Update in Rheumatoid Arthritis 2012

Gwen Kane-Wanger, MD Division of Rheumatology

Beth Israel Deaconess Medical Center

Rheumatoid Arthritis Overview of lecture

1. Review of pathogenesis, natural history and diagnosis of rheumatoid arthritis

2. Current DMARD therapy 3. Biologics 4. Changing treatment strategies

Rheumatoid arthritis: epidemiology

Prevalence 1% in varied ethnic groups, 1.3 million people in the US

Female predominance

Associated with HLA-DR4 and the DR associated DR4 B chains (not in all populations)

Variable age of onset: peak age of onset 30-55

Harris, ED. Clinical features of rheumatoid arthritis..In:Kelley WN, Harris ED Jr, Ruddy S, Sledge CB (eds). Textbook of Rheumatology 6th ed. Phila: WB Saunders 2001

ACR criteria for the classification of rheumatoid arthritis

Need at least four of seven criteria for diagnosis:

1. Morning stiffness lasting at least 1 hr 2. Soft- tissue swelling or fluid in at least

3 joint areas simultaneously 3. At least one area swollen in a wrist,

MCP, or PIP joint 4. Symmetric arthritis 5. Rheumatoid nodules 6. Abnormal amounts of serum

rheumatoid factor 7. Erosions or bony decalcification on

radiographs of the hand and wrist * Criteria 1 through 4 must have been

present for at least 6 weeks.

Point system out of 10 1 .Confirmed presence of 1 or more

joints with synovitis 2. Absence of alternative diagnosis 3. Number and site of involved joints 4. Serology (RF and CCP) 5. Acute phase reactants 6. Symptom duration

1987 2010

Neogi T, Aletaha D, Sillman AJ et al. Arthritis Rheum 2010; 62:2569-2581, 2582-2591

RA Progression RA Progression

Adapted from Kirwan JR. J Rheumatol. 2001;28:881886.Adapted from Kirwan JR. J Rheumatol. 2001;28:881886.

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Duration of Disease (years)Duration of Disease (years)

55 1010 1515 2020 2525 3030

InflammationDisabilityRadiographs

InflammationDisabilityRadiographs

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Rheumatoid arthritis: morbidity and mortality

1. Joint destruction Joint erosions seen within 2 years Many patients have erosions at presentation

2. Decline in functional status 80% decline in functional status over 5 years 3. Increased work disability Disability is >7 fold increased in RA patients

compared to general population earnings 50% lower for RA patients 4. Comorbid disease increased cardiovascular disease increased risk of infection 5. Increased mortality rate severe disease associated with mortality rate

comparable to 3V CVD or Stage IV Hodgekins lymphoma

Life expectancy decreased by 5-15 years

Pincus et al, Clin Exp Rheumatol 2004;22(suppl 35):s2-s11.

Pathogenesis of Rheumatoid Arthritis

A quick review

Images courtesy of John Cush, MD.

The Clinical Spectrum of RA

ASSESSMENT OF DISEASE ACTIVITY IN RA History/Physical exam

- joint swelling and tenderness, loss of motion, deformity Functional status

-joint pain, morning stiffness, fatigue Extraarticular findings -fever, weight loss, nodules

Imaging techniques -radiographs, ultrasound, MRI

Laboratory tests -acute phase reactants, hemoglobin, RF, anti-cyclic citrullinated

peptide antibody (anti CCP) Assessing disease: early, intermediate, and long standing Mild, moderate, and severe DAS score: a measurement of disease activity that has

been used in clinical trials and can be helpful in daily clinical practice

206 patients dx with RA; cohort study 1993-1996: Treatment with analgesics then DMARD (median time to treat 123 days) 1996-1998: Treatment with DMARD (median time to treat 15 days) Conclusion: Decreased radiologic damage in early treatment group

Data from 14 randomized controlled trials of DMARD therapy 1400 patients analyzed Patients receiving treatment within 1 year of disease responded best to treatment. Patient with long term disease receiving treatment has less response.

