key updates in acr and eular recommendations: applying to...

Key Updates in ACR and EULAR Recommendations:

Applying to PracticeLeonard H. Calabrese, DO

Professor of MedicineCleveland Clinic Lerner College of MedicineRJ Fasenmyer Chair of Clinical Immunology

Department of Rheumatic and Immunologic DiseasesCleveland, OH

Key Updates in ACR and EULAR Recommendations Applying to Practice

• Diagnosis• Treatment• Treat to Target (T2T)

The Old Days

Arnett FC, et al. Arthritis Rheum. 1988;31(3):315-324.

1987 ACR Classification Criteria for RA1987 Classification Criteria

Criteria 1. Morning stiffness (at least 1 hour)2. Arthritis in ≥3 joint areas3. Arthritis of hand joints (≥1 swollen joints)4. Systemic arthritis5. Rheumatoid nodules6. Serum RF7. Radiographic changes (erosions) on X-ray of hands

Applicable for All arthritis patients

Results in Classification of RA (yes/no)

Positive in case

Four of the seven criteria must be present. Criteria one through four must have been present for at least six weeks

Test characteristics

Sensitivity of 79-80% and specificity of 90-93% for established RA.Sensitivity of 77-80% and specificity of 33-77% for early RA.

2010 ACR/EULAR Classification Criteria for RA

• Emphasis now placed on identifying patients that may benefit from earlier interventions

• The goal is to halt the development of the disease fulfilling the 1987 ACR criteria

Aletaha D, et al. Ann Rheum Dis. 2010;69(9):1580-1588.

1 large joint 02-10 large joints 11-3 small joints 24-10 small joints 3>10 joints (≥1 small joint) 5

Negative RF and ACPA 0Low-positive RF or ACPA 2High-positive RF or ACPA 3

<6 weeks 0≥6 weeks 1

Normal CRP and normal ESR 0Abnormal CRP or abnormal ESR 1

Serology (0-3)

Symptom Duration (0-1)

Acute Phase Reactants (0-1)

Swollen/Tender Joints (0-5)

Patients with a score of ≥6have “definite” RA

2010 RA Classification Criteria

• ≥1 joint with synovitis(excluding the DIP, first MTP and first CMC joints)

• Absence of alternative diagnosis that better explains synovitis

• Achievement of total score of ≥6 (of 10) from individual scores in 4 domains

– Joint involvement patterns

– Serologic abnormality

– Elevated acute-phase response

– Symptom duration

2010 ACR/EULAR Classification Criteria for RA

Aletaha D, et al. Ann Rheum Dis. 2010;69(9):1580-1588. DIP: Distal interphalangealMTP: MetatarsophalangealCMC: carpometacarpal

Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64(5):625-639.

2012 Update of the 2008 American College of Rheumatology Recommendations for the Use

of Disease-modifying Antirheumatic Drugs and Biologic Agents in the Treatment of

Rheumatoid ArthritisSingh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM,

Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL,

Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG.

EARLY RA

• Presence of 1 or more of the following features:– Functional limitation (eg, HAQ DI or similar, valid tools)– Extraarticular disease (eg, presence of rheumatoid

nodules, RA vasculitis, Felty’s syndrome)– Positive rheumatoid factor or anti-cyclic citrullinated

peptide antibodies or bony erosions by radiograph • OTHER:

– Imaging (US or MRI, Biomarkers? Genetic studies)

Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64(5):625-639.

EULAR Recommendations for the Management of Rheumatoid Arthritis with

Synthetic And Biological Disease-modifying Antirheumatic Drugs: 2013 Update

Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, Emery P, Gaujoux-Viala C, Gossec L, Nam J, Ramiro S, Winthrop K, de Wit

M, Aletaha D, Betteridge N, Bijlsma JW, Boers M, Buttgereit F, Combe B, Cutolo M, Damjanov N, Hazes JM, Kouloumas M, Kvien TK, Mariette X, Pavelka K, van Riel PL, Rubbert-Roth A, Scholte-Voshaar M, Scott DL,

Sokka-Isler T, Wong JB, van der Heijde D.

Smolen JS, et al. Ann Rheum Dis. 2014;73(3):492-509.

EULAR Recommendations

• In cases of MTX contraindications (or early intolerance), sulfasalazine or leflunomide should be considered as part of the first treatment strategy

• In DMARD-naïve patients, irrespective of the addition of glucocoritcoids, csDMARD monotherapy or combination therapy of csDMARDs should be used

• In patients responding insufficiently to MTX and/or other csDMARDstrategies, with or without glucocorticoids, bDMARDs (TNF inhibitors, abatacept or tocilizumab, and, under certain circumstances, rituximab) should be commenced with MTX


• If a first bDMARD has failed, patients should be treated with another bDMARD; if a first TNF inhibitor therapy has failed, patients may receive another TNF inhibitor or a biological agent with another mode of action

• Tofacitinib may be considered after biological treatment has failed

• If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, especially if this treatment is combined with a csDMARD



• In cases of sustained long-term remission, cautious reduction of the csDMARD dose could be considered, as a shared decision between patient and physician

• When therapy needs to be adjusted, factors apart from disease activity, such as progression of structural damage, comorbidities and safety issues, should be taken into account



Algorithm Based on the 2013 European League Against Rheumatism Recommendations on

Rheumatoid Arthritis Management


ACPA, Anti-citrullinated Protein Antibody; DMARD, Disease-modifying Antirheumatic Drug; RF, Rheumatoid Factor;TNF, Tumour Necrosis Factor

Treat-to-Target Algorithm


Pathogenesis and Underlying Immunologic Mechanisms

Leonard H. Calabrese, DOProfessor of Medicine

Cleveland Clinic Lerner College of MedicineRJ Fasenmyer Chair of Clinical Immunology


Pathogenesis of RA:Notes From the Field

• RA historical perspective• Putative scheme of pathogenesis• Pre-rheumatoid

– Genetic/epigenetic– Stochastic – microbiome– Innate /TLR signaling– Protein modifications in autoimmune disease

• Effector pathways• Methodologic considerations

History

• 6000-3000 BC – Evidence of RA in skeletal remains in Alabama, USA

• 1492 – Old World meets New World• ~1600 First evidence of RA in fine art as depicted by Peter

Paul Rubens• 1800 – Landre-Beauvais publishes the first medical paper on

RA in “La goutte asthenique primitive”• 1859 – Alfred Baring Garrod coins term “rheumatoid arthritis”• ~1950 – First cases of RA documented in Africa and Asia

Scher JU, et al. Nat Rev Rheumatol. 2011;7(10):569-578.

PRE-RHEUMATOID ARTHRITISGenetic predisposition + environmental interactions

Breach of immunologic tolerance

Pre-clinical synovial inflammation

Symptomatic synovial disease

RHEUMATOID ARTHRITIS

Unknown additional event(s)

Case Report

• 18-year-old asymptomatic female in multi-RA family– Study of indigenous people in the Southwest– Patient had no symptoms whatsoever Low positive anti-CCP Followed over several months: began to have

arthralgia

Willemze A, et al. J Rheumatol. 2008;35(11):2282-2284.

RA=rheumatoid arthritis;

HLA and Non-HLA Genes are Linked in ACPA-positive Genome-wide Association Studies

(GWAS)*

• Study looking at 100,00+ genes• 60-100 genes have become of interest

– All have some role in the integrated immune response– More research needed to understand the function of

most of these genes

Plenge RM, et al. N Engl J Med. 2007;357(12):1199-1209.

RA Monozygotic Twin Concordance Correlates With HLA-DR4 and SE1

• Overall RA concordance in twin studies: 12% to 15%2-3

• Other immune disease concordance in twin studies– Multiple sclerosis: 24%4

– Primary biliary cirrhosis: 63%5

1Jawaheer D, et al. Arthritis Rheum. 1994;37(5):681-686.2Qho K, et al. J Rheumatol. 1986;13(5):899-902.3Silman AJ, et al. Br J Rheumatol. 1993;32(10):903-907.4Hansen T, et al. Mult Scler. 2005;11(5):504-510.5Invernizzi P, et al. Lancet. 2004;363(9408):533-535.

N=91 Caucasian pairs1

Factors RA ConcordanceHLA-DR4 21%

Shared epitope (SE) 18%

Homozygous 27%

Heterozygous 13%

ACPA-positive vs. ACPA-negative Disease Characteristics

• ACPA-positive disease: Majority of patients with established disease1

– Associated with:

Genetic signatures1-3

Worse erosive disease4,5

Cardiovascular disease6

• ACPA-negative disease: Not well understood1

– More research needed– To date, has not been associated with7

Genetic signatures Environmental factors Other characteristics of autoantibody-positive disease

1Morgan AW, et al. Arthritis Rheum. 2009;60(9):2565-25762Berglin E, et al. Arthritis Res Ther. 2004;6(4):R303-308.3Pedersen M, et al. Arthritis Rheum. 2007;56(5):1446-1453.4Goldbach-Mansky R, et al. Arthritis Res. 2000;2(3):236-243.

