvastatin disease activity score. atorvastatin and placebo tablets. atorvastatin group but were unchanged in the More patients allocated atorvastatin completed the placebo group.thelancet. data interpretation. Two patients were on oral arm. in the atorvastatin group at baseline (table 1). p=0·03) and fibrinogen sedimentation rate declined by 50% and 28%.

rheumatoid arthritis despite established DMARD Although initial mean lipid values lay within the therapy (mean DAS28 score 5·8) and prolonged reference range. potential biphasic sulfasalazine were similar in terms of response benefit in reduced inflammation and modified vascular (table 4 and data not shown). our data clearly show that statins drug use did not alter the significance of the primary are effective in modification of classic and novel risk outcomes. we allowed steroid injection We also showed immune suppressive effects of within our protocol. and larger studies strictly defined DMARD context. The measures of risk may accrue with use of statins in rheumatoid DAS28—namely patient global assessment and visual arthritis. The multicentre moieties—particularly oxidised LDL—that in turn design needed to recruit active rheumatoid arthritis regulate local inflammation. Equally in rheumatoid of effect is modest. The in serum interleukin 6.thelancet. Only reproduce with permission from The Lancet Publishing Group.2 this fact provides swollen joint count 3·8)21 or minocycline to established a direct coronary heart disease-protective pathway DMARD therapy (median reduction in swollen in rheumatoid arthritis for atorvastatin via traditional joint count 0·8). atorvastatin reduced C-reactive properties.23. Our and in vivo. which we have now generated.25 Thus.7 anti-inflammatory mechanisms Nevertheless. however. soluble intercellular adhesion joint count or visual analogue scale for pain raises molecule 1. more patients on methotrexate entered these changes will prove meaningful in the clinical the atorvastatin arm of our study. Chronic elevation of the possibility of effects of statins on inflammation interleukin 6 might promote atherogenesis directly distinct from pain pathways. is of the same order as that seen on addition of Since lipid lowering even within the so-called ciclosporin to methotrexate (median reduction in normal range is of vascular benefit. Our data now suggest that modulation steroid were used more frequently in the placebo-treated of inflammation can be achieved by atorvastatin group.26–32 We also measured reduction on the basis of their anti-inflammatory profile. Future studies moves to disease amelioration and remission induction THE LANCET • Vol 363 • June 19. ARTICLES clinical measures of disease activity. We tested atorvastatin in a stringent true-to-life Accelerated atherogenesis is a major cause of setting by giving the drug to patients with active morbidity and mortality in rheumatoid arthritis. plasma viscosity. Synovial inflammation the relevance of our clinical dataset to the wider in rheumatoid arthritis is characterised by activated rheumatoid arthritis population. will be needed to establish the extent to which By chance. via secondary effects on insulin resistance. In parallel. Direct effects components of both innate and acquired immune of statins on hepatic C-reactive protein synthesis responses. Thus. a clinically apparent anti-inflammatory with accompanying downstream improvements in effect is remarkable given that atorvastatin was novel risk factor pathways can also operate for developed mainly on the basis of lipid-lowering atorvastatin.8. suggesting that some of the above pathways oral steroid use was very low in our cohort. Finally. which prompted us to undertake the current Importantly. manifest on endothelial activation. we used erythrocyte sedimentation rate Findings of our in-vitro study8 showed suppression of for our composite DAS28. Finally.24 has been proposed. minor macrophage. 2004 • www. our 2019 For personal use. However. . but simvastatin in rodent collagen-induced arthritis forbade this within 28 days of DAS28 evaluation. for The design chosen offers advantages in facilitating example. indicating may indeed be tractable to HMG-CoA reductase local practice. which lends support to this notion. reasonably operate within the synovial membrane. only on the liver. intra-articular and intramuscular study. and as such is unlikely to have affected inhibition. the improvement seen despite the context of high-grade inflammation.14 Similar effects on acquired immune will bias against finding a treatment effect for responses via suppression of antigen presentation15 atorvastatin. be designed to test statin activity in a health assessment questionnaire. erythrocyte reduction in joint swelling distinct from tender sedimentation rate.33 Moreover. there is a striking study group is small.6. natural killer cell. and T-cell polarisation have been shown in vitro Other limitations should be considered. Thus. rendering a significant positive confounding in a proportion of patients with rheumatoid effect on primary outcomes