1. No category

What is Rheumatoid Arthritis?
• Chronic, progressive, and disabling
inflammatory disease
– Affects the synovial tissue of joints,
especially
p
y of the hands/feet, although
g
any joint can be involved
– Affects extra-articular sites, such as
the heart
• Most common type of inflammatory
arthritis
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
Pathogenesis: Overview
• Balance of pro- and anti-inflammatory
mediators skewed when external factors
trigger an autoimmune reaction
Pathogenesis:
Joint Inflammation
– Known mediators include:
• Cytokines: IL-1, IL-6, IL-8; TNF-alpha
• Lymphocytes: T cells (CD4+), B cells
– Results in:
• Chronic inflammation and destruction of joint
bone and cartilage
• Extra-articular manifestations
Risk Factors for RA
• Genetic factors1,2
– 3-5x more common in first-degree relatives
– May account for up to 60% of RA risk
• Infectious
agents3
• Hormones3
• Miscellaneous factors: smoking, periodontitis4
• Interaction between risk factors4
– More severe RA disease in smokers with
periodontal disease
RA, rheumatoid arthritis. 1. Hemminki K, et al. Arthritis Rheum. 2009;60:661-668. 2. de Vries R. Curr Opin
Rheumatol. 2011; 23:227-232. 3. Oliver JE, et al. Scand J Rheumatol. 2006;35:169-174. 4. Cooles FAH,
et al. Curr Opin Rheumatol. 2011;23:233-240.
Scott DL, et al. Lancet. 2010;376:1094-1108.
Who is Affected by RA?
• Most commonly presents
between the ages of
35 and 45 years1
• Overall lifetime risk of
RA2
– 3.6%
3 6% for women
– 1.7% for men
• For women with a firstdegree relative with RA,
lifetime risk of RA
approaches 18%2
Cumulative Lifetime Risk of RA • %
IL, interleukin; TNF, tumor necrosis factor.
Cooles FAH, et al. Curr Opin Rheumatol. 2011;23:233-240.
5
4
Women
3
2
Men
1
0
20
40
60
80
100
Age • Years
RA, rheumatoid arthritis.
1. Ferri FF. In: Ferri’s Clinical Advisor; 2012, 1st ed. 2. Crowson CS, et al. Arthritis Rheum. 2011;63:633-639.
1
Commonly Affected Joints
Extra-articular Complications
• Symmetrical and polyarticular
–
–
Affected tissue
or organ
Typically involves MCP, PIP, MTP joints
Typically spares certain joints
•
Thoracolumbar spine, DIPs of the fingers,
IPs of the toes
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
PREVALENCE OF JOINT INVOLVEMENT IN RA
90%
80%
60%
– Shoulders
50%
– MCPs
– Ankles
– PIPs
– Wrists
– Elbows
– Hips
– MTPs
– Knees
– Acromioclavicular
40%
– Cervical
spine
30%
– Sternoclavicular
– Temporalmandibular
DIP, distal interphalangeal; MCP, metacarpophalangeal; MTP, metatarsophalangeal;
PIP, proximal interphalangeal.
What About
Long-Term Prognosis?
• 50% risk of permanent work disability within
4.5 to 22 years of RA diagnosis1
– Associated with decreased quality of life and high
healthcare costs
• Mortality in patients with RA2
– Compared with the general population:
• 50% increased risk of premature mortality
• Life expectancy decreased by 3 to 10 years
– Mortality risk increases with disease severity
(e.g., RF-positive RA), number of comorbidities,
and duration of disease
RA, rheumatoid arthritis; RF, rheumatoid factor. 1. Burton W, et al. Occup Med. 2006;56:18-27.
2. Myasoedova E, et al. Curr Rheumatol Rep. 2010;12:379-385.
Comments
Infections
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.
Patient Case
• Ms. Nelson is a 32 year old new mom
(4 months postpartum) presenting to
your primary care clinic complaining of
4 weeks of bilateral hand/wrist pain
and swelling
– She reports
p
significant
g
fatigue
g
– She works as a nanny and is having a hard time
lifting and caring for the children
• Other history
– Several colds over the last 3 months, but no rash
– She currently has rhinitis, resolving
non-productive cough
– No GU symptoms
– No new sexual partners
Physical Exam
Laboratory Findings
• Skin warm and dry without rash
or lesions, and no nail changes
• Parvovirus studies: negative
• Lungs: CTA bilaterally; cardiac: S1-S2
without murmur or extra heart sounds, RRR
• No lymphadenopathy
• Musculoskeletal exam
– Bilateral MCPs 1-3 swollen and tender
– Bilateral wrists swollen and tender
– Right knee tender
– Hands warm with mild erythema over MCPs
– Full active ROM spine, shoulders, hips, knees
and ankles
CTA, clear to auscultation; MCP, metacarpophalangeal; ROM, range of motion;
RRR, regular rate and rhythm.