Randomized controlled trial of 155 patients with early active RA (pre anti TNF era) 2 treatment arms 2 year trial with extension to 5 years Assess clinical and radiographic outcome 11 year data: suggestion that there is improved mortality rate in patients on combination therapy

Window of Opportunity for Treating RA

window of opportunity

Early

Established End Stage

van der Heijde DM, et al. J Rheumatol. 1995;22:17921796. ODell JR. Arthritis Rheum. 2002;46:283285. Editorial. Landewe RBM, et al. Arthritis Rheum. 2002;46:347356.

Treatment of Rheumatoid arthritis 2012 Non pharmacologic treatment Medications

Non pharmacologic treatment Education and counseling Rest Exercise, physical and occupational therapy Bone protection Immunizations Modifying cardiovascular risk factors:

Cardiovascular risk assessment should be performed yearly; risk modification according to accepted guidelines Peters MJL, et al Ann Rheum Dis. 2010; 69:325-331.

Pharmacologic therapy

Drug

Response Rate; Onset of Action

Magnitude of

Efficacy Major Toxicities Dosage

Cyclosporine 30%; 2-3 mo ++ Renal (irreversible), hypertension,

hypertrichosis, immunosuppression 2.5-5.0 mg/kg/day

Gold 30%; 3-6 mo ++ Skin rash, hematologic, renal 5.0 mg/wk I.M. x 6

mo

Hydroxychloroquine 30%-50%; 2-6 mo ++ Retinopathy, myopathy,

hyperpigmentation 200 mg b.i.d.

Leflunomide 50%; 2-3 mo ++ Liver, teratogen, gastrointestinal,

skin rash 20 mg/day

Methotrexate > 70%; 6-8 wk +++ Liver (fibrosis, elevated

enzymes), hematologic, oral ulcers 7.5-20 mg/wk

Sulfasalazine > 30%; 2-3 mo ++ Dyspepsia, hemolysis in glucose-

6-phosphate dehydrogenase deficiency 1 g b.i.d. or t.i.d.

DMARDs

Biologic Response

Modifiers

Biologics: anti TNF agents Biologic Description dosing Approval

date Half life

etanercept TNF receptor Fc fusion molecule human

50mg sc q w or 25 mg biw

1998 4 days

infliximab Chimeric murine/human monoclonal antibody

3-10mg/kg IVq 4-8 weeks

1999 8-10 days

adalimumab Humanized monoclonal antibody

40 mg sc q 2 weeks

2002 10-20 days

Efficacy of Anti-TNF Therapy Summary of Clinical Trials

Randomized controlled studies including 6000 patients

Most in comparison to methotrexate Effect on early RA and established RA (moderate

to severe disease) Outcome measures: ACR core set of disease

activity variables (20,50,70): physician and patient assessment, functional status and lab data to evaluate efficacy of therapy.

Response to anti-TNF: Early RA

ACR 70: -methotrexate monotherapy 19-28% -TNF inhibitors with methotrexate 33-48% -Significant reduction in progression of

erosions radiographically -Significant improvement of functional scores

compared to MTX monotherapy COMET, ERA,ASPIRE, Premier trials

Response to anti-TNF: Established RA

ACR 70: Methotrexate monotherapy

Long term data

1. >10 year experience with etanercept demonstrates persistent response to treatment

2. 7 years of adalimumab therapy: ACR response rates were maintained throughout

3. No increased rate of serious toxicity over time

Safety considerations with anti-TNF treatment

Administration reactions

Most common side effect, 20-37%. Rarely lead to discontinuation of drug. Decrease with time. Reactions include erythema, pruritis,

swelling, recall reactions. Infliximab associated with infusion

reaction: premedicate with steroids, antihistamines or tylenol.

Infection Up to 1/3 in clinical trials report minor infection,

same rate as placebo. RA patients are more susceptible to serious

infections; most individual trials did not show significant difference in compared to methotrexate.