5El-Khoury GY, et al. Radiology. 1988;168:517-520.6Södergren A, et al. Ann Rheum Dis. 2007;66(2):263-266.7Källberg H, et al. Am J Hum Genet. 2007;80:867-875.

Development of ACPA Repertoire Prior to Clinical Onset

• Before RA develops, a patient’s titer of antibodies to various citrullinatedpeptides rises

van der Woude D, et al. Ann Rheum Dis. 2010;69(8):1554-1561. Abstract 1091.

Environmental Factors Implicated in RA Predisposition

1Padyukov L, et al. Arthr & Rheum. 2004;50(10):3085-3092.2Klareskog L, et al. Arthritis Rheum. 2006;54(1):38-46.3Liao F, et al. Medical Hypotheses. 2009;72(6):732-735. 4Rosenstein ED, et al. Inflammation. 2004;28(6):311-318.5Wegner N, et al. Arthritis Rheum. 2010;62(9):2662-2672.

6Caplan A. Thorax. 1953;8(1):29-37.7Costenbader KH, et al. Arthritis Research & Therapy. 2006;8(1):204.8Kerr JR. Ann Rheum Dis. 2000;59(9):672-683.

Smoking

• Relative risk of 2.2 for RF+ disease1

• Dose-dependent relationship with ACPA+ disease (extent of smoking and frequency of elevated ACPAs)2

Bacteria in lungs/

gingiva3-5

• Elevated incidence of RA in patients with chronic periodontitis

Other6-8 • Silica and other air pollutants, viruses,gut flora, etc

Smoking Causes Pulmonary Inflammation and May Promote Breaching of Tolerance

Pulmonary Inflammation

PADI Citrullination& ACPA Formation

Smoking Increases the Risk of ACPA-positive RA*

• Citrullination is a part of basic biology:– It occurs where inflammation occursLungs of smokers

♦Smokers without RA have citrullinatedproteins on bronchial alveolar lavage

Källberg H, et al. Am J Hum Genet. 2007;80(5):867-875.

Some of my Best Friends are Germs

Periodontitis (PD) as Possible Risk Factor for RA

• Incidence of RA in people with PD is 3.95% (<1% normal population)1

• Measures of RA disease severity are associated with periodontal bone loss2

• P. gingivalis is the most commonly isolated strain3,4

• Theory: P. gingivalis produces PADI*-like enzyme causing citrullination3,4

1Mercado FB, et al. J Clin Periodontol. 2003;30(9):761-772.2Liao F, et al. Medical Hypotheses. 2009;72(6):732-735.3Rosenstein ED, et al. Inflammation. 2004;28(6):311-318.4Wegner N, et al. Arthritis Rheum. 2010;62(9):2662-2672.

PADI=peptidylarginine deiminase

Role of the Gut Microbiota in Immunity and Autoinflammatory Diseases

• 100 trillion organisms– Digestion/fermentation/vitamin production– Development of innate and adaptive immunity – Protection from ‘dybiosis’

• When homeostasis is disrupted the microbiota can contribute to disease

Kamada N, et al. Nat Rev Immunol. 2013;13(5):321-335.

Image used with permission. Source: Scher JU, et al. Nat Rev Rheumatol. 2011;7(10):569-578.

Microbiota and Experimental Arthritis

Image used with permission. Source: Scher JU, et al. Nat Rev Rheumatol. 2011;7(10):569-578.

Conclusions

• RA is a disease with a molecular nosologic classification that is meaningful

• RA appears to have stages (pre, early, established) that have implications for pathogenesis and treatment

• Pathways of high interest include environmental triggers (ie, microbiome, others) that may have therapeutic implications

• Neo-antigenesis is important in RA and should be explored

Understanding Cardiovascular Risk in Patients with RA –

A Primer in Cardiology for the Rheumatologist

M. Elaine Husni, MD, MPHDirector, Arthritis and Musculoskeletal Center

Cleveland ClinicCleveland, OH

Overview

• Convincing data from epidemiologic studies indicate that rheumatoid arthritis (RA) is an independent risk factor for accelerated cardiovascular (CV) disease– Holds true after adjustment for traditional CV risk factors

• Chronic inflammatory burden implicated in the initiation and progression of CV disease; however, not conclusively proven

• Ongoing studies investigating the link between RA and CV outcomes

Systemic Rheumatic Disease and Cardiovascular Risk

Increased CV risk– Rheumatoid arthritis– Lupus– Psoriatic arthritis– Ankylosing spondylitis– Wegener’s

granulomatosis– Takayasu’s arteritis– Kawasaki’s disease– Systemic sclerosis

No increased CV risk– Giant cell arteritis

Not well studied– Polyarteritis nodosa– Henoch–Schönlein

purpura, – Cryoglobulin-

associated vasculitis– Cutaneous

leucocytoclasticangiitis

Hollan I, Meroni PL, Ahearn JM, et al. Autoimmun Rev. 2013;12(10):1004-15.

Risk Factors for Atherosclerosis in Rheumatic Diseases

• Greater prevalence of traditional risk factors– Recent studies have adjusted for traditional risk factors and

comorbidities, patients with RA still ↑ CV events– Sedentary lifestyle/ inactivity

• Treatment specific – Steroids cause ↑ CV risk– NSAID use

• Disease specific– Duration of disease– Active disease or uncontrolled disease

Del Rincon I, et al. Arthritis Rheum. 2001;44:2737-2745.Navarro-Cano G, et al. Arthritis Rheum. 2003;48:2425-2433.

Mortality in Rheumatoid Arthritis

• Observational studies (17/21) demonstrate an increased standardized mortality ratio (SMR) 1.7–3.31

• Decreased life expectancy 3 to 18 years• Recently, 3 larger prospective trials confirmed this finding

1Van Doornum S, et al. Arthritis Rheum. 2002;46:862-873.2Solomon DH, et al. Circulation. 2003;107:1303-1307.

114,342 Nurses health study

527 confirmed RA cases

3622 CV events (MI/strokes)

RR for MI 2.0

(95% CI 1.23-3.29)

Increased CVD Case Fatality and Unrecognized Disease & Sudden Death in RA

• Compared to patients without RA, those with RA have an increased cumulative incidence of:– Unrecognized MI (p=0.050)– Angina Pectoris (P=0.025)– Sudden Death (P=0.052)

Maradit-Kremers, H et al. Arthritis Rheum. 2005;52(2):402-411.

The Widening Mortality Gap Between RA Patients and the General Population

• The observed mortality rate (per 100 patient years) in RA patients has been consistently higher than expected– Gap has widened since 1970– Greater widening of gap seen in males

Gonzalez A, Kremers HM, Crowson CS, et al. Arthritis Rheum. 2007;56(11):3583-3587.

Does RA Equal Diabetes Mellitus as an Independent Risk Factor for CVD? A Prospective Study

• Nondiabetic RA patients and patients with Type 2 diabetes were found to have similar cardiovascular event-free probability over a 3-year period. Both showed a steady decline in probability compared to nondiabetic controls. – Hazard ratios:

For patients with T2DM: 2.0 (95% CI, 1.1-3.7)

For nondiabetic patients with RA: 2.2 (95% CI, 1.3-3.6)

Peters MJ, et al. Arthritis Rheum. 2009;61(11):1571-1579.

Initiation and Adherence to Secondary Prevention Pharmacotherapy after MI in Patients with RA:

A Nationwide Cohort Study

• Treatment initiation with secondary prevention drugs after MI on days 30 and 180 after discharge: reduced treatment is associated with RA– RA patients are less likely to receive guideline-

recommended secondary prevention pharmacotherapy Aspirin, β-blocker, clopidogrel, RAS blockers, statins

– Contributes to worsened prognosis post-MI compared with the general population

Lindhardsen J, et al. Ann Rheum Dis. 2012; 71(9):1496-501.

Epidemiology of CVD in RA

Figure adapted from Symmons, DP, et al. Nat Rev Rheumatol. 2011;7(7):399-408.

Inflammation in Atherosclerosis

• Healthy vascular endothelial layer– 1 cell layer thick– Good cell-to-cell contact

• Loss of endothelial layer integrity– Cell-to-cell contact weakens, allowing cytokine entrance, foam cell

production, and luminal narrowing– Active inflammatory process

• Endpoint (e.g., myocardial infarction) is reached upon plaque rupture– Many people can live with 40% luminal narrowing for years without

sequelae; it is plaque rupture that leads to the endpoint

Ross R. N Eng J Med. 1999;340:115-126.

