Heather Marie Mathis <mathishm@gmail.

com>

DynaMed Plus Rheumatoid Arthritis

Heather Marie Mathis <HMathis@dilworthderm.com> Fri, Dec 21, 2018 at 10:37 AM
To: Heather Mathis <mathishm@gmail.com>

[+]Updated 2018 Nov 29 03:59 PM (ET)

National Institute for Health and Care Excellence (NICE) guidance on management of
rheumatoid arthritis in adults (NICE 2018 Jul) view update
hand stretching and strengthening exercise program might improve hand function, but not pain
or grip strength, in medium-to-long term in adults with RA (Cochrane Database Syst Rev 2018
Jul 31) view update
higher number of poor prognostic factors may be associated with less improvement in disease
activity but not with increased treatment acceleration in adults with RA in United States (J
Rheumatol 2018 Jul 1 early online) view update

Overview and Recommendations

Background
Rheumatoid arthritis is a systemic inflammatory disease characterized by symmetric, relapsing
or chronic destructive synovitis. There may also be multisystem involvement.
The condition is more common in women and affects about 1% of adults over the age of 35
years.
Rheumatoid arthritis characteristically involves 3 or more proximal interphalangeal (PIP) joints,
metacarpophalangeal (MCP) joints, wrist and metatarsophalangeal (MTP) joints, although other
joints may be involved as well.
Structural damage begins 1-2 years from the disease onset and progresses as a linear function
of the amount of prior synovitis.
The most common complication is musculoskeletal disability from destructive arthritis.
Extraarticular complications include rheumatoid nodules, dermal vasculitis, keratoconjuctivitis
sicca with associated Sjogren syndrome, interstitial lung disease, pericarditis, mononeuritis
multiplex, amyloidosis, and increased