Rheumatoid Arthritis: Clinical Overview

Roger Kornu, MD

Associate Clinical Professor

Division of Rheumatology

University of California, Irvine

Take Home

• RA is a prevalent, inflammatory disease with potential of high morbidity both in articular and extra-articular manifestations.

• Symmetrical, small joint pain and morning stiffness with joint swelling on physical exam are the most important clinical features.

• Rheumatoid factor, anti-CCP antibody, and inflammatory markers are useful in diagnosis.

• Modern clinical criteria allows for earlier diagnosis and more aggressive therapy to minimize joint damage.

• Methotrexate is the standard disease modifying agent, but there is a low threshold to add combination therapy as we are in the era of treat to target.

Case Presentation

• 52 year old Caucasian female presents with 6 months of swelling and stiffness in her bilateral hands, wrists, and feet. She has one hour of morning stiffness.

• She is still able to work full-time as a supervisor, but has difficulty in grasping objects and opening doors.

Case Presentation

• She has no significant medical history and is taking OTC ibuprofen.

• Her mother may have had rheumatoid arthritis, but she is not sure.

• Physical exam shows joint swelling and tenderness in her bilateral 2nd-5th PIP and 2nd-3rd MCP joints with right wrist swelling. She has tenderness in bilateral MTP joints.

Case Presentation

• On work-up, she has a normal CBC, electrolytes, and LFTs

• ESR 46, CRP 1.5, RF negative, anti-CCP antibody 120 and ANA negative

Case Presentation

What’s the diagnosis?

Rheumatoid arthritis

“One must from time to time attempt things that are beyond one’s capacity.”

—Pierre-Auguste Renoir

Epidemiology

• Prevalence up to 1%• Annual incidence 40 per 100,000• Peak age of onset between 50-75 years• Female:Male ratio, 2-3:1• Prevalence of RA in females over 65 years

is up to 5%• Monozygotic twins 13.5% vs dizygotic

twins 3.5%

Genetics

• HLA-DRB1: “shared epitope”– Individuals with certain sequence found in

DR4, DR14 and DR1 beta-chains have higher RA and anti-CCP positivity

• Risk of RA and Smoking– Men 2x higher and Women 1.3x higher– Also related to the shared epitope– No relationship of heavy or light smoking

McInnes and Schett, NEJM 2011

McInnes and Schett, NEJM 2011

Clinical Presentation of RA

Early RA Intermediate RA

Severe RA

Latinis KM, et al. The Washington ManualTM Rheumatology Subspecialty Consult. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004.

Establishing a Diagnosis for RA

• Joint stiffness upon awakening• Swelling in specific fingers or wrist joints, with or

without pain• Swelling in soft tissues around the joints• Symmetrical pattern of affected joints• Fatigue, depression, occasional fevers, anemia,

general sense of malaise• Symptoms may last for years and get

progressively worse for the majority of patients

Diagnosis of RA: 2010 ACR Criteria

Diagnostic Tools in Rheumatoid Arthritis

• Rheumatoid factor

• Anti-CCP antibodies

• Plain X-ray

• MRI

• Ultrasound

Rheumatoid Factor

• Antibody directed against the Fc portion of IgG

• Present in approximately 80% of RA patients– Sensitivity for RA is ~80%– Specificity is 85-95%

• May be involved in disease pathogenesis• Higher levels tend to be associated with

poorer prognosis• Found in other conditions, especially

Hepatitis C

Anti-Cyclic Citrullinated Peptide (CCP) Antibodies in RA

• Anti-citrulline Abs produced in RA synovium • Early RA Diagnosis

– sensitivity 48%; specificity 96%– seen in 2% of pts with other autoimmune

diseases and infections (vs. 14% for RF)– less than 1% of healthy controls

• Predicts erosive disease PPV - 63% and NPV - 90%

• Present years before the onset of symptoms. 34% of blood samples obtained 2.5 yr before onset of symptoms (vs. 1.8% of controls)

Plain X-ray

Magnetic Resonance Imaging as a Diagnostic Tool

McQueen FM et al. Ann Rheum Dis. 1999;58:156-163.McQueen FM et al. Ann Rheum Dis. 1998;57:350-356.