Cardiac Risk in theGeneral Population

Primary Prevention of Cardiovascular Disease and Stroke in The General Population:

Risk Intervention

Risk Intervention Goal(s)Smoking Complete cessation; no environmental exposure

Blood Pressure Control <140/90 mmHG; <130/80 mmHg in patients with DM

Dietary Intake Overall healthy eating pattern

Aspirin (ASA) Low-dose ASA if moderate or high CHD riska

LDL Cholesterol <100 mg/dl if high CHD risk; <130 mg/dl if moderately high or moderate CHD risk; <160 mg/dl if low CHD riska

Physical Activity At least 30 min of moderate-intensity activity on most (preferably all) days of the week

Weight BMI 18.5 – 24.9 kg/m2

Diabetes Mellitus (DM) Fasting glucose,110 mg/dl and HbA1c<7%CHD: Coronary heart disease, HbA1c: Glycosylated hemoglobin A1c.aHigh risk refers to known CHD (history of myocardial infarction, unstable or stable angina, revascularization, or clinically significant myocardial ischemia) or CHD risk equivalent (noncoronary forms of clinical atherosclerotic disease, DM, and multiple (.2) CHD risk factors with 10‐year risk for CHD >20%). Moderately high risk refers to ≥2 risk factors with 10‐year risk of 10‐20%. Moderate risk refers to ≥2 risk factors with 10‐year risk of <10%. Low risk refers to up to 1 risk factor. Risk factors include age (men ≥45 years of age; women >55 years of age), cigarette smoking, hypertension (blood pressure >140/90 mmHg or on an antihypertensive medication), low HDL (<40 mg/dl), and family history of premature CHD (in male first‐degree related <55 years of age or female <65 years of age), 10‐year CHD risk refers to 10‐year risk for ‘hard’ CHD events (myocardial infarction and death from CHD), and is calculated on the basis of these risk factors.

Traditional CV Risk Factors:Framingham Cardiac Risk Score

http://www.mdcalc.com/framingham-cardiac-risk-score.

Risk Factor Variable (choose one)Sex Male or femaleAge (note: not validated for ages <35y or >75y)

30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74

Total cholesterol (mg/dL) <160, 160–199, 200–239, 240–279, >270

HDL (mg/dL) <35, 35–44, 45–49, 50–59, >60BP <120/80,120–129/80–84, 130–139/85–89,

140–149/90–99, ≥150/100Patient a diabetic? Yes or noPatient a smoker? Yes or no

Patient’s 10-year risk for CHD Algorithm calculates % riskComparative risk to same age/sex Algorithm calculates % risk

Traditional CV Risk Factors:Framingham Cardiac Risk Score

http://www.mdcalc.com/framingham-cardiac-risk-score.

Risk Factor Variable (choose one)Sex Male or femaleAge (note: not validated for ages <35y or >75y)

30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74

Total cholesterol (mg/dL) <160, 160–199, 200–239, 240–279, >270

HDL (mg/dL) <35, 35–44, 45–49, 50–59, >60BP <120/80,120–129/80–84, 130–139/85–89,

140–149/90–99, ≥150/100Patient a diabetic? Yes or noPatient a smoker? Yes or no

Patient’s 10-year risk for CHD Algorithm calculates % riskComparative risk to same age/sex Algorithm calculates % risk

Low risk <10%

Intermediate risk 10%-20%

High risk >20%

Heart Score: CHD Risk Charts (SCORE)

• The CHD Risk Charts ( SCORE) is an example of a practical model using several predictors.

• It is available at: www.escardio.org/EACPR

Conroy RM, et al. Eur Heart J. 2003;24(11):987-1003. Available at the European Society of Cardiology. www.escardio.org/EACPR

RA and Traditional Risk Factors

• Hypertension– BP may be increased by NSAIDs or steroids

• Smoking– Risk factor for development and severity of RA

• Diabetes mellitus– Increased insulin resistance

• Obesity– Reversed relationship in RA? Increased mortality with

BMI <20 kg/m2

– Linked to increased CRP• Metabolic SyndromeKrekes G, et al. Nat Rev Rheumatol. 2014; doi: 10.1038/nrrheum.2014.121. [Epub ahead of print]

RA and Novel CV Risk Factors

• Homocysteine– Increases associated with MTX use and reduction of folate– Treatment with MTX decreased CV mortality by 70%

• TNFα• CRP• Lp(a)• Fibrinogen• Soluble ICAM-1• Dysfunctional HDL

Kumar N and Armstrong DJ. Clin Med. 2008;8(4):384-7.

http://www.reynoldsriskscore.org/

Reynolds Risk Score

• Risk calculator• Takes into consideration smoker status,

systolic blood pressure, total cholesterol, HDL, and family history

• Can be accessed at http://www.reynoldsriskscore.org/

Usefulness of Risk Scores to Estimate Risk in Patients with RA

• Standard tools for estimating CV risk may underestimate CV risk in patients with RA

• CVD rate in women with RA was double that predicted by Framingham scores

• Systemic inflammation is widely believed to be a contributing factor in the CV damage in RA, but using the Reynolds scores (which include the inflammatory marker C-reactive protein) did not improve the ability to predict who would develop CVD

• Further research is needed

Crowson CS, et al. Am J Cardiol. 2012;110(3):420-4.

EULAR Recommendations for CVD Risk Management

• RA should be regarded as a condition associated with higher risk for CV disease. This may also apply to AS and PsA, although the evidence base is less. The increased risk appears to be due to both an increased prevalence of traditional risk factors and the inflammatory burden.

• Adequate control of disease activity is necessary to lower the CV risk• CV risk assessment using national guidelines is recommended for all patients

with RA and should be considered annually for all patients with AS and PsA.Risk assessments should be repeated when antirheumatic treatment has been changed.

• Risk score models should be adapted for patients with RA by introducing a 1.5 multiplication factor. This multiplication factor should be used when the patient with RA meets 2 of the following 3 criteria:

– Disease duration of more than 10 years– RF or anti-CCP positivity– Presence of certain extra-articular manifestations

Peters MJL et al. Ann Rheum Dis. 2009;69:325-331.

Cardiac Risk Specific to Systemic Rheumatic Disease

Anti-CCP Antibodies and Increased Risk of Ischemic Heart Disease

Lopez-Longo FJ, et al. Arthritis Rheum. 2009;61(4):419-424.

Cardiovascular events in patients with RA with anti-CCP antibodies (>500 units/ml) vs. patients with RA without anti-CCP antibodies (<500 units/ml) in a

bivariate logistic regression analysis*

Anti-CCP Positive (n=299)

Anti-CCP Negative (n=638)

OR (95% CI) P

Heart Failure 22 (7.3) 44 (6.9) 0.801

Ischemic Heart Disease 28 (9.4) 23 (3.6) 2.76 (1.59-4.78) <0.001

Acute Stroke 16 (5.3) 23 (3.6) 0.325

Thrombosis 18 (6.0) 26 (4.1) 0.182Death 27 (9.0) 66 (10.3) 0.522*Values are the number (percentage) unless otherwise indicated. RA: Rheumatoid arthritis, Anti-CCP: anti-cyclic citrullinated peptide, OR: Odds ratio, 95% CI: 95% Confidence interval

More Recent Epidemiologic Studies: RA Genetics and Risk Stratification

• HLA-DRB1 0404 strongly associated with increased risk of CV mortality

• Suggesting that both genetics and inflammatory burden contribute to accelerated CVD in patients with RA

182 patients with RA vs controls

Baseline HLA DRB1 phenotypesRA Disease Activity (erosions, ESR, and CRP)

29 (21%) CV event

ESR

CRP

HLA DRB1 *0404

Gonzalez-Gay MA, et al. Arthritis Rheum. 2007;57:125-132.

Impact of RA Disease Duration

• CVD risk is present in early RA – More likely to be hospitalized for acute MI

(OR 3.17, CI 1.16-8.68) More likely to experience unrecognized MI

(OR 5.86,1.29-26.64)• CVD risk in established RA

– Experience unrecognized MI (HR 2.13) and sudden deaths (HR 1.94)

Maradit-Kremers H, et al. Arthritis Rheum. 2005;52:402-411.Chung CP, et al. Arthritis Rheum. 2005;52:3045–3053.

NSAIDs

• NSAIDs are commonly prescribed for pain relief in patients with arthritis despite the known toxicity

• Blackbox warnings exist on both prescription and OTC NSAIDs regarding the potential cardiovascular and gastrointestinal adverse effects associated with its use

• In 2007, the FDA issued an advisory that low-dose aspirin may interact with ibuprofen

• It is unclear whether selective COX inhibitors are equivalent or safer than nonselective NSAIDs

PRECISION Trial

• First of its kind, prospective randomized clinical trial comparing the cardiovascular safety of celecoxib, ibuprofen, and naproxen

• Approximately 20,000 patients will be enrolled and followed for up to 3 years assessing for cardiovascular events, as well as typical arthritis outcomes

Becker MC, et al. Am Heart J. 2009;157(4):606-612.

