Rheumatoid Arthritis 2013 Jeffrey Carlin, MD Section Head, Division of Rheumatology Virginia Mason Medical Center.

Rheumatoid Arthritis2013

Jeffrey Carlin, MD

Section Head,

Division of Rheumatology

Virginia Mason Medical Center

Rheumatoid Arthritis Symmetric, inflammatory polyarthritis,

involving large and small joints Serological studies may be negative at onset

and may remain negative in 15-20%! RA is a clinical diagnosis, no laboratory test is

diagnostic, just supportive!

Rheumatoid Arthritis:Patterns of Onset

Acute polyarticular Acute, severe onset 10-15 % Subacute 20%

Additive Palindromic

The Challenges of RA• Reliable diagnosis of early RA

– RA is a heterogeneous disease that differs substantially from patient to patient in presentation and progression

• Detection of early inflammatory arthritis• Detection of the earliest events that predictably

lead to destructive synovitis

Early RA: A problematic diagnosis

Most patients will not meet ACR criteria Most patients will not be sero-positive ( 19- 45%) Most patients will not seek medical care Most PCPs prefer to evaluate, rather than refer Many patients will remit with symptomatic Rx Histopathology similar: RA, ERA, UPA Few features to distinguish RA vs UPA

Duration, # Jts, RF+, CCP+, ESR/CRP

Longitudinal Course of RA

Klareskog L et al, Lancet 2009;373:659-672

The Natural History of RA

at presentation after 5 years after 15 years

Immunological Pathways in the Arthritic Joint

Klareskog L et al Lancet; 2009;373:659-672

Pathogenesis of RA

Joint histology demonstrating a

multinuclear osteoclast boring into surrounding

bone

Synovial lining with rich

lymphocytic infiltrate

Genetic Factors Associated with RA

Risk Factor Anti – CCP +

Anti- CCP-

Comment

HLA-DRB1 Alleles Yes No Strong evidence; RF+ disease

PTPN 22 Yes No Strong evidence; RF+ disease

TRAF1-C5 locus Yes No Strong evidence

OLIG3-AIP3 locus Yes --

STAT4 Yes --

PADI4 Strong evidence for Asian population only

CLEC4A No Yes Needs confirmation

IRF5 No Yes Needs confirmation

Adapted from: Klareskog L et al Lancet; 2009;373:659-672

Environmental Factors Associated with RA

Environmental RiskFactor

Anti-CCP + Anti-CCP- Comments

Cigarette Smoking Yes No Strong evidence; associated with RF+

Mineral Oils Yes No Needs confirmation

Airway exposures Yes No Air pollution, Silica, Charcoal dust (Caplan’s Syndrome)

Peridontal disease Yes No

Environmental Protective Factor

Alcohol Yes Yes Needs confirmation

Adapted from: Klareskog L et al Lancet; 2009;373:659-672

Aids to Early Diagnosis

ACR 1987 Criteria for RA

• AM stiffness > 1hr*• Swelling of 3 or more joint areas*• Swelling in Hands (MCP’s,PIP’s) or Wrists*• Symmetrical Joint Swelling*• Erosions on X-Ray• Nodules• Positive Rheumatoid Factor

*- Present > 6 weeks

Criteria may not apply for early RA

(4/7 Criteria Necessary)

New ACR/EULAR Criteria for Classification of RA

Domain/Criteria PointsJoint involvement (0-5)

1 medium/large joints 0

2-10 medium-large joints 1

1-3 small joints 2

4-10 small joints 3

>10 joints (at least 1 small) 5

Serology (0-3)

Neither RF nor anti-CCP + 0

At least one test low titer + 2

At least one test + high titer 3

Duration of Synovitis

< 6 weeks 0

> 6 weeks 1

Acute Phase Reactants

Neither CRP or ESR elevated 0

Abnormal ESR/CRP 1

Patients with > 6 points

considered to have definite RA

Hawker GA ACR meeting 2009

Low titer < 3X ULNHigh titer >3X ULN

Extra-articular ComplicationsAffected tissue or organ Comments

Infections Association with RA due to disease, medications; important implications for vaccination

Cardiovascular Pericarditis, endocarditis, myocarditis, MI; association due to underlying inflammatory disease, medications, reduced exercise, genetics

Nervous system Depression; PML (rare but often fatal in immunosuppressed; more common with biologics such as rituximab)

Skin Subcutaneous nodules

Pulmonary Pulmonary nodules; interstitial lung disease

Eyes Scleritis, episcleritis, retinal vasculitis

Other Vasculitis, diabetes, GI bleeding, cancer (e.g., lymphoma)

GI, gastrointestinal; MI, myocardial infarction; PML, progressive multifocal leukoencephalopathy.Prete M, et al. Autoimmun Rev. 2011; Sept 10. Epub ahead of print.