14

45

0

10

20

30

40

50

X-ray MRI

Erosions Detected: X-rays vs MRI (%)

Ultrasound as a Diagnostic Tool

Keen et al. Rheum Dis Clinic N Am 31 (2005) 699-714

Adapted from Kirwan JR. J Rheumatol. 1999;26:720-725.

Sev

erit

y (A

rbit

rary

Un

its)

0

Duration of Disease (Years)

5 10 15 20 25 30

Inflammation

Relationship of Radiographic Joint Damage to Disability

Disability

Radiograph Scores

Features Related to Poor Outcomes

· Extra-articular disease· High rheumatoid factor titer, positive anti-CCP antibody· Poor functional status· Involvement of multiple joints· Radiographic erosions· Sustained elevation of acute-phase reactants (eg, ESR)· Low socioeconomic status/educational level· Increased genetic risk of developing RA plus smoking

Anaya JM, et al. Ann Rheum Dis. 1994;53:782-783. Pincus T, et al. Balliere’s Clin Rheumatol. 1992;6:161-191. Furst DE. Rheum Dis Clin North Am. 1994;20:309-319. Padyukov L, et al. Arthritis Rheum. 2004;50:3085-3092.

Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Rheumatoid arthritis: episcleritis

Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Rheumatoid arthritis: scleromalacia perforans

RA: Pulmonary Manifestations

• Interstitial lung disease may appear in 2-5% of RA patients– Nonspecific interstitial pneumonitis (NSIP)

• Homogeneous mononuclear infiltrate• Ground glass infiltrate on HRCT• Better prognosis

– Usual interstitial pneumonitis (UIP)• Non productive cough and dyspnea• Honeycombing of HRCT• Worse prognosis

RA: Pleural Disease

• Males > females• In <5% of patients• Long-standing disease• Low pleural fluid glucose• Must exclude infections, malignancy

RA: Felty’s Syndrome

• Seropositive rheumatoid arthritis– Long standing RA, can have bland synovitis

• Splenomegaly• Leukopenia

– WBC < 4000– Neutropenia <1500

• Recurrent infections

Large Granular Lymphocyte (LGL) Syndrome

• Neutropenia, splenomegaly, and recurrent infections• Clinical features may mimic Felty’s syndrome (“pseudo” Felty’s)• Neutropenia with normal or increased total WBC due to

lymphocytosis• May have associated anemia, thrombocytopenia• Clonal populations of LGL in some patients may represent

neoplastic proliferation and some patients ultimately develop leukemia or lymphoma

RA and Lymphoma

• Majority Non-Hodgkin’s Lymphoma (NHL)– Diffuse Large B cell type– MALT (mucosal associated lymphoid tissue)

• EBV association in 12%• Higher incidence with age• In early biologic trials with TNF alpha

inhibitors, increased incidence of NHL

Adult Still’s Disease

• Triad – Quotidian fever– evanescent salmon rash– inflammatory arthritis

• High acute phase reactants– High ferritin (>4000)– Elevated CRP

• Lymphadenopathy, heptomegaly

Treatment

• NSAIDs, glucocorticoids• Biologics

– TNF alpha inhibition– T-cell inhibition– B cell inhibition– IL-6 inhibition

• Small molecules– JAK kinase inhibition

Joint Erosions Occur Early in Rheumatoid Arthritis

van der Heijde DM, et al. J Rheumatol. 1995;22:1792-1796. Fuchs HA, et al. J Rheumatol. 1989;16:585-591. McQueen FM, et al. Ann Rheum Dis. 1998;57:350-356.

Year

0

10

20

30

0 1 2 3

Max

imum

Per

cent

age

of J

oint

s A

ffect

ed

Metatarsophalangealjoint

Total

Hand

Ch

ang

e in

Med

ian

S

har

p S

core

0

2

4

6

8

10

12

14

0 6 12 18 24

Time (Months)

*Patients were treated with chloroquine or sulfasalazine

Lard LR, et al. Am J Med. 2001;111:446-451.

