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Key Updates in ACR and EULAR Recommendations:

Applying to Practice Leonard H. Calabrese, DO

Professor of Medicine Cleveland Clinic Lerner College of Medicine RJ Fasenmyer Chair of Clinical Immunology

Department of Rheumatic and Immunologic Diseases Cleveland, 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 RA 1987 Classification Criteria

Criteria 1. Morning stiffness (at least 1 hour) 2. Arthritis in ≥3 joint areas 3. Arthritis of hand joints (≥1 swollen joints) 4. Systemic arthritis 5. Rheumatoid nodules 6. Serum RF 7. 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 0 2-10 large joints 1 1-3 small joints 2 4-10 small joints 3 >10 joints (≥1 small joint) 5

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

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 Arthritis Singh 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 csDMARD strategies, with or without glucocorticoids, bDMARDs (TNF inhibitors, abatacept or tocilizumab, and, under certain circumstances, rituximab) should be commenced with MTX

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

• 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

EULAR Recommendations

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

• 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

EULAR Recommendations

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

Algorithm Based on the 2013 European League Against Rheumatism Recommendations on

Rheumatoid Arthritis Management

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

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

Algorithm Based on the 2013 European League Against Rheumatism Recommendations on

Rheumatoid Arthritis Management

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

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

Algorithm Based on the 2013 European League Against Rheumatism Recommendations on

Rheumatoid Arthritis Management

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

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

Treat-to-Target Algorithm

Smolen JS, et al. Ann Rheum Dis. 2010;69(4):631-637.

Pathogenesis and Underlying Immunologic Mechanisms

Leonard H. Calabrese, DO Professor of Medicine

Cleveland Clinic Lerner College of Medicine RJ Fasenmyer Chair of Clinical Immunology

Department of Rheumatic and Immunologic Diseases Cleveland, OH

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 ARTHRITIS Genetic 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 Concordance HLA-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