Balancing Benefit and Risks of NSAIDs

• Little data exists to specifically compare the efficacy and safety of pain pharmacotherapies for patients with rheumatoid arthritis

• Given the current uncertainty, NSAIDs should be used with caution in patients with rheumatoid arthritis while highlighting the added need for extra vigilance in patients with established cardiovascular disease or risk factors for its development

Peters MJL, et al. Ann Rheum Dis. 2010;69:325-331.

Aspirin as Cardioprotection

• Aspirin use in secondary prevention has been well established, however the use in primary prevention (without prior cardiovascular disease) is less clear

• Regarding primary prevention, the risk of bleeding from chronic aspirin use may or may not outweigh the cardioprotectionbenefit and treatment decision must be individualized

• Low-dose aspirin (e.g., 81 mg) is as beneficial as standard doses (e.g., 325 mg). In addition, low-dose aspirin may confer less gastrointestinal bleeding risk. However, the overall risk of GI bleeding is still twice as high as in patient withoutaspirin therapy

Park K and Bavry AA. Clev Clin J Med. 2013;80(5):318-326.Campbell CL, et al. JAMA. 2007;297(18):2018-2024.

Novel Studies to Assess CVD Earlier

• Role of HDL (dysfunctional HDL)• Cardiovascular imaging • Role of CRP in RA

HDLAnti-oxidant-inhibit LDL oxidation

Anti-inflammatory-reduce leukocyte recruitment-promote leukocyte exit

Anti-thrombotic-antagonize platelet aggregation-inhibit adhesion molecules

Reverse cholesterol transport-promote cholesterol efflux

Modulate endothelial function-stimulate endothelial cell progenitor cells-produce NO

Protective Mechanisms of HDL: Function Not Level

Assmann G and Grotto AM. Circulation. 2004; 109:III-8-III-14.

Measuring Subclinical Disease

Screening for Risk Factors

• High HDL• Low LDL• High BP• Diabetes• Smoking• CRP• Metabolic Syndrome• Lp(a)• Numerous others

Screening with Structure/Function Tests

• Carotid IMT and plaque (by US)• Aortic and carotid plaque (by MRI)• Coronary calcium score (by CT)• Ankle-Brachial Index• Brachial Vasoreactivity (by US)• Vascular compliance

(by radial tonometry)• Microvascular reactivity (by

fingertip tonometry)

Naghavi M. Herz. 2007 ;32(5):356-361.

Value of CRP Measurements in Patients with RA?

• Systemic markers of inflammation (hs-CRP) predicts cardiovascular events in men and women with or without a history of heart disease

• RA synovium and atherosclerotic plaque share many similar cytokines and cells

• Inflammation plays a major role in heart attack and stroke

• JUPITER Trial

Ross R. N Eng J Med. 1999;340(2):115-126.

What is the Cardiovascular Inflammation Reduction Trial (CIRT)?

• RCT sponsored by the U.S. National Heart Lung and Blood Institute– Directly test whether methotrexate (10 to 20 mg per

week) can reduce the risk of heart attack, stroke, and cardiovascular death in patients who have suffered a prior heart attack

• While inflammation is as important as cholesterol and high blood pressure, no clinical trial has tested whether reducing inflammation can reduce rates of these life-threatening disorders

Clinicaltrials.gov Identifier: NCT01594333

Clinical Implication

• RA may serve as a unique model to study the impact of chronic inflammatory burden on premature atherosclerosis

• The potential of inflammatory modulation in RA may provide insights to halting atherosclerosis in inflammatory arthritis as well as the general population

Sattar N, et al. Circulation. 2003;108:2957-2963.

Summary

• Robust studies support patients with inflammatory arthritis have an increased risk of CVD and early morbidity

• Traditional CV risk assessment are inadequate in RA• RA specific prediction tools for cardiovascular risk is

needed• Consensus needed on ideal subclinical measure for CVD

in RA • Further clinical trials to define the impact of

immunomodulatory therapies and “tight control” of RA disease on cardiovascular outcomes

RA and CVD: ACR 2010 Highlights l January 2011 l 69

Assessing the Impact of RA Treatments on CVD Risk

Jeffrey R. Curtis, MD, MS, MPHDirector, UAB Arthritis Clinical Intervention Program (ACIP)

Co-Director, UAB Center for Education and Research on Therapeutics (CERTs) of Musculoskeletal DisordersDivision of Clinical Immunology and Rheumatology

University of Alabama at BirminghamBirmingham, AL

Overview

• Effect of biologics on CVD events• Effect of RA-related drugs on lipids in

rheumatoid arthritis• Issues related to screening for CVD

risk factors• Evidence gaps and the future

Systematic Review and Meta-analysis:Anti-TNFα and CV Events in RA

Adapted from: Barnabe C, et al. Arthritis Care Res. 2011;63(4):522-529.

• Meta-analysis of 3 randomized controlled trials (2126 patients) also produced a point estimate indicating lower risk of cardiovascular events, but this was not statistically significant (pooled RR 0.85; 95% CI 0.28, 2.59)

• Across 8 cohort studies (80,644 patients) anti-TNFα therapy is associated with a reduced risk for:

– All CV events (pooled adjusted RR 0.46; 95% CI 0.28, 0.77)– MI (pooled adjusted RR 0.81; 95% CI 0.68, 0.96)– CVA (pooled adjusted RR 0.69; 95% CI 0.53, 0.89)

Emery (ETN vs. MTX)

St. Clair (INF vs. MTX)

Van De Putte(ADA vs. placebo [previous DMARD])Overall (t-squared = 0.0%, P = 0.898)

0.98(0.14, 6.99) 32.30

0.97(0.19, 5.03) 46.17

0.51(0.05, 5.69) 21.53

0.83(0.28, 2.59) 100.00

.046 21.8

Relative risk of CV events in patients with RA receiving anti-TNFα in RCT of a duration of ≥26 weeks

CORRONA: TNF Antagonist Use and CVD Risk:Adjusted Risk of Composite* CV Events by

DMARD and Steroid Exposure

Greenberg JD, et al. Ann Rheum Dis. 2011;70(4):576-582.

TNF antagonist use was associated with a reduced risk of composite cardiovascular events, while prednisone use was associated with a dose-dependent increased risk (P=0.04 for trend).

Exposure periods (N) HR 95% CI

TNF antagonists 4585 0.39 0.19 to 0.82MTX 4791 0.94 0.49 to 1.80Other non-biologic DMARDs 1724 Referent —Prednisone

None 6689 Referent —<7.5 mg daily 3141 1.78 1.06 to 2.96≥7.5 mg daily 1090 2.62 1.29 to 5.31

*Composite includes MI, transient ischemic attack/stroke, and cardiovascular-related deaths.

Risk of MI in Patients Treated with TNF Compared to New DMARD Users*

*Both TNF and DMARD users had ‘failed’ MTXSolomon DH, et al. Am J Med. 2013;126(8):730.e9-730.e17

Outcomes HR (95% CI)

Primary outcomeComposite CV outcome

First exposure carried forward 0.80 (0.62 – 1.04)

As treated 0.71 (0.52 – 0.97)

Secondary outcomeMyocardial Infarction

First exposure carried forward 0.78 (0.49 – 1.24)

As treated 0.65 (0.38 – 1.13)

StrokeFirst exposure carried forward 0.93 (0.61 – 1.41)

As treated 0.84 (0.52 – 1.36)

RevascularizationFirst exposure carried forward 0.72 (0.49 – 1.06)

As treated 0.74 (0.46 – 1.19)

TNF-α Antagonists and CVD

• N = 8659 starting a TNF-α and 2170 continuing a non-biological (nb) DMARD• Only patients with DAS >5.1 qualify for TNFα in UK (mean 6.6); nb DMARD

must have had a DAS >4.1 (mean 5.0)• MI diagnosed based on rheumatologist report, patient report, and UK General

Register Office; medical records sought• Adjusted for age, sex, BMI, DAS28, tobacco use, comorbidities, statins,

NSAIDs, social deprivationDixon WG, et al. Arthritis Rheum. 2007;56:2905-2912.