Treatment: The Earlier, the Better

Delayed treatment 1993-1995*(median lag time to treatment=123 days; n=109)

Early treatment 1996-1998* (median lag time to treatment=15 days; n=97)

Goals of Therapy

• Treat early • Treat to limit and/or prevent

– Pain– Joint damage– Extra-articular disease– Disability– Premature death

• Treat to target

Traditional DMARD Selection

AgentTime to Benefit

Potential Toxicity Toxicities to Monitor

Methotrexate 1–2 mo Moderate Myelosuppression, hepatic fibrosis and cirrhosis, pulmonary infiltrates

Hydroxychloroquine 2–6 mo Low Macular damage

Sulfasalazine 1–3 mo Low Myelosuppression

Leflunomide 4–12 wk Low Diarrhea, alopecia, rash, headache, risk of immunosuppression infection

Minocycline 1–3 mo Low Hyperpigmentation, dizziness, vaginal yeast infections

McInnes and Schett, NEJM 2011

RA Biologics: TNF alpha blockers

• TNF alpha is expressed on surface of macrophages• Binding to its receptors trigger a variety of other inflammatory

cytokines• Appears to have improved efficacy in combination with

methotrexate and lowers immunogenicity• Receptor blocker

– Etanercept (Enbrel)• Monoclonal antibody

– Infliximab (Remicade)– Adalimumab (Humira)– Golimumab (Simponi)– Certilizumab (Cimzia)

RA Biologics: B and T cells

• B-cell targeted therapy– Rituximab (Rituxan) is anti CD20

• Eliminates peripheral B cells within days• FDA approved in TNF alpha failures

• T-cell targeted therapy– Abatacept (Orencia) is CTLA4Ig

• Interferes with optimal T cell activation which results in decreased proinflammatory cytokines

RA Biologics: Interleukin inhibitors

• IL-1 inhibition– Anakinra (Kineret)

• First biologic for RA• Not as effective in RA• Used more in JIA, Adult Still’s disease

• IL-6 inhibition– Tocilizumab (Actemra)

• Inhibits IL-6 signaling on cells which lowers proinflammatory cytokines

RA Nonbiologics: JAK inhibitors

• JAK1/JAK3 inhibition– Tofacitinib (Xeljanz)

• JAK proteins are intracellular that associate with and transduce signals from several cytokine and growth factor receptors

• Oral therapy, FDA approved

• JAK1/JAK 2 inhibition– Baricitinib– Just finished Phase III trials

RA Therapies: The Next Generation

• Biosimilars• Anti-IL-6 receptor

– Sarilumab• Anti-IL-17A

– Secukinumab• Anti-IL-20• Anti-CD22

– Epratuzamab• Chemokine inhibitor: CCX354-L2• PDE4 inhibitor: aprimilast

RA Therapies: Infections

• Serious bacterial infection: 3-4%• TB especially in TNF alpha blockers

as TNF is important in granuloma formation

• Increased risk of fungal infections• Active hepatitis B

Safety Issue: TB

Bieber and Kavanaugh, Rheum Dis Clin N Am 30 (2004) 257-270

RA Therapies: Malignancies

• TNF is important in inducing apoptosis in tumor cells

• Long term use has not shown increase in solid tumors and still controversial with lymphoma

• Increased risk of melanoma and non-meloma skin cancers

RA Therapies: Vaccines

• Non-live vaccines recommended– Influenza injection– DTap– Pneumococcal vaccine– Hepatitis B– HPV

• Live vaccines– Not recommended with biologics

• Shingles, MMR, flu nasal, yellow fever, oral typhoid– Ok if prednisone <20mg, Methotrexate <0.4mg/week,

azathioprine <3 mg/kg/day

Together we can work to prevent this:

Take Home

• RA is a prevalent, inflammatory disease with potential of high morbidity both in articular and extra-articular manifestations.

• Symmetrical, small joint pain and morning stiffness with joint swelling on physical exam are the most important clinical features.

• Rheumatoid factor, anti-CCP antibody, and inflammatory markers are useful in diagnosis.

• Modern clinical criteria allows for earlier diagnosis and more aggressive therapy to minimize joint damage.

• Methotrexate is the standard disease modifying agent, but there is a low threshold to add combination therapy as we are in the era of treat to target.