• Hepatitis panel and HIV negative
when tested 1 year prior
(during pregnancy)
• ESR:
ESR 45 mm/hr
/h
• CRP: 12 mg/L
• Rheumatoid factor: 28 IU/mL
• Anti-CCP: negative
• ANA: negative
ANA, antinuclear antibody; anti-CCP, anticyclic citrullinated peptide CRP, C-reactive
protein; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency virus.
2
Autoantibodies in RA
• Rheumatoid factor (RF)
– Not highly sensitive or specific for RA
• 45% of patients positive in first 6 months
• 85% of patients positive with established disease
– Frequently negative at diagnosis
– May be elevated in other autoimmune conditions such as
PsA, SLE, etc; frequently elevated in hepatitis C
• Anti-CCP
– More specific for rheumatoid arthritis than RF
• Not elevated in hepatitis C
– Predictive of more aggressive disease
– May be positive up to 5 years before onset of disease
Anti-CCP, anticyclic citrullinated peptide; PsA, psoriatic arthritis; RA, rheumatoid arthritis;
SLE, systemic lupus erythematosus. Arnett FC, et al. Arthritis Rheum. 1988;31:315-324.
2010 ACR/EULAR
Classification Criteria for RA
ACR RA Classification Criteria
• Classification criteria NOT diagnostic criteria
– Patient has at least 1 joint with
ith definite clinical
synovitis (swelling)
• Does not include DIPs,
MTP, or
1st
0
2-10 large joints
• 2 requirements for applying classification
criteria to patients
1st
JOINT DISTRIBUTION (0-5)
1 large joint
– Instead, developed to study early RA
CMC
– Synovitis is not better explained by “another
disease”
• Differential diagnosis varies on clinical presentation
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581. CMC, carpometacarpal; DIP, distal
interphalangeal; MCP, metacarpophalangeal.
Classification Criteria in Practice
1
≥6 = definite RA
1-3 small joints (large joints not counted)
2
4-10 small joints (large joints not counted)
3
>10 joints (at least one small joint)
5
What if the score is <6?
Negative RF AND negative ACPA
0
Patient might fulfill the criteria…
Low positive RF OR low positive ACPA
2
High positive RF OR high positive ACPA
3
SEROLOGY (0-3)
SYMPTOM DURATION (0-1)
<6 weeks
0
≥6 weeks
1
ACUTE PHASE REACTANTS (0-1)
Normal CRP AND normal ESR
0
Abnormal CRP OR abnormal ESR
1
Æ Prospectively over time
(cumulatively)
Æ Retrospectively if data on all
four domains have been
adequately recorded in the past
Large joints are shoulders, elbows, hips, knees, and ankles. Small joints refer to the MCP
joints, PIP joints, second through fifth MTP joints, thumb IP joints, and wrists.
When are Radiographs Needed?
• In general:
– Radiographs not required for RA classification
8 small
joints
– Should not be taken for classification only
Slightly
RF+
• Exceptions:
– To rule out RA in someone with longstanding
symptoms of unknown origin
x1mo
ESR
45
• In someone with longstanding disease symptoms, if
radiographs do not show erosions or RA changes,
then the diagnosis is less likely
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.
3
Radiographic Features of RA
• Soft-tissue swelling
• Joint space
narrowing
Algorithm to Classification of RA
Including Radiographs
≥1 swollen joint,
which is not best explained by
another disease?
≥6/10 on the
scoring system?
Yes
No
• Erosions
– Presence of typical
erosions allows for
the classification of
RA even without
fulfillment of the
scoring system
Yes
Longstanding
inactive disease
suspected?
Document result of
the scoring system
Yes
Perform radiographic
assessment
No
No
Radiographs
already available
Not RA
No
RA
Yes
Yes
Erosions typical for
RA present?
No
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.
Referral to Rheumatology
• Utilizing the classification criteria for RA may help
get the patient in faster to rheumatology
– Classification criteria are not intended to help referral.
However, scoring the patient and providing rheumatology
with your assessment and labs may help to demonstrate
the need for the patient to be seen by
y rheumatology
gy
• Call your rheumatology provider if you are
concerned about a patient
Options for
RA T
Treatment
t
t
– Unclear diagnosis, poor treatment response, disease
flare, difficult-to-manage side effects, etc.
• Early recognition and treatment of RA is important
to help prevent joint damage and ultimately lead to
better outcomes in the long-term
ACR Referral Guidelines, 2010.
Treatment Goals for RA
• Eliminate pain
• Prevent joint damage
• Prevent loss of function
• Prevent comorbidities/increased
mortality
Effective disease control may be possible if
treated early and aggressively.