Citrullination of Arginine in Proteins

L-arginine residue(+charged)

L-citrulline residue(neutral)

Peptidylargininedeiminase (PAD)

Ca2+

H

N

O

NH

NH2H2N+

H

N

O

NH

NH2O

Anti-CCP Predicts Progression to RA• How well can the clinical parameters predict development of RA?

(1 year follow-up)

• ACR criteria plus CCP

• 0.923• ROC AUC

• <0.001• (9.9–151.0)

• 38.6• Positive anti-CCP2 antibody

• 0.001• (2.4–31.2)• 8.7• Erosions on radiographs

• 0.406• (0.5–5.6)• 1.7• Positive IgM rheumatoid factor

• 0.795• (0.0–∞)• 0.003• Rheumatoid nodules

• 0.002• (2.0–19.0)• 6.1• Symmetric involvement of joints

• 0.762• (0.4–3.3)• 1.2• Arthritis of wrist, MCP, PIP

• 0.001• (1.8–13.2)• 5.0• Arthritis of three or more joints

• 0.108• (0.8–5.3)• 2.1• Morning stiffness >1 hour

• p-value• 95% CI• OR

van Gaalen et al, Arthritis Rheum 2004;50:709–15

Diagnostic Accuracy of Anti-CCP Antibody and RF for Rheumatoid Arthritis

– 37 studies of anti-CCP antibody and 50 studies of RF

– pooled sensitivity, specificity, and (+) and (-) LR’s

Anti-CCP RF

Sens. 67% 69%

Spec. 95% 85%

(+) LR 12.46 4.86

(-) LR 0.36 0.38

Ann Intern Med. 2007;146:797-808

Tests in RA

Proposal: Clinical Suspicion of Early RA

Rheumatoid Factor

Negative

(<20 U/mL)

Positive

Low titer

(20-50UmL)

High Titer

(>50UmL)

Anti-CCP

Add significant diagnostic &

prognostic value

Good tool for diagnosis

Good predictor of erosiveness

Diagnosis of Early RA

Joint swelling> 6 weeks?

N

Synovial swellingin 3 joints?(symmetric, typical)

Crystal arthritisReactive arthritisChlamydial arthritisViral arthritisPalindromic rheumatism

Y

Observed

Patient hasRA

Y

N

SlowlyProgressive

Aggressive(high risk)

N Y

CCP = cyclic citrullinated protein; HAQ = Health Assessment Questionnaire.Cush JJ. J Rheumatol. 2005;32:203–207.

RF positive orAnti-CCP Ab?

Undifferentiated polyarthritisPsoriatic arthritisReactive arthritisSpondyloarthropathyPseudogoutConnective tissue diseasePolymyalgia rheumaticaInflammatory osteoarthritisHemochromatosis

Y

N

Possible RA

High RF titer?Anti-CCP Ab positive?X-ray erosions?Many swollen joints?Nodules?Extra-articular manifestation?

Assess Severity

RA Therapy

Goals of RA Treatment

• Improvement in Pain, Stiffness, and Constitutional Complaints

• Prevention of Joint Damage/Disability• Normal Quality of Life• Prevention of Co-Morbidities

– Cardiovascular Disease– Osteoporosis– Infections– Malignancies

Treatment Challenges in Early RA

• Defining Who Is At Risk for Progression• Deciding What is the Appropriate Rx for

the Individual

Factors Suggesting Poor Prognosis

• >20 swollen joints• High RF titer• Elevated anti-CCPs• Elevated Sed Rate• Elevated CRP• Late implementation of

treatment

• Joint erosions• Presence of rheumatoid

nodules• Socioeconomic

characteristics• Smoking• Poor functional status

RA Therapeutic Classes• NSAIDS• Corticosteroids• DMARD’s

– Hydroxychloroquine, Sulfasalazine• Immunosuppressive Agents

– Methotrexate, Leflunomide, Azathioprine• Biological Agents

– Anti TNF Agents• Etanercept, Infliximab, Adalimumab, Golimumab,

Certolizumab – New Biologics

• Abatacept, Rituximab,Tociluzimab, Tofacinitib

TICORA

Response to treatment

Intensive group (n=55), n (%)

Routine group (n=55), n (%)

EULAR good response*

45 (82) 24 (44)

EULAR remission** 36 (65) 9 (16)

ACR20 response 50 (91) 35 (64)