Possibly, patients with comorbid disease are more susceptible to infection while on anti TNF therapy.

Post marketing studies/observational studies suggest increased risk of serious infection compared to DMARDs, occurs early in treatment; may be higher risk of upper respiratory infections, soft tissue and skin infections

Patients on anti TNF medications should not receive live vaccines.

Opportunistic infection

Cases of bacterial, fungal, parasitic, viral all reported

Mycobacterial infection most widely described in association with therapy

TB: reactivation of TB, occurs early in therapy, and is commonly disseminated

PPD testing is mandatory

Cardiovascular disease RA patients have increased risk; higher risk in

patients with more severe disease. Anti TNF agents has been associated with

worsening CHF (patients without RA) ? Anti TNF protection against cardiac disease Recent prospective study of >12,000 patients

with RA found no evidence of association between anti-TNF treatment and mortality in patients with rheumatoid arthritis

Nicola, PJ et al. Arthritis Rheum 2005;52:412-420 Jacobsson J , et al J Rheum 2005; 32: 1213-18 Peters MJL, et al Ann Rheum Dis. 2010;69:325-331 Lunt M, Watson KD, Dixon WG, Symmons DP, Hyrich KL. Arthritis Rheum. Nov 2010;62(11):3145-53.

Malignancy No increased rate of solid tumor to date

(when compared to NCI database rates). Lymphoma: increased rate in RA

patients, risk increases with severity of disease

Lymphoma rates observed in patients treated with TNF antagonists are higher than in the general population, but appear to approximate those seen in RA patients in general

Demyelination SLE-like illness

Optic neuritis, MS, transverse myelitis

Improvement with discontinuation

Very few cases reported overall; relationship not known

Avoid use in patients with history of demyelinating disease

ANA found in RA patients (20-40%)

Does not indicate disease Rare cases of SLE;

usually arthritis, rash, serositis, anti DNA antibodies

Resolves with discontinuation of therapy

Evaluating Therapeutic Strategies 2012

TICORA: Intensive vs Routine Control of Disease Activity in RA

Objective: 18-month study to determine whether closely monitored

step-up therapy with nonbiologic DMARDs would result in significantly better outcomes than routine care

Study Population: 110 patients aged 1875 years with RA of < 5 years duration and active disease

(DAS > 2.4) Outcomes:% of patients achieving a DAS score of < 2.4

% of patients achieving remission (DAS score < 1.6) Intensive Care Group: Monthly review of disease activity and measurement of DAS Structured escalation of therapy if DAS > 2.4 after 3 months of a new DMARD. Routine Care Group: Review every 3 months (with no measure of disease activity) Management at the discretion of attending rheumatologist (ie, DMARD

therapy; intra-articular, intramuscular, and/or oral corticosteroids)

TICORA = Tight Control for Rheumatoid Arthritis. Grigor C, et al. Lancet. 2004;364:263269.

TICORA: Disease Activity Scores Intensive vs Routine Therapy

TICORA = Tight Control for Rheumatoid Arthritis. Grigor C, et al. Lancet. 2004;364:263269.

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Intensive Therapy

Routine Therapy

P < 0.0001 for intensive therapy vs routine therapy after month 3

Primary end point

Remission

Intensive Routine Therapy Therapy P Value DAS < 2.4 82% 44% < 0.0001 DAS < 1.6 65% 16% < 0.0001

BeSt Trial: treatment strategies for early RA

Randomized clinical trial of 508 patients comparing four treatment strategies with evaluation and treatment changes according to strict guidelines.

Goal: to attain DAS score

BeSt Trial: Results At 1 year: Patients on initial combination therapy had better response

in faster time. At 2 years: The same proportion of patients in all groups attained low

level of disease activity At 3 years: Patients who responded had less progression of xray

changes compared to non responders Rate of radiologic progression was slower in combination

groups. 51% in group with infliximab discontinued treatment and maintained remission for average 2.5 years.