Before Starting Therapy
• Obtain CBC, LFTs, creatinine level, and
hepatitis B and C status
– Repeat at regular intervals depending on
the therapy
• Influenza vaccination
• Ophthalmologic exam for
hydroxychloroquine
• TB screening for biologic DMARDs
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.
4
Approach to RA Treatment
• Treatment choice based on disease activity, severity,
prognosis, comorbidities, and likelihood of
compliance
– Consider patient preferences related to cost, convenience,
monitoring requirements, potential adverse reactions, etc.
• The earlier the start, the better
– Should start at diagnosis
– Can start with nonbiologic or biologic DMARDs
• Follow evidence-based guidelines
– 2008 ACR guidelines
– Updated ACR RA guidelines: 2012
2008 ACR RA Guideline
• Guideline focus:
– Use of nonbiologic and biologic therapies for the
treatment of RA
– Concomitant use of antiinflammatory drugs and
interarticular and oral glucocorticoids
– Background of optimal and appropriate use of
nonmedical therapies (e.g., physical and
occupational therapies)
• Recommendations based on disease duration,
disease activity, and prognostic features
ACR, American College of Rheumatology; RA, rheumatoid arthritis.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
ACR Updated Guidelines for Use
Of DMARDS and Biologic Drugs
ACR Updated Guidelines for Use
Of DMARDS and Biologic Drugs
• 2012 update concentrated on 4 updated
sections
• Low disease activity or remission remains the goal for
each patient
– Indications for use and switching of DMARDs and
biologics
• Each therapy must be specific to each patient’s
health needs
– Use of biologic agents in high-risk RA patients
with hepatitis, cancer, or congestive heart failure,
qualifying for more aggressive treatment
• Recommends change to more intensive earlier
therapy to potentially provide better outcomes
– Screening for TB in RA patients starting or
receiving biologic drugs
– Vaccination in patients starting or receiving
DMARDS or biologics
American College of Rheumatology. Available at:
http://www.rheumatology.org/about/newsroom/2012/2012_04_01A.asp
Medical Management of RA
• Non-biologic
DMARDs
– Single agent
• Methotrexate
• Leflunomide
L fl
id
• Hydroxychloroquine
• Biologic DMARDs
– Not recommended
in patients with
early RA and only
low or moderate
disease activity
• Minocycline
• Combination with
methotrexate
• Sulfasalazine
• Monotherapy
– Dual DMARDs
– Triple DMARDs
DMARDs, disease-modifying antirheumatic drugs; RA, rheumatoid arthritis.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
• Guideline link:
http://www.rheumatology.org/practice/clinical/guidelin
es/Singh%20et%20al-ACR%20RA%20GLMay%202012%20AC&R.PDF
American College of Rheumatology. Available at:
http://www.rheumatology.org/about/newsroom/2012/2012_04_01A.asp
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.
5
Methotrexate:
Gold Standard for RA
Mechanism Interferes with DNA replication, inhibits lymphocyte
of action 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
C t
ContraP
Pregnancy
category
t
X;
X liliver and
d renall ffailure,
il
platelet
l t l t
indications 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 Mouth ulcers, nausea, fatigue, alopecia, diarrhea, achiness,
reactions irritability
Sulfasalazine
Mechanism
of action Potent antiinflammatory effects
Dose 1000 mg bid-tid
Contra3
indications Liver disease, platelet count <50,000/mm
Prescreening
Adverse
reactions Blood toxicity
Other Slightly inferior to MTX; pregnancy category B
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.
CBC, complete blood count; LFT, liver function test; MTX, methotrexate.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
Hydroxychloroquine
Mechanism
Antimalarial drug
of action
Dose 200 mg bid or 400 mg qd
ContraIn patients with retinal or visual field changes
indications
g CBC,, LFT,, creatinine,, ophthalmologic
p
g exam
Prescreening
Monitoring Yearly ophthalmologic exams
Adverse Risk of ocular reactions; otherwise wellreactions tolerated
Other Reduces signs and symptoms of RA, but
does not slow radiographic progression as
monotherapy; reduces the risk of new-onset
diabetes. Pregnancy Category C.
RA, rheumatoid arthritis.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784; Solomon D, et al. JAMA. 2011;305:2525-2531.
Leflunomide
Mechanism
of action Decreases T lymphocytes
Dose 10-20 mg/day
Contra- Pregnancy category X; liver disease, platelet
indications 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 Diarrhea, weight loss, elevated blood pressure;
reactions 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.
Anti-TNF Agents in RA
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:
I f ti
TB
TB, h
hepatitis,
titi ffungal,
l and
db
bacterial
t i l ((sepsis)
i )
– 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.