ACR50 response 46 (84) 22 (40)

ACR70 response 39 (71) 10 (18)

Monthly visits vs q 3 month visitsRapid escalation of MTX progressing to combination Rx

Grigor,C et al. Lancet 2004:364;263-269

Biological Agents

– Anti TNF Agents• Etanercept, Infliximab, Adalimumab, Golimumab,

Certolizumab

– T Cell Co-stimulation inhibitor• Abatacept

– B-cell inhibitor• Rituximab

– IL-6 Inhibitor• Tociluzimab

– Signal molecule inhibitors• Tofacitinib- Jak-3 • Experimental-

– LY3009104- Jak- ½– Fostamatinib- Syk

Modes of Action of Various Biologic Therapies

Klareskog L et al Lancet; 2009;373:659-672

Tofacitinib

Cochrane Review of Biological Therapy for RA - Benefit

Singh JA et al Cochrane Library 2010

Cochrane Review of Biological Therapy for RA - Safety

Singh J A et al Cochrane Library 2011

2

Kinase inhibitors: a new approach to rheumatoid arthritis treatment.Cohen, Stanley; Fleischmann, Roy

Current Opinion in Rheumatology. 22(3):330-335, May 2010.DOI: 10.1097/BOR.0b013e3283378e6f

Figure 3 ACR response: 12-week results of a placebo-controlled dose-ranging RCT of CP-690 550 an oral JAK1/3 kinase inhibitor as monotherapy

Tofacitinib vs Adalumimab

Side Effects of Tofacitinib

• Neuro- headache, light-headedness• GI- abdominal pain, nausea• Liver- abnormal LFT’s• Renal- mild elevation of creatinine• Infections- influenza, URI’s, UTI’s• Hematologic- anemia, leukopenia• Metabolic- hypercholesterolemia

Treatment Strategies in RA

Step –Up (Conservative)

Parallel(Intensive)

Early Biological(Expensive)

Initial:MTXMonotherapy

Initial:MTX + 2nd DMARD +/-steroids

Initial:MTX + anti-TNF Rx

If active:Add 2nd DMARD +/- steroids

If Active:Increase dosage or switch DMARD

If Active :Switch anti-TNF Rx

If Active :Add anti –TNF agentIf Inactive:MTX monotherapy

If Active :Add anti-TNF AgentIf inactive:MTX monotherapy

If Active:Switch to alternative biological agentIf Inactive:MTX monotherapy

Intensity & Cost of RX

1-3 months

3-6 months

6-12months

Scott D et al Lancet 2010;376:1094-1108

Soubrier, M. et al. Rheumatology 2009 48:1429-1434

ACR Responses at Weeks 12 and 52

N=65

2 Strategies:Data from the GUEPARD Trial

Recommendations from GUEPARD

• Initial therapy with TNF inhibitor is not justified

• If there is persistent disease activity on MTX mono therapy at 12 weeks, TNF inhibitors should be added

• Regardless of the strategy, tight control is effective

Initial treatment choiceSSZ, MTX, Leflunomide

MTX+HCQ+SSZ+/- Prednisone

Maintain regimenAssess q 3 mo

Monitor side effects

Change Rx2nd DMARD

Change DMARDCombine anti-TNF + MTX

Maintain regimenAssess q 3 mo

Monitor side effects

Change RegimenIf on MTX+anti-TNF,

switch to different anti-TNF

Maintain regimenAssess q 3 moMonitor side effects

Change RegimenT or B Cell FocusAnti-IL6

Rheumatoid Arthritis Treatment Strategies

• Things we agree on:– Early diagnosis is good– Early institution of DMARD therapy is good– Tight control improves outcomes– “Treat-to- Target”

• Unanswered questions:– Optimal treatment strategy in early disease

• ? Monotherapy with step up• ? Initial combination therapy• ? Early institution of biologics • How much steroid initially

CBC, complete blood count; DMARD, disease-modifying antirheumatic drug; LFT, liver function test; TB, tuberculosis. Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Before Starting Therapy• Obtain CBC, LFTs, creatinine level, HIV

and hepatitis B and C status– Repeat at regular intervals depending on

the therapy

• Vaccinations• TB screening for biologic DMARDs

CRP, C-reactive protein; CV, cardiovascular; DXA, dual-emission X-ray absorptiometry; ESR, erythrocyte sedimentation rate; FRAX, fracture risk estimation; PLT, platelet. Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

• Assess disease activity regularly– Labs: ESR, CRP, PLT, CMR etc. every 1-3 months