All Patients

DMARD(n=2,170)

Anti-TNFα(n=8,659)

Person-years 2,893 13,233Number of reported MIs 17 63Rate of MIs per 1000 person-years (95% CI) 5.9 (3.4–9.4) 4.8 (3.7–6.1)Incidence rate ratio Referent 0.81 (0.47–1.38)Incidence rate ratio, adjusted for age and sex Referent 1.13 (0.65–1.96)Incidence rate ratio, multivariate analysis Referent 1.44 (0.56–3.67)

TNF-α Antagonists and CVDAmong TNF-α Responders

• Among TNF-α users, response examined every 6 months (data missing on some)• Response at 6 months defined as reduction in DAS28 >1.2 or of >0.6 plus

DAS28 ≤5.2

Dixon WG, et al. Arthritis Rheum. 2007;56:2905-2912.

Non-responders (n=1,638)

Responders(n=5,877)

Person-years 1815 9886

Number of reported MI’s 17 35

Rate of MI’s per 1000 person-years(95% CI) 9.4 (5.5 -15.0) 3.5 (2.5 - 4.9)

Incidence rate ratio Referent 0.38 (0.21 - 0.67)

Incidence rate ratio, adjusted for age and sex Referent 0.38 (0.22 - 0.68)

Incidence rate ratio, multivariate analysis Referent 0.36 (0.19 - 0.69)

Overview

• Effect of biologics on CVD events• Effect of RA and RA-related drugs on lipids

in rheumatoid arthritis• Issues related to screening for CVD risk

factors• Evidence gaps and the future

Trends in Lipid Levels in Patients With or Without RA

• Lipid levels vary over time after RA diagnosis relative to patients without RA:– Total cholesterol decreases– LDL decreases– HDL slightly increases– Triglycerides remain relatively unchanged

Myasoedova E, et al. Ann Rheum Dis. 2010;69(7):1310-1314.

Is There a “Lipid Paradox”in RA or Not??

LDL and MI Risk

• LDL between 100-150 mg/dL, HR approximates 1

• Patients with lower LDL levels and LDL levels >160 mg/dLhad higher CVD risK

HDL and MI Risk

• HDL levels were protective against MI

• The greater the HDL level, the lower the MI risk

Myasoedova E, et al. Ann Rheum Dis. 2011;70(3):482-487.Zhang J, et al. Annals Rheum Disease. Epub ahead of print.

Does LDL mean the same thing in RA and is there really a “lipid paradox”?

Increase in Total Cholesterol Associated with Anti-TNF Therapy

28.0

1.4

7.2 5.8

0.7 0.4

9.0

13.0

20.0

6.7 6.02.5 3.6

0.0

5.0

10.0

15.0

20.0

25.0

30.0

1 2 3 4 5 6 7 8 9 10 11 12 13

Cha

nge

from

Bas

elin

e (m

g/dL

) Infliximab* Adalimumab

n = 80n = 45n = 97

n = 10n = 52

n = 32

n = 55

n = 19

n = 56

n = 69n = 33

n = 50n = 8

*Two additional studies with total n of 35 had a mean change in total cholesterol of –5.4 (Popa C, et al. Ann Rheum Dis. 2005;64(2):303-305; and –2.–3 mg/dL (Pérez-Galán MJ, et al. Med Clin (Barc). 2006;126(19):757 [Spanish]).

Study

Adapted from: Pollono EN, et al. Clin Rheumatol. 2010;29(9):947-955. Navarro-Millán I, et al. Arthritis Rheum. 2013; 65(6):1430-1438.

Changes in Lipids Associatedwith Tocilizumab* (IL-6 Receptor Antagonist)

5

20

4

25

3

13

0

5

10

15

20

25

30

Tocilizumab 8 mg/kg (n = 288)Tocilizumab 8 mg/kg + DMARD (n = 1582)

Tocilizumab 4 mg/kg + MTX (n = 774)

HDL (mg/dL)

LDL (mg/dL)

Mea

n C

hang

e Fr

om B

asel

ine

in 6

-Mon

th C

ontr

olle

d Pe

riod

* Tocilizumab [package insert]. South San Francisco, CA: Genentech, Inc; 2013.

Tofacitinib*: LDL and Total Cholesterol

0

20

40

60

80

100

120

140

160

180

200

PBO TFA 5 mg TFA 10mg

ADA 40mg

Baseline

3 months

12 months

mg/

dL

LDL

0

50

100

150

200

250

300

PBO TFA 5 mg TFA 10 mg ADA 40 mg

Baseline

3 months

12 months

mg/

dl

Total Cholesterol

TFA = tofacitinib, ADA = adalimumab* Tofacitinib [package insert]. New York, NY: Pfizer, Inc; 2014.

Effect of HCQ on Lipids and Insulin Sensitivity

Solomon DH. Arthritis Care & Research. 2014;66(8):1246-1251.

Means and standard deviations for measures of insulin, glucose metabolism, and lipid parameters

Baseline PlaceboPeriod Value

ChangeDuring

Placebo

HCQ Period Value

Change DuringHCQa

P Unadjustedb

P,Adjustedc

ISI 7.7 ± 4.8 7.8 ± 4.0 0.14 ± 3.1 8.1 ± 4.5 0.4 ± 2.9 0.930 0.785

HOMA-IR 2.0 ± 1.7 1.6 ± 0.79 -0.42 ± 1.4 1.7 ± 1.0 -0.3 ± 1.5 0.575 0.308

HOMA-B 116.5 ± 100.4 109.7 ± 82.6 -6.8 ± 78.0 110.8 ± 81.6 -5.8 ± 72.9 0.468 0.902

TC, mg/dL 192.4 ± 37.5 189.4 ± 37.9 -3.0 ± 22.4 179.7 ± 44.3 -12.7 ± 20.0 0.004 0.004

LDL, mg/dL 114.1 ± 29.8 109.9 ± 33.1 -4.2 ± 17.7 101.7 ± 36.7 -12.4 ± 20.1 0.009 0.011

HDL, mg/dL 58.1 ±17.9 60.3 ± 17.8 2.2 ± 9.8 59.4 ± 18.2 1.3 ± 6.7 0.730 0.208

TGs, mg/dL 100.6 ± 44.0 95.6 ± 44.9 -5.0 ± 20.1 92.4 ± 41.7 -8.2 ± 45.0 0.487 0.884

ISI: Insulin Sensitivity Index, HOMA-IR: Homeostasis Model Assessment-Insulin Resistance, HOMA-B: Homeostasis Model Assessment- Beta Cell Function, HCQ: Hydroxychloroquine, TC: Total Cholesterol, LDL: Low Density Lipoprotein, HDL: High Density Lipoprotein, TG: TriglyceridesaChange calculated from baseline value under the assumption of no carryover effectbFor the difference between the change during HCQ vs. placebo using Wilcoxon’s signed rank tests.cFor the difference between the change during HCQ vs. placebo from linear regression model adjusting for weight change.

Aggressive DMARD Therapy + Glucocorticoids and Hyperlipidemia

• Both treatment groups (sulfasalazine vs. combination therapy) showed strong increases from low baseline levels– By Week 16, HDL increase was more profound in the

combination group Difference still apparent at Week 28

• In established RA, disease activity is associated with an atherogenic lipid profile– Especially apparent in early RA– Dyslipidemia can be quickly reversed with aggressive

antirheumatic agents

Boers M. Ann Rheum Dis. 2003;62:842-845.

Other CVD Biomarkers

• Lipid particle size• Oxidation status• Other factors

– Paraoxonase– Apo B– Lipoprotein A

• Coronary calcium score

• On treatment or pre-treatment?• What is the clinical importance of these?

Management of Hyperlipidemia

Problems with the Old Paradigm

• Treat-to-target– Current clinical trial data do not indicate what the target

should be– Unknown magnitude of additional ASCVD risk reduction

achieved with one target lower than another– Does not take into account potential adverse effects from

multi-drug therapy needed to achieve a specific goal• Lowest is best — does not consider the potential

adverse effects of multi-drug therapy with an unknown magnitude of ASCVD event reduction

2013 ACC/AHA Blood Cholesterol Guidelines: Treat Level of Risk

• RA patients should be treated according the ACC/AHA guidelines

• Guidelines are available at: http://circ.ahajournals.org/content/129/25_suppl_2/S1.full.pdf

Stone NJ, et al. Circulation. 2014;129:S1-S45.

High- Moderate- and Low-Intensity Statin Therapy - ACC/AHA Guidelines

Stone NJ, et al. Circulation. 2014;129:S1-S45.