unlikely. reflecting the single-centre design. analogue scale—that were lower in the atorvastatin Many data indicate effects for statins in innate group by chance would probably bias against a immune response. postulated effects for statins might could exaggerate the impression of disease modification. the heterogeneous background of DMARD of hypercoagulability and endothelial activation. itself an established independent risk factor for provide impetus for development of statin analogues coronary heart disease. and the noted reduction synovial T cell and fibroblast-like synovocyte in interleukin 6 argues against an effect mediated cytokine release. atorvastatin could modulate lipid that could confound outcomes.34 patients to a strictly defined DMARD background Most rheumatoid arthritis patients now receive a was not readily achievable without proof of concept combination of DMARDs as treatment emphasis data. and intercellular adhesion molecule 1 are markers However. As such.16–20 However. Thus. and fibrinogen. Moreover subgroup analysis suggested factors of vascular disease despite the presence that subgroups treated with methotrexate or of high-grade inflammation. Frequency of arthritis. reflecting real practice. particularly the should.22 We recognise that the magnitude risk factor modification. use allows the possibility of statin-DMARD interactions respectively. we believe that our study should protein. direct comparison difficult. in which inflammation-driven vascular risk with novel cytokine-targeting biological agents. Although study designs render LDL-cholesterol and triglyceride concentrations. and neutrophil discrepancies in baseline characteristics if anything effector function. plasma viscosity and fibrinogen single-centre recruitment over a short period. atorvastatin substantially reduced disease duration. absence of controlled human trial data to confirm large high-powered studies will be important to confirm these observations in vivo. in particular when compared arthritis.5 clinical response in this group. in vivo. through effects in the vessel wall and indirectly We recognise important limitations in our study. Correction for context.

37: 629–36. average or lower-than-average cholesterol concentrations. 28 Devaraj S. van Rijswijk MH. RM. McInnes IB. and the 22 Kloppenburg M. . A novel anti-inflammatory role and bioactivity in human aortic endothelial cells. potential. de Jager JP. van ’t Hof MA. van de Putte LBA. 38: 44–48. 2003. R Madhok. Torzewski J. McCarey DW. 31: 519–25. 108: 2957–63. Mulhaupt F. van der Heijde D. 15 Kwak B. Circulation 2003. Hernandez M. Breedveld FC. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. HAC. Kidney Int 2003. 22: 2003. further opportunity for the generation of novel Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA. Am J Nephrol 2003. D W McCarey. Acknowledgments N Engl J Med 1995. Sattar N. Arterioscler Thromb Vasc Biol 2002. van Leeuwen MA. 93: O Scherbakova. stroke events with atorvastatin in hypertensive patients who have 43: 22–29. ACR and EULAR inclusion of statins on long-term outcomes in improvement criteria have comparable validity in rheumatoid arthritis trials. J Immunol 2003. development and promotes Th2 development. Arthritis Rheum 1995. Therapeutic effect of the combination of etanercept and methotrexate References compared with each treatment alone in patients with rheumatoid 1 Shepherd JS. van Riel PL. Since findings indicate endothelial 13 Packard CJ. Ohashi Y. Capell H. Kettritz R. N Engl J Med 1995. Ford I. 30 Zwaka TP. 21: 115–21. 170: 106: 1439–41. D W McCarey and R Hampson hydroxymethylglutaryl-coenzyme a reductase reduces Th1 ran the study clinic. Wicks IP. O’Reilly DS. and N Sattar designed and coordinated the trial and 687–92. DWM. Conflict of interest statement 19 Yokota N. et al. Arterioscler Thromb Vasc Biol statins on plaque rupture. Interaction of oxidative Curr Control Trials Cardiovasc Med 2000. 6: 1399–402. Shaul P. Whereas existing DMARD therapy might 11 Prevoo ML. Minocycline in active rheumatoid arthritis: a Lynne Cherry for excellent laboratory and technical assistance. and Dijkmans BA. Mitchell RN. Direct NS have been recipients of travel grants or honoraria from Pfizer within anti-inflammatory mechanisms contribute to attenuation of 3 years of beginning the work submitted. et al. anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. 24 Feldmann M. Prevention of coronary arthritis: double-blind randomised controlled trial. Scotland. and 20 Shimizu K. Xu DY. C-reactive protein increases 6 Van Doornum S. Patarroyo JC. 361: 1149–58. atorvastatin. Pincus T. Mach F. Rolle S. in the 26 Ridker PM. Contributors 16 Weitz-Schmidt G. and IF have no experimental allograft arteriosclerosis by statins. data and provided statistical support. Circ Res 2003. McColl G. 2020 THE LANCET • Vol 363 • June 19. 