– Joint examination: 28-joint count

– MHAQ, RAPID-3, DAS28

– Disease flares

• Monitor treatment-specific side effects

• Monitor comorbidities– CV: lipid profile, tobacco use, etc

– Osteoporosis: DXA, calcium, vitamin D, exercise, FRAX

– Mental health

Ongoing Monitoring

Conventional DMARD Safety Concerns

• Reproductive• MTX, Leflunomide

• Pulmonary• MTX, Leflunomide

• Allergic• SSZ, HCQ

• Cutaneous• Leflunomide

• Lymphoma• MTX, Leflunomide, Azathioprine

• Hematologic • All

• Host Defense• MTX, Leflunomide, Azathioprine

• Hepatic • MTX, Leflunomide, Azathioprine

• Gastro-intestinal• All

• Ocular • HCQ

Soluble Biomarkers in RA and the Metabolic Syndrome

Improvement of Cardiovascular Risk with use of anti-TNF Agents

Solomon D et al, Ann Rheumatic Disease 2011; 70:576-582

Additional Interventions• Exercise recommended for all RA patients to:

– Keep joints loose, support affected joints– Maintain/improve balance and strength– Ward off depression/improve mood

• Smoking cessation• Stress management• Foot health• Vaccination

– Yearly influenza vaccine– Pneumococcal vaccine when indicated

• Risk factor assessment for cardiovascular disease– Lifestyle modification – Glucose and lipid monitoring

Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Thank you!

Potential Contraindications to DMARD Treatment

• Infectious disease: bacterial infection, TB, shingles, serious fungal infection, or pneumonitis (ILD)

• Hematologic and oncologic • Cardiac: class III-IV heart failure• Liver: abnormal LFTs, hepatitis B or C• Renal • Neurologic: MS• Pregnancy and breastfeeding • Perioperative infectious risk

DMARDs, disease-modifying antirheumatic drugs; ILD, interstitial lung disease; LFT, liver function test; MS, multiple sclerosis; TB, tuberculosis.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Methotrexate: Gold Standard for RA

Mechanism of action

Interferes with DNA replication, inhibits lymphocyte proliferation (folate antagonist), and has anti-inflammatory effects (adenosine accumulation)

Dose • Initial: 7.5-10 mg/wk• Increase every 4-8 wk by 2.5-5 mg• Max: 20-25 mg/wk

Contra-indications

Pregnancy category X; liver and renal failure, platelet count <50,000/mm3

Prescreening CBC, LFT, creatinine, hepatitis B and C

Monitoring Hepatic, pulmonary, blood toxicity; CBC, LFT, creatinine every 2-4 weeks for 3 months, then every 8-12 weeks

Adverse reactions

Mouth ulcers, nausea, fatigue, alopecia, diarrhea, achiness, irritability

Other Consider folic acid supplementation; no alcohol; >180 mg/day caffeine reduces efficacy; high alert for incorrect dosing

CBC, complete blood count; LFT, liver function test; TB, tuberculosis.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

SulfasalazineMechanism

of action Potent antiinflammatory effects

Dose 1000 mg bid-tid

Contra-indications Liver disease, platelet count <50,000/mm3

PrescreeningCBC, LFT, creatinine

Monitoring CBC, LFT, creatinine every 2-4 weeks for 3 months, then every 8-12 weeks

Adverse reactions Blood toxicity

Other Slightly inferior to MTX; pregnancy category B

CBC, complete blood count; LFT, liver function test; MTX, methotrexate.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

HydroxychloroquineMechanism

of action Antimalarial drug

Dose 200 mg bid or 400 mg qd

Contra-indications In patients with retinal or visual field changes

Prescreening CBC, LFT, creatinine, ophthalmologic exam

Monitoring Yearly ophthalmologic exams

Adverse reactions

Risk of ocular reactions; otherwise well-tolerated

Other Reduces signs and symptoms of RA, but does not slow radiographic progression as monotherapy; reduces the risk of new-onset diabetes

RA, rheumatoid arthritis.Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Solomon D, et al. JAMA. 2011;305:2525-2531.