As used in the RCTs reviewed by the Expert Panel*

*Individual responses to statin therapy varied in the random controlled trials and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response.†Evidence from 1 random controlled trial only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47).‡Although simvastatin 80 mg was evaluated in random controlled trials, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

High Intensity Statin Therapy

Moderate-Intensity Statin Therapy

Low-Intensity Statin Therapy

Daily dose lowers LDL-C on average, by ~ ≥50%

Daily dose lowers LDL-C on average, by ~ 30 to <50%

Daily dose lowers LDL-C on average, by <30%

Atorvastatin (40†)-80 mgRosuvastatin 20 (40) mg

Atorvastatin 10 (20) mgRosuvastatin (5) 10 mgSimvastatin 20-40 mg‡Pravastatin 40 (80) mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg BIDPitavastatin 2-4 mg

Simvastatin 10 mgPravastatin 10-20 mgLovastatin 20 mgFluvastatin 20-40 mgPitavastatin 1 mg

ASCVD prevention benefit of statin therapy may be less clear in other groupsIn selected individuals, consider additional factors influencing ASCVD risk and potential ASCVD risk benefits and adverse effects, drug-drug interactions, and patient preferences for statin treatment.

ASCVD prevention benefit of statin therapy may be less clear in other groupsIn selected individuals, consider additional factors influencing ASCVD risk and potential ASCVD risk benefits and adverse effects, drug-drug interactions, and patient preferences for statin treatment.

Moderate-to-high intensity statin

Moderate-to-high intensity statin

Moderate-intensity statin

Moderate-intensity statin

Estimated 10-y ASCVD risk ≥7.5%

High-intensity statin

Estimated 10-y ASCVD risk ≥7.5%

High-intensity statin Estimate 10-yr ASCVD Risk with Pooled Cohort Equations Estimate 10-yr ASCVD Risk with Pooled Cohort Equations

Di b t

years

DiabetesType 1 or 2

Age 40 to 75 years

≥7.5% estimated 10-yr ASCVD risk

and age 40 to 75 years

No

No

Yes

Yes

No

LDL–C ≥190 mg/dL Treat Level of Risk (cont.)

Adapted from: Stone NJ, et al. Circulation. 2014;129:S1-S45.

Summary

• A number of RA medications, especially TNF inhibitors, appear to reduce risk for CVD events

• Many RA medications affect lipids, mostly in numerically unfavorable ways– Clinical importance of these changes not clear– Likely more to the story than simply the ‘numbers’

• New CVD risk assessment and management tools and guidelines available for hyperlipidemia

• Management of CVD risk factors often suboptimal in RA despite greater CVD risk in these patients

Jonathan Kay, MDDirector of Clinical Research, Rheumatology

Professor of Medicine University of Massachusetts Medical School

Worcester, MA

Comparing Safety & Efficacy Data for Currently

Approved Therapies

Comparative Effectiveness

• “Comparing treatment options for different health conditions”– “Provides comparisons of drugs, medical devices, tests,

surgeries, or ways to deliver health care so that patients and their families understand what treatments work best and how their risks compare.”

– “Improve[s] health care quality by providing patients and physicians with state-of-the-science information on which medical treatments work best for a given condition.”

Comparative Effectiveness: Comparing treatment options for different health conditions. October 2012. Agency for Healthcare Research and Quality, Rockville, MD.http://www.ahrq.gov/cpi/portfolios/comparative-effectiveness/index.html

Need for ComparativeEffectiveness Studies

“Evidence from indirect comparisons across trials is weaker than evidence from direct randomized head-to-head trials. Results of placebo-only trials do not answer many clinicians’ and patients’ questions about the comparative benefits and harms of treatment, and therefore head-to-head trials are needed to determine the real comparative risk/benefit profiles of different treatments.”

Estellat C, et al. Arch Intern Med. 2012;172(3):237-244.

Comparative Effectiveness Studies of Biologics in RA

• Analyses of prospective, observational cohort studies comparing response to switching from TNF inhibitor (TNFi) to biological agent with alternative mechanism or to alternative TNFi in RA patients who had been treated with ≥1 TNFi– Finckh et al., SWITCH-RA, CORRONA

• Randomized, double-blind, clinical trial comparing efficacy of abatacept & infliximab indirectly, by comparing each to placebo in parallel, and safety of each directly in RA patients inadequately responsive to MTX – ATTEST

• Head-to-head studies of biologic agents in RA– AMPLE, ADACTA

Finckh A, et al. Arthritis Rheum. 2007;56:1417-1423; Emery P, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203993; HarroldLR, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203936; Schiff M, et al. Ann Rheum Dis. 2008; 67:1096-1103; Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38; Schiff M, et al. Ann Rheum Dis. 2013;doi: 10.1136/annrheumdis-2013-203843; Gabay C, et al. Lancet.2013;281:1541-1550; Kavanaugh A, et al. 2012 ACR Annual Meeting, Abstract 772.

Switching from TNF Inhibitor to Rituximab or Alternative TNF Inhibitor

• First study comparing effectiveness of 2 therapeutic strategies in RA patients inadequately responsive to ≥1 TNF inhibitor

• Prospective, observational longitudinal cohort study of 116 patients with RA enrolled in Swiss Clinical Quality Management Program for RA (SCOM-RA) inadequately responsive to 1 TNF inhibitor– 50 (43%) received rituximab 1000 mg i.v. 2 + i.v. glucocorticoids– 66 (57%) received a 2nd or 3rd TNF inhibitor

49% treated with adalimumab 40 mg s.c. every other week 27% treated with etanercept 50 mg s.c. weekly 24% treated with infliximab IV (starting at 3 mg/kg)

• Treatment decisions made by the treating physician (not randomized)

Finckh A, et al. Arthritis Rheum. 2007;56:1417-1423.


• Greater improvement in DAS 28, TJC, & ESR at 6 months with rituximab, than with an alternative TNF inhibitor

• Over 9 months, there was a significant decrease in:– RA disease activity– Number of tender joints– ESR– Number of swollen joints (not significant)

• Results favored rituximab



• Conclusion– RTX may be more effective than switching to an alternative TNF inhibitor

for patients with RA who experienced an inadequate response to ≥1TNF inhibitor

• Limitations– Non-randomized assignment of treatment with RTX vs. an alternative

TNF inhibitor Could result in selection bias or confounding by indication

– Patients receiving RTX had experienced an inadequate response to significantly more TNF inhibitors than patients receiving an alternative TNF inhibitor May have had more aggressive disease, which would tend to bias results

toward the null hypothesis


Switching from TNF Inhibitor to Rituximab or Alternative TNF Inhibitor:

Structural Progression & Functional Disability

• Conclusions– No significant differences in rates of erosion progression between patients

taking an alternative TNF inhibitor and patients taking RTX– Longitudinal evolution of functional disability was statistically significantly

better in RTX group, compared to alternative TNF inhibitor group (P=0.015) Mean difference of 0.09 HAQ-DI units was far less than minimally clinically

important difference, estimated to be at least 0.22 HAQ-DI units

• Limitations– Selection bias may arise because of non-random assignment to therapy– Difficult to determine whether RTX & TNF inhibitors were used optimally– Did not assess the relative benefit of RTX & TNF inhibitors on joint space

narrowing or cartilage degradation

Finckh A, et al. Ann Rheum Dis. 2012;71:1680-1685.

SWITCH-RA: Rituximab vs. Alternative TNF Inhibitor

• Prospective, multicenter, observational cohort study to evaluate in routine clinical practice the relative effectiveness of RTX vs. a 2nd TNF inhibitor following an inadequate response to a single previous TNF inhibitor

• Primary endpoint: 6-month change from baseline in DAS28-3-ESR

Emery P, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203993.

SWITCH-RA: Rituximab vs. Alternative TNF inhibitor

Emery P, et al. Ann Rheum Dis. 2014 doi:10.1136/annrheumdis-2013-203993.

Patients with an inadequate response to a single previous TNF

inhibitor

Baseline(n=728)

Seropositive(n=559)

Rituximab(n = 331)

Alternative TNF inhibitor (n = 228)

Seronegative(n = 169)

Rituximab(n = 74)

Alternative TNF inhibitor (n = 95)

Baseline DAS28-3-ESR Scores,at Time of Switch (mean SD) Rituximab Alternative TNF

inhibitor P

Seropositive* patients 5.2 1.2 4.8 1.3 <0.0001

Seronegative patients 5.3 1.1 4.7 1.3 0.0019

*RF+ and/or ACPA+

SWITCH-RA: Mean Change in DAS28-3-ESR from Baseline to 6 Months

• There was greater improvement in the overall population with the DAS28-3-ESR– Improvement was greater in the rituximab

group vs. the alternative TNF inhibitor This was observed in patients who stopped the TNF

inhibitor because of inefficacy, not intolerance

Emery P, et al. Ann Rheum Dis. 2014 doi:10.1136/annrheumdis-2013-203993.Analyses were adjusted for baseline value and other covariates found to be statistically significantly different between the twogroups at baseline. Values are DAS28-3-ESR least squares means.