CBC, LFT, creatinine
Monitoring CBC, LFT, creatinine every 2-4 weeks for 3
months, then every 8-12 weeks
Agent
Description
Dosing and administration
Adalimumab
Fully human
anti-TNF
antibody
40 mg SC every other week, with or without
MTX
Certolizumab
Peglyated antiTNF antibody
400 mg SC at week 0, 2, and 4, then 200
mg every other week (or 400 mg monthly)
Etanercept
TNF receptor
receptorIgG fusion
protein
50 mg SC weekly with or without MTX via
single-dose, prefilled syringes or
autoinjectors
Golimumab
Fully human
anti-TNF
antibody
50 mg SC monthly via single-dose, prefilled
syringes or autoinjectors
Infliximab
Mouse-human
chimeric antiTNF antibody
In conjunction with MTX, 3 mg/kg IV at 0, 2,
and 6 weeks, then every 8 weeks; titration
to 8 mg/kg IV or every 4 weeks as needed
IV, intravenous; SC, subcutaneous; MTX, methotrexate; TNF, tumor necrosis factor.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784; prescribing information of individual agents.
6
Other Biologic DMARDs
Dosing and
administration
Other Agents: NSAIDs
Comments
• Help with inflammation & pain
500-1000 mg (weightbased) 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
• No disease-modifying capability
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
Agent
Description
Abatacept
T-cell modulator
Anakinra
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: Corticosteroids
Pros
Cons
• Helps with pain and
inflammation
• Can mask severity of disease
through anti-inflammatory action
• 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
• To reduce potential complications:
– Calcium and vitamin D supplementation
• Some disease-modifying
• Long- and short term risks include:
capability, so can help while
− Immunosuppression
other agents take effect (3-6
− Osteoporosis
months
th or more))
− Glucose intolerance/diabetes
– Bisphosphonates when on long-term
therapy
• When used with a DMARD,
additive disease-modifying
activity is noted
– To decrease adrenal suppression:
− Weight gain
− Hyperlipidemia
− Hypertension
– DXA to monitor bone health
− Cataracts
• Keep daily dose <7.5 mg
− Skin atrophy
• Give once a day in the morning
− Acne
− Steroid psychosis
DMARD, disease-modifying antirheumatic drug.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
Drugs No Longer Considered
Appropriate for RA Treatment
• Gold, oral & injectable
• Azathioprine
• Consider qod dosing
DXA, dual-emission X-ray absorptiometry.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
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
• Chlorambucil
• Smoking cessation
• Cyclophosphamide
• Stress management
• Cyclosporin
• Foot health
• Minocycline
• Vaccination
• Mycophenolate mofetil
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
– Yearly influenza vaccine
– Pneumococcal vaccine when indicated
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
7
Emerging Therapies in RA
Compounds
Patient Case
• Treatment considerations
Target(s)
Phase
Tofacitinib (CP-690,550)
Jak3
III
– Patient is breastfeeding and
not on birth control
Fostamatinib
Syk
III
– Options:
p
BAFF
III
LY2127399
• Hydroxychloroquine
• Biologic DMARD
Secukinumab (AIN457),
LY2439821
IL-17
I-II
LY3009104 (INCB28050)
Jak1/2
II
Clinicaltrials.gov, 07/2011
Ongoing Monitoring
Monitoring for
Safety and
Therapeutic
Response
• Assess disease activity
– Labs: ESR, CRP, PLT, etc.
– Joint examination: 28-joint count
– Disease flares
• Monitor treatment-specific
treatment specific side effects
• Monitor comorbidities
– CV: lipid profile, tobacco use, etc
– Osteoporosis: DXA, calcium, vitamin D, exercise,
FRAX
– Mental health
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.
3-Month Follow-Up
Patient Education
• Started on etanercept 2 weeks
after first visit by rheumatologist
• Appropriate use of medications
• Feeling much better, able to work
• Expectations regarding treatment efficacy and
potential side effects
• Laboratory findings:
– RF 112 IU/mL, ESR 12 mm/hr,
CRP 0.8 mg/L
• Physical examination:
– Right wrist still painful and swollen,
otherwise no joint complaints
• Requesting influenza vaccine
– Medication adherence
• Need
N d tto monitor
it and
d reportt adverse
d
events
t
– Frequent lab monitoring may be needed, particularly
with non-biologic DMARDs
• Implications of being immunocompromised
– Importance of vaccinations
– But avoidance of live vaccines
8
Summary
• New ACR RA classification criteria
facilitate:
– Earlier recognition of RA
– Earlier referral to rheumatology
• E
Early
l ttreatment
t
t initiation
i iti ti provides
id b
bestt
protection against joint damage and
functional impairment
• Ongoing monitoring critical for ensuring
safe treatment, managing side effects,
and improving patient adherence
ACR, American College of Rheumatology; RA, rheumatoid arthritis.
9