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
Severe RA
Early RA
Intermediate 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
Erosions Detected:
X-rays vs MRI (%)
50
45
40
30
20
14
10
0
McQueen FM et al. Ann Rheum Dis. 1999;58:156-163.
McQueen FM et al. Ann Rheum Dis. 1998;57:350-356.
X-ray
MRI
Ultrasound as a Diagnostic Tool
Keen et al. Rheum Dis Clinic
N Am 31 (2005) 699-714
Relationship of Radiographic Joint
Damage to Disability
Severity
(Arbitrary Units)
Inflammation
Disability
Radiograph Scores
0
5
10
15
20
Duration of Disease (Years)
Adapted from Kirwan JR. J Rheumatol. 1999;26:720-725.
25
30
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.
Rheumatoid arthritis: episcleritis
Copyright © 1972-2004 American College of
Rheumatology Slide Collection. All rights
reserved.
Rheumatoid arthritis: scleromalacia perforans
Copyright © 1972-2004 American College of
Rheumatology Slide Collection. All rights
reserved.
RA: Pulmonary Manifestations
• Interstitial lung disease may appear in 25% 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
Maximum Percentage of Joints
Affected
Joint Erosions Occur Early in
Rheumatoid Arthritis
30
Metatarsophalangeal
joint
20
Total
Hand
10
0
0
1
2
3
Year
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.
Treatment: The Earlier, the Better
Delayed treatment 1993-1995*
(median lag time to treatment=123 days; n=109)
Change in Median
Sharp Score
14
Early treatment 1996-1998*
12
(median lag time to treatment=15 days; n=97)
10
8
6
4
2
0
0
6
12
18
Time (Months)
*Patients were treated with chloroquine or sulfasalazine
Lard LR, et al. Am J Med. 2001;111:446-451.
24
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
Agent
Time to
Benefit
Potential
Toxicity
Methotrexate
1–2 mo
Moderate
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
Toxicities to Monitor
Myelosuppression, hepatic fibrosis
and cirrhosis, pulmonary infiltrates
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 nonmeloma 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.