SWITCH-RA: Rituximab vs. Alternative TNF Inhibitor Changes in DAS28-3-ESR at 6 months

Seropositive patients* (n=559) Seronegative patients† (n=169)

LS mean (SE) Rituximab TNF Inhibitor P-value Rituximab TNF Inhibitor P-value

All patients -1.6 (0.3) -1.2 (0.3) 0.011 -1.3 (0.4) -1.1 (0.4) 0.449

Inefficacy -1.9 (0.3) -1.5 (0.4) 0.021 -0.5 (0.6) -0.2 (0.7) 0.472

Intolerance -0.5 (0.5) -0.5 (0.5) 0.997 -2.1 (1.2) -1.9 (1.3) 0.815

Emery P, et al. Ann Rheum Dis. 2014 doi:10.1136/annrheumdis-2013-203993.

*Seropositive patient numbers (all/inefficacy/intolerance): rituximab = 331/253/74; TNF inhibitor = 228/171/51.†Seronegative patient numbers (all/inefficacy/intolerance): rituximab = 74/58/15; TNF inhibitor = 95/65/28.

• Following discontinuation of initial TNF inhibitor, seropositive patients with RA who switched to rituximab achieved significantly improved effectiveness over 6 months, in particular those interrupting therapy due to inefficacy, compared with patients switching to a 2nd TNF inhibitor

– These differences were not evident in seronegative patients

SWITCH-RA: Rituximab vs. Alternative TNF Inhibitor

• Conclusions– Patients inadequately responsive to an initial TNF inhibitor achieve

significantly better clinical responses over 6 months if they receive rituximab rather than an alternative TNF inhibitor

– Difference was particularly evident in Seropositive patients Patients switched because of inefficacy

• Limitations– Substantial missing data - many patients with a missing baseline (due to

enrollment of patients up to 4 weeks after starting the 2nd biological therapy)

– Number and timing of study visits were left to discretion of investigators– Anti-drug antibodies were not measured– Lower numbers of seronegative patients limited assessment of relative

effectiveness of rituximab and TNF inhibitor therapy in this subgroup Emery P, et al. Ann Rheum Dis. 2014 doi:10.1136/annrheumdis-2013-203993.

CORRONA: Switching from TNF Inhibitor to Abatacept or Alternative TNF Inhibitor

• Conclusion– Patients with RA exposed previously to a TNF inhibitor had similar

outcomes if they switched to another TNF inhibitor as compared to initiation of abatacept

• Limitations– Retrospective analysis of observational cohort – despite propensity

score matching, there may be residual confounding for unmeasured covariates

– Timing of study visits was based upon clinic visits and not mandated -influenced which patients were included, based on follow-up visits

– Acute phase reactant data were not available for all patients in study– Most of patients were white - limits generalizability to other racial

groups

Harrold LR, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203936.

ATTEST: Abatacept or Infliximabvs. Placebo

Schiff M, et al. Ann Rheum Dis. 2008;67:1096-1103.

Randomized, double blind, double-dummy, 12-month global trial.

Day 198

Treated (n=431)

Abatacept + MTX (n=156)

Placebo + MTX (n=110)

Infliximab + MTX (n=110)

Day 1 Day 197 Day 365

Screening & DMARD washout period (≥28 days)

excluding MTX

Randomization• Abatacept ~ 10 mg/kg• Infliximab ~ 3 mg/kg

Primary EndpointSecondary Endpoint• DAS28 reduction

AdditionalSecondary Endpoints

• Placebo reallocated to abatacept• Dose modification allowed for

MTX and concomitant medications

ATTEST: Abatacept or Infliximab vs. PlaceboACR Responses Over 1 Year

• ACR 20, 50, and 70 for the two treatments were similar at 6 months and 1 year– Patients had very similar responses to the two

treatments


ATTEST: Abatacept or Infliximab vs. PlaceboSafety Summary

Days 1–197 Days 1–365

Abatacept + MTX (n = 156)

Placebo + MTX (n = 110)

Infliximab + MTX (n = 165)

Abatacept + MTX (n = 156)

Infliximab + MTX (n = 165)

n (%)* n (%)* n (%)* n (%)* n (%)*

Deaths 1 (0.6) 0 1 (0.6) 1 (0.6) 2 (1.2)

SAEs 8 (5.1) 13 (11.8) 19 (11.5) 15 (9.6) 30 (18.2)

Related SAEs 3 (1.9) 3 (2.7) 8 (4.8) 5 (3.2) 14 (8.5)

Discontinuations due to SAEs 2 (1.3) 0 4 (2.4) 4 (2.6) 6 (3.6)

AEs 129 (82.7) 92 (83.6) 140 (84.8) 139 (89.1) 154 (93.3)

Related AEs 64 (41.0) 46 (41.8) 74 (44.8) 72 (46.2) 96 (58.2)

Discontinuations due to AEs 3 (1.9) 1 (0.9) 8 (4.8) 5 (3.2) 12 (7.3)

Serious infections 2 (1.3) 3 (2.7) 7 (4.2) 3 (1.9) 14 (8.5)

Autoimmune symptoms and disorders 1 (0.6) 1 (0.9) 1 (0.6) 2 (1.3) 1 (0.6)

Malignant neoplasms 1 (0.6) 1 (0.9) 2 (1.2) 1 (0.6) 2 (1.2)


* ≥1 AE or SAE could be reported in each patient; percentages represent the proportion of patients who reported ≥1 event.

ATTEST: Abatacept or Infliximabvs. Placebo

• Conclusions– Abatacept & infliximab (3 mg/kg every 8 weeks)

demonstrated similar efficacy– Over 1 year, fewer SAEs, AEs, infections, and

discontinuations due to AEs or SAEs were observed with abatacept than with infliximab

• Limitations– Abatacept & infliximab were not compared directly– Abatacept was dosed as in clinical practice, but optimal

doses of infliximab may not have been used


Head-to-Head Studies of Biologic Agents in RA

Study Name Reference Regimen

AMPLE

Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38 &

Schiff M, et al. Ann Rheum Dis. 2013; doi:10.1136/annrheumdis-2013-203843

Abatacept + MTX vs.adalimumab + MTX

ADACTA

Gabay C, et al. Lancet. 2013;281:1541-1550 &

Kavanaugh A, et al. 2012 ACR Annual Meeting, Abstract 772

Tocilizumab vs. adalimumabmonotherapy

AMPLE: Abatacept vs. Adalimumab

Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38.

Noninferiority trial design (12% NI margin)Inclusion CriteriaRA ≤5 yearsMTX-IRBiologic naïveDAS28(CRP) > 3.2 + ↑ESR + ↑CRP

Abatacept 125 mg SC Weekly (n=318)

Concomitant MTX

Adalimumab 40 mg SC biweekly (n=328)

RandomizationDay 3651o Endpoint:• ACR20 (NI=12%)2o Endpoints:• Radiographic inhibition: TTS• Safety• Injection-site reactions

(prespecified)• Retention

Day 7292o Endpoints

No IV abataceptloading dose was

utilized

N=646

Screening

AMPLE: Abatacept is Noninferior to Adalimumab ACR20 Response At 1 Year

Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38.

• Efficacy rates of both were almost superimposable

• Estimate of difference (95% CI) between groups was 1.8% (-5.6, 9.2)– Intent-to-treat, confirmed with per protocol

population

AMPLE: Comparable Efficacy & Kinetics of Response: ACR Scores Over 2 Years

• ACR 20-90 results for both drugs were nearly superimposable at every time period measured

• Efficacy similar despite differing mechanism of action– Is this measure sensitive enough to detect a

difference between two drugs? ACR measures were developed to compare active drug

to placebo, not to assess comparative effectiveness

Schiff M, et al. Ann Rheum Dis. 2014 Jan;73(1):86-94.

AMPLE: Comparable Efficacy & Kinetics of Response: Mean DAS28 (CRP)

• Change in mean DAS28 (CRP) over time and at 1 year was also nearly identical between treatment groups


DAS28 at Year 1 Abatacept AdalimumabLDAS ( 3.2) 59.3% 61.4%

Remission (<2.6) 43.3% 41.9%

AMPLE: Comparable Efficacy & Kinetics of Response: Physical Function Over 2 Years

• Increases in physical function were also identical between the 2 groups


AMPLE: Similar Inhibition of Radiographic Progression Over 2 Years

• The vast majority of patients in the study had no change in structural damage– Very few patients had structural improvement

and some saw deterioration• Rates were identical between study groups


AMPLE: Abatacept vs. Adalimumab

• Conclusions– In combination with MTX, efficacy of SC abatacept is

comparable to that of SC adalimumab (by noninferiorityanalysis) in RA

– Safety was generally similar Fewer discontinuations with abatacept Significantly more local injection site reactions with adalimumab

• Limitations– Patients were not blinded as to treatment allocation

Clinical assessors were blinded to each patient’s treatment– A higher dose of adalimumab (40 mg SC weekly) is

sometimes used in clinical practice, but was not included in this trial

Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38.Schiff M, et al. Ann Rheum Dis. 2014 Jan;73(1):86-94.