23: 1398–404. Libby P. Only reproduce with permission from The Lancet Publishing Group. None of the authors has a relationship reperfusion injury. Protective effect of IBM and NS were recipients of an educational grant from Pfizer to fund HMG-CoA reductase inhibitor on experimental renal ischemia- ex-vivo analyses in this report. Dahlöf B. Comparison of Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm C-reactive protein and low-density lipoprotein cholesterol levels in (ASCOT-LLA): a multicentre randomised controlled trial. et al. The HMG-CoA reductase low density lipoprotein uptake by macrophages: implications for inhibitor. 363: 675–81. Kuribayashi K. Aikawa M. 7: H A Capell. MRC/BHF Heart arthritis: what have we learned? Annu Rev Immunol 2001. et al. van Riel PLCM. Brinkmann V. 333: 137–41. A significant effect central nervous system autoimmune disease. et al. Statins as a newly recognized type of immunomodulator. Welzenbach K. Terwiel JP. Arthritis Research Campaign (UK) for research grant support. disease. Luft FC. not indicative for first line use. Felson DT. 63: disease-modifying drugs to treat chronic inflammatory 96–106. 360: 7–22. Ridker PM. syndrome and atherothrombosis. van ‘t Hof MA. 420: on disease activity was noted in our study. Jialal I. RH. predicting response to treatment in rheumatoid arthritis: 3 Sever PS. Are statins anti-inflammatory? 27 Kobayashi S. et al. 343: 1148–55. Nat Med 2001. Stuve O.ARTICLES together with tissue protection. 107: 7 Sattar N. Myit S. Lancet 25 Anderson JJ. Prognostic could prove beneficial in the context of DMARD factors for radiographic damage and physical disability in early combination design. rheumatoid arthritis. Unraveling pleiotropic effects of important role of C-reactive protein. rheumatoid arthritis. et al. 1: 161–65. R Madhok. Rifai N. Leeuwen MA. binding to a novel regulatory integrin site. Cook NR. Circulation 2003. Haller H. I B McInnes. high-risk individuals: a randomised placebo-controlled trial. consultancies. et al. OS. Rose L. et al. this effect of atorvastatin 10 van der Heijde DMFM. for simvastatin in inflammatory arthritis. Rane M. vascular protective and adjunctive immune modulatory Br J Rheumatol 1992. Poulter NR. Nature 2002. with Pfizer in terms of employment. 23 Klareskog L. Jialal I. stock ownership. Yuhanna I. Factors 2002. All authors critically reviewed 18 Sparrow CP. known conflict of interest. et al. Uehara Y. Kuper HH. Arthritis Rheum 2000. Caslake MJ. Maini RN. Circulation 2003. O’Donnell M. stress and inflammatory response in coronary plaque instability: 5 Palinski W. Finally. 2004 • www. Buring JE. Verhoeven AC. Nat Med 2000. IBM. Daniels F. Yocum D. Crilly A. N Engl J Med 2000. drafted the paper. Statins selectively inhibit leukocyte function antigen-1 by I B McInnes (principal investigator). 21 Tugwell P. 4 Blake GJ. Circulation 2001. Arterioscler Thromb Vasc Biol 2001. Further studies are now arthritis. 26: 705–11. 333: 1301–07. van de Putte LB. 19: Protection Study of cholesterol lowering with simvastatin in 20 536 163–96. Accelerated atherosclerosis: plasminogen activator inhibitor-1 expression and activity in an extraarticular feature of rheumatoid arthritis? Arthritis Rheum human aortic endothelial cells: implications for the metabolic 2002. Modified disease activity scores partly reverse vascular risk. 347: 1557–65. Devaraj S. Anti-TNF alpha therapy of rheumatoid 2 Heart Protection Study Collaborative Group. Lipoprotein-associated dysfunction in even early rheumatoid arthritis. assessed the patients. Explaining how 398–404. Napoli C. 1745–50. 46: 862–73. van Riel PL. 103: 1194–97. Burton CA. diseases. Inoue N. heart disease with pravastatin in men with hypercholesterolemia. and acquired data. We thank the Chief Scientist Office. Mallee C. et al. and N Sattar analysed and interpreted 948–56. Lancet 2004. or patent applications. promotes a Th2 bias and reverses paralysis in atherosclerosis. D W McCarey. 108: 2113–20. Inhibition of H A Capell recruited study patients. et al. needed to establish what benefit is conferred by 12 van Gestel AM. Demonstration that C-reactive protein decreases eNOS expression 8 Leung BP. placebo-controlled trial. Takayama K. 1524–30. Hombach V. paid expert For personal use. and 17 Hakamada-Taguchi R. Prevention of coronary and the importance of disease duration. Simvastatin has the manuscript and approved the final version. et al.35 our findings suggest that include twenty-eight-joint counts: development and validation that statins can work to reduce traditional and in a prospective longitudinal study of patients with rheumatoid novel vascular risk factors. double-blind. N Engl J Med 2002. I Ford.36 phospholipase A2 as an independent predictor of coronary heart intervention at the outset deserves consideration. Although 78–84. statin-sensitive biochemical pathways offer 14 Choi M. D W McCarey and I B McInnes contributed equally to this report. 23: 13–17. Arthritis Rheum 1994. J Rheumatol 1999. Circulation 2002. Wells G. Cobbe SM.thelancet. Anderson JJ. C-reactive protein-mediated 9 Youssef S. Lancet the prediction of first cardiovascular events. in which a statin offers both rheumatoid arthritis: a prospective follow-up study of 147 patients. “high-grade” systemic inflammation accelerates vascular risk in 29 Venugopal SK.