LeflunomideMechanism

of action Decreases T lymphocytes

Dose 10-20 mg/day

Contra-indications

Pregnancy category X; liver disease, platelet count <50,000/mm3

Prescreening CBC, LFT, creatinine, hepatitis B and C

Monitoring CBC, LFT, creatinine every 2-4 weeks for 3 months, then every 8-12 weeks

Adverse reactions

Diarrhea, weight loss, elevated blood pressure; potential for abnormal LFTs

Other Newer nonbiologic DMARD

CBC, complete blood count; DMARD, disease-modifying antirheumatic drug; LFT, liver function test.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Biologic DMARDs: Overview• Considerations for injectable agents:

– Rotate injection sites– Some needle covers made from latex; caution in latex allergy

• Adverse reactions– Injection-site or infusion reactions– Infections: TB, hepatitis, fungal, and bacterial (sepsis)– Rare: lupus and MS

• Contraindications – Active or recurrent cancer – Untreated infection, active or latent TB– Cannot receive live virus vaccinations– Severe heart failure (class III-IV)

MS, multiple sclerosis; TB, tuberculosis.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Other Biologic DMARDsAgent Description Dosing and

administration Comments

Abatacept T-cell modulator

500-1000 mg (weight-based) IV week 0, 2, and 4, then q4 weeks; or IV day 1, 125 mg SC day 2, then 125 mg SC weekly

Use in patients with > 6m of disease; monitor respiratory status closely in COPD patients and discontinue if problems occur

Anakinra IL-1 receptor antagonist

100 mg/day SC; 100 mg qod in pts with severe renal disease

Less effective than anti-TNF agents; used in <5% of RA patients; contraindicated in asthma; latex needle cover

Rituximab Anti-CD20 antibody

Two 1,000 mg IV infusions separated by 2 weeks

Used in combination with MTX; may decrease vaccine effectiveness; used when anti-TNF agents fail; rare but often fatal PML

Tocilizumab IL-6 receptor blocker

4 mg/kg IV over 60 minutes every 4 weeks, titrated to 8 mg/kg as needed

Used alone or in combination with MTX or other DMARDs in patients with inadequate response to anti-TNF therapy

IL, interleukin; IV, intravenous; PML, progressive multifocal leukoencephalopathy; SC, subcutaneous; TNF, tumor necrosis factor. Saag KG, et al. Arthritis Rheum. 2008;59:762-784; prescribing information of individual agents.

Other Agents: NSAIDs• Help with inflammation & pain• No disease-modifying capability• Contraindicated in patients with renal

disease• Caution in patients with heart disease

& peptic ulcer disease• Increased incidence of heart attack,

stroke, GI disease, renal disease

GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug.Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Trelle S, et al. BMJ. 2011;342:c7086.

Other Agents: Corticosteroids

DMARD, disease-modifying antirheumatic drug.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Pros Cons• Helps with pain and

inflammation• Some disease-modifying

capability, so can help while other agents take effect (3-6 months or more)

• When used with a DMARD, additive disease-modifying activity is noted

• Can mask severity of disease through anti-inflammatory action

• Long- and short term risks include: Immunosuppression Osteoporosis Glucose intolerance/diabetes Weight gain Hyperlipidemia Hypertension Cataracts Skin atrophy Acne Steroid psychosis

Other Agents: Corticosteroids• To reduce potential complications:

– Calcium and vitamin D supplementation– Bisphosphonates when on long-term

therapy– DXA to monitor bone health– To decrease adrenal suppression:

• Keep daily dose <7.5 mg• Give once a day in the morning• Consider qod dosing

DXA, dual-emission X-ray absorptiometry.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

Cochran Review of Biological Therapy for RA - Safety

Singh J A et al Cochrane Library 2011

Long Term Data on anti-TNF Agents

• No increased risk of solid tumors– Swedish registry: 6yr f/u

• anti-TNF agents RR1.0 vs MTX, Combo Rx or general population

– Meta-analysis- 6 studies of early Rx with anti-TNF Rx vs MTX• Malignancy RR 1.07

• Increased risk of non-melanoma skin cancers• Mortality rates on anti-TNF Rx = to patients not on Rx

– 12,672 pts on Anti-TNF agents vs 3552 pts on DMARDS• 4 yr follow up on anti-TNF Rx vs 2.7 yr follow up on DMARD Rx (50,803 vs 9445 Pt yrs) • 856 deaths vs 204 deaths • Similar pattern of mortality- (weighted hazard 0.86)• Deaths: circulatory, neoplasm, respiratory

1.Askling et al Arth & Rheum 2009;6:3180-31892. Thomson et al Arth & Rheum 20113.Lunt M et al, Arth & Rheum 2010;62:3145-3153

Who to Treat? Who to Refer?• Patients with features of an early

inflammatory arthritis:

- joint swelling

- symmetric distribution of symptoms

- MCP and MTP involvement

- significant early morning stiffness (>1 hr)

- a good anti-inflammatory response

- family history

Principles of RA Therapy

• More aggressive therapy

• Early institution of DMARD therapy

• Maximization of MTX dosing

• Combination therapy

• Addition of biologic agents for persistent

activity