ADACTA: Tocilizumab vs. Adalimumab

• First trial specifically designed to determine superiority of one approved biologic vs. another as monotherapy for RA

• Phase 4 randomized, double-blind, 24-week study in patients with RA– ≥6-month duration– DAS28 >5.1 – MTX intolerant or for whom continued

treatment with MTX was considered ineffective or inappropriate

Gabay C, et al. Lancet. 2013;281:1541-1550; Kavanaugh A, et al. 2012 ACR Annual Meeting, Abstract 772

ADACTA: Tocilizumab vs. Adalimumab


Superiority trial design

• Criteria for escape: <20% improvement from baseline in SJC & TJC at week 16 or later

• Escape therapy: weekly SC (adalimumab/placebo) injections; study medication remained blinded

Treated(N=325)

Tocilizumab 8 mg/kg IV q 4 wks + SC placebo q 2 wks

1:1 Randomization Week 16+:Escape

Week 24: Primary Endpoint:Change in DAS

Adalimumab 40 mg SC q 2 wk + IV placebo q 4 wk

8-wk safety follow-upRandomized Drug Treatment

Gabay C, et al. Lancet. 2013;281:1541-50.

ADACTA: Mean DAS28 over Time

• By week 24 there is a lower mean DAS28 with tocilizumab 8 mg/kg than adalimumabmonotherapy (P<0.0001)

ADACTA: Safety

• Similar incidence between groups of:– AEs: tocilizumab: 82.1%; adalimumab: 82.7%– SAEs: tocilizumab: 11.7%; adalimumab: 9.9%– Serious infections: tocilizumab: 3.1%; adalimumab: 3.1%

• Laboratory abnormalities occurred in both arms, but were more common with TCZ– hepatic transaminases– LDL– neutrophil counts

• Two deaths occurred, both in the tocilizumab arm: – Sudden death– Reported illicit drug overdose

Gabay C, et al. Lancet. 2013;281:1541-1550.

ADACTA: Conclusions

• Conclusions– Tocilizumab monotherapy was superior to adalimumab

monotherapy in reducing signs and symptoms of RA in MTX-intolerant patients or patients for whom MTX treatment was considered ineffective or inappropriate

– Overall safety profile of both tocilizumab & adalimumab was consistent with previously reported data

• Limitation– Higher tocilizumab dose (8 mg/kg IV monthly) was compared to

adalimumab monotherapy, which is less effective than adalimumab + MTX

Gabay C, et al. Lancet. 2013;281:1541-1550; Kavanaugh A, et al. 2012 ACR Annual Meeting, Abstract 772.

Comparative Effectiveness Studies of Biologics in RA: Summary

• Switching to RTX may be more effective than switching to an alternative TNF inhibitor (TNFi) for patients with RA inadequately responsive to ≥1 TNFi

• Switching to abatacept or to an alternative TNFi may be similarly effective in patients with RA who had been exposed to ≥1 TNFi

• Abatacept & infliximab (3 mg/kg every 8 weeks) demonstrated similar efficacy when compared indirectly

– Over 1 year, fewer SAEs, AEs, infections, and discontinuations due to AEs or SAEs were observed with abatacept than with infliximab

Schiff M, et al. Ann Rheum Dis. 2008;67:1096-1103

Finckh A, et al. Arthritis Rheum. 2007;56:1417-1423; Emery P, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203993

Harrold LR, et al. Ann Rheum Dis. 2014;doi:10.1136/annrheumdis-2013-203936

Comparative Effectiveness Studies of Biologics in RA: Summary

• Head-to-head study of SC abatacept + MTX vs. SC adalimumab + MTX in patients with RA inadequately responsive to MTX – Comparable efficacy by noninferiority analysis– Generally similar safety

• Head-to-head study of tocilizumab monotherapy vs. adalimumabmonotherapy in RA patients inadequately responsive to MTX or intolerant of MTX– Tocilizumab monotherapy was superior to adalimumab monotherapy in

reducing signs and symptoms of RA – Overall safety profile of both tocilizumab & adalimumab was consistent with

previously reported data

Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38; Schiff M, et al. Ann Rheum Dis. 2013;doi:10.1136/annrheumdis-2013-203843


Implications of Data fromHead-to-Head Trials

• What is the significance of assessing different patient populations in these studies?– Patients with an inadequate response to anti-TNF

therapy– Patients with an inadequate response to MTX– Patients intolerant of MTX or where continued

treatment with MTX is considered inappropriate• How can/should current comparative effectiveness clinical

trial data guide daily clinical practice?• Do we have enough information to help clinicians choose

the most appropriate biologic therapy for individual patients with RA?

Case Presentation I

Leonard H. Calabrese, DOProfessor of Medicine

Cleveland Clinic Lerner College of MedicineRJ Fasenmyer Chair of Clinical Immunology


Case 1

• Demographics– 25-year-old woman– Asian

• Diagnoses– RA x 1 year, CCP (+)– Fibromyalgia– Mild depression (controlled)– HTN (controlled)

• Medication– Naproxen: 500 mg BID– Prednisone: 5 mg BID– HCQ: 200 mg BID– Sertraline: 50 mg QD– HCTZ: 50 mg QD

• Physical Exam– Tender joints (hands, MTPs)– Swollen joints (both wrists, left elbow)– Generalized soft tissue tenderness– 28 Joint Count: T 11, S 3– DAS-28: 5.03

• X-Ray– Non-erosive disease

• Labs– CRP: 0.9 mg/dL; ESR: 15 mm/hr– CCP: 27 IU, RF: 29 IU

CC: “I feel so drained and stiff, and I have trouble sleeping”

This patient has normal acute phase reactants, low + CCP RF RA, 11 tender and 2 or 3 swollen joints and a calculated DAS of > 5 of what

severity do YOU BELIEVE this patient has?

1. Mild2. Moderate/severe

If a patient like this was referred to your practice would you perform any additional tests to determine

treatment course at the first visit?

1. Plain films of the hands and wrist2. Ultrasound3. 14-3-3 ETA4. Multibiomarker disease activity test (MBDA)5. Other

In general, what would be your preferred initial therapy for this patient?

1. Methotrexate2. Triple DMARD3. Biologic monotherapy4. Methotrexate and a TNF inhibitor

Case 1

• Therapeutic options– Likely not early, aggressive therapy with a

biologic– Methotrexate– Triple DMARD therapy– Attention/treatment of fibromyalgia

Jonathan Kay, MDDirector of Clinical Research, Rheumatology

Professor of Medicine University of Massachusetts Medical School

Worcester, MA

Case Presentation II

Case 2

• Demographics– 55-year-old woman

• Diagnoses– Seropositive RA x 5 years

• Labs– CCP: 276 IU– RF: 124 IU– CRP: 4.8 mg/dL– ESR: 10 mm/hr

CC: “I’ve been having a lot of painful, swollen joints lately”

• Physical Exam– Swelling/tenderness in:

Multiple MTP joints Both wrists, elbows,

knees, ankles Both shoulders and MTPs

of feet (tender only)– 28 Joint Count: T 22, S 24– DAS-28 (CRP): 6.85

MPT: Metacarpophalangeal

Case 2

Current: MTX: 25 mg SC QW Adalimumab: 40 mg SC QW Prednisolone: 10 mg PO QD Alendronate: 70 mg PO QW CaCO3/Vitamin D: 1200/400 PO BID Fluoxetine: 20 mg PO QD Levothyroxine: 100 mcg PO QD

Past (Failed Trials): Methotrexate: 20 mg PO QW Infliximab: 3 mg/kg IV Q8W Infliximab: 10 mg/kg IV Q8W Etanercept: 50 mg SC QW Adalimumab: 40 mg SC QOW

Medication History

Case 2

• Analysis– Secondary non-responder to infliximab– Primary non-responder to etanercept– Currently failing her adalimumab trial despite

an increase in dosing frequency• Her high-disease activity and clinical

presentation warrants a change in therapy

What changes do you recommend tohis regimen?

1. Switch to a different anti-TNF agent2. Switch to tofacitinib3. Switch to abatacept4. Switch to tocilizumab5. Switch to rituximab

Case 2

• Two, but not 3 anti-TNF agents– Results from the GO-AFTER trial demonstrate that

non-responders to an initial anti-TNF agent may respond to a second, but not a third, TNF inhibitor

• With our patient, it is best to switch her to an agent with a different mechanism of action– Abatacept, tocilizumab, rituximab, or tofacitinib

Smolen JS, et al. Lancet. 2009;374:210-221.

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