At 7 years: 16-17% of patients in all groups achieved remission Radiological damage progression rates were similar in all

groups. (no difference in total damage after 7 years) Patients treated initally with infliximab maintained

improved function compared to other groups and a greater percentage remained on initial therapy.

Anti TNF therapy v. methotrexate Swefot trial

open label randomized trial 487 pts

30% reached target on methotrexate alone

Pts responded best clinically and radiographically to infliximab treatment compared to DMARD combination therapy.

Tear trial Randomized blinded

controlled trial of 755 received immediate

triple/antiTNF or step up therapy

there was no difference in clinical measurements between groups

Preliminary radiographic results: etanerecpt treated patients have less xray proogression

Van Vollerhoven RF, Ernestam S, Geborek P et al Lancet 2009, 374:459-466. American College of Rheumatology (ACR) 2009 Annual Meeting; October 17-21, 2009; Philadelphia. Presentation LB6. Moreland, L and ODell, J et al. American College of Rheumatology (ACR) 2009: Abstract 1895. Presented October 20, 2009, Presented at ACR 2010 abxtract 1368..

Newer Therapies for RA

Approved: Abatacept: Selective blocker of costimulatory molecule

required for T cell activation. Rituximab: Chimeric mouse-human monoclonal

antibody target CD20 antigen on B cells. Golimumab: monthly injection, similar to Infliximab Certolizumab pegol: PEGylated anti-TNF agent Tocilizumab: monoclonal antibody targeting IL-6

receptor

1980

Treatment of RA

ACR Treatment Algorithm

Adapted from: American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328346.

Change/Add DMARDs

MTX naive Suboptimal MTX response

MTX Other mono

Combination Combination Other mono

Biologics Mono Combination

Adequate response

Inadequate response

Rheumatologist

Establish diagnosis of RA early

Initiate therapy (3 months)

Periodically assess disease activity

PCP

Multiple DMARD failure

Symptomatic and/or structural joint damage

surgery

Clinical signs that aid in detection of early RA and reasons for referral

> 3 swollen joints

Diagnosis is possible in 6-12 weeks, but not firm

Symmetric arthritis

RF positive or anti-CCP positive

Hand-joint involvement

Elevated ESR or C-reactive protein Emery P, Breedveld FC, Dougados M,et al Ann Rheum Dis. 2002;61:290-7.

Conclusion Early and aggressive treatment of RA

slows progression. Treatment goals in 2012: decrease risk of

joint damage as well as symptomatic relief.

Future research: Better identification of patients at high risk of developing erosive disease (biomarkers, MRI/ultrasound, genetic markers) in order to individualize therapy

Update in Rheumatoid Arthritis 2012Rheumatoid ArthritisOverview of lectureRheumatoid arthritis: epidemiology ACR criteria for the classification of rheumatoid arthritisSlide Number 5Rheumatoid arthritis: morbidity and mortality Pathogenesis of Rheumatoid ArthritisSlide Number 8Slide Number 9Slide Number 10ASSESSMENT OF DISEASE ACTIVITY IN RASlide Number 12Slide Number 13Slide Number 14Slide Number 15Treatment of Rheumatoid arthritis 2012Non pharmacologic treatmentPharmacologic therapyDMARDsBiologic Response ModifiersBiologics: anti TNF agentsEfficacy of Anti-TNF TherapySummary of Clinical TrialsResponse to anti-TNF:Early RAResponse to anti-TNF:Established RALong term data Safety considerations with anti-TNF treatmentAdministration reactionsInfectionOpportunistic infectionCardiovascular diseaseMalignancyDemyelination SLE-like illnessEvaluating Therapeutic Strategies 2012Slide Number 34Slide Number 35BeSt Trial: treatment strategies for early RABeSt Trial: ResultsAnti TNF therapy v. methotrexateNewer Therapies for RASlide Number 40Slide Number 41Slide Number 42Conclusion