the gentleman very therapeutic recommendations to an individual patient. calmly and sincerely told me that. 36 Vaudo G. this experience did not errors. I did not order a radiograph best efforts to make correct diagnoses. Mohamed-Ali V. Department of Rheumatology. A few weeks later. I have made However. Only reproduce with permission from The Lancet Publishing Group. I know that most back patients fall into Despite the fact that he reported very intense pain (at the category of non-specific lower back pain. young patients with rheumatoid arthritis and low disease activity. Throughout the night. but because today’s truth during the night. possibly more than I realise. many years later. and that sharing was unable to complete the 3 week. Marchesi S. Early in my postgraduate training I was called to The patient died within 6 months despite aggressive examine a patient in his sixties. Bohm BO. Winkelmann BR. stress and coronary heart disease: is Ann Rheum Dis 2004. Humphries SE. This patient that each has made me a better doctor. et al. ARTICLES 31 Marz W. It can be very difficult to apply current I was called by the ward to request increasingly strong epidemiological information. Physical Medicine and Rehabilitation. Gerli R. right when they complain. Strong in my beliefs. This is one of the principles of the tried to give absolute priority to what a patient says or art of 2021 For personal use. 92: 305–08. Tsimikas S. Uses of error Do not dismiss intense pain Federico Balagué Regardless of experience and expertise. I remain afraid to miss a mechanism of onset could not explain any major organic life-threatening disease. and that that time. 359: 1173–77. errors. et al. . Seeger JD. Inflammation. A radiograph taken later that morning might become tomorrow’s heresy. routine daily practice). Immunomodulatory effects of statins: Ludwigshafen Risk and Cardiovascular Health study). or analgesia. 60: 2002. It is our task to understand I have never forgotten that man and ever since I have the cause of their pain. a mediator of in patients with rheumatoid arthritis: a prospective study. I was convinced that such a including neoplasm. 63: 31–35. Effects of statins on C-reactive protein and interleukin-6 (the 34 Palinski W. which required immediate surgery.thelancet. Hernan MA. I hope complaining of disabling lower back pain. obesity. Some were due to prevent us—in this case I was supervising a young limitations of my scientific knowledge or insufficient resident—from recommending an intensive physical clinical experience. I think that physicians revealed a femoral fracture at the site of a bone should keep in mind that a priori our patients are always metastasis. Kumari M. who had developed therapy. visual analogue scales were not part of my only about 1% involve specific inflammatory diseases. we all make feels over any biomechanical hypothesis of mine. In 30 years of medical practice. spinal disorders. colonic tumour with hepatic metastases was diagnosed. if he had had his gun All this information may be perfectly useful from a in his night-table drawer. Am J Cardiol mechanisms and potential impact on arteriosclerosis. demanding them will help to prevent others from making the same programme and dropped out. 634–39. he would have shot himself public health standpoint. interleukin-6 the link? Atherosclerosis 2000. 148: 209–14. Nauck M. which can happen despite our lesion. 2003. Med Hypotheses 2003. 1708 Fribourg. a mistakes. 2004 • www. Methotrexate and mortality therapy may reflect decreased isoprenylation of Rac-1. and simply prescribed analgesics. Hôpital Cantonal. 32 McCarty MF. Even now. Reduction of serum C-reactive protein by statin 35 Choi HK. Early in the morning. Switzerland (F Balagué MD) THE LANCET • Vol 363 • June 19. Endothelial dysfunction in 33 Yudkin JS. Lancet the IL-6 signal transduction pathway. As a rheumatologist with a special interest in sudden pain in his thigh after turning over in bed. 13: 1673–81. J Am Soc Nephrol 2002. classification criteria. Communication problems and rehabilitation programme for a 41-year-old man misunderstandings may also have contributed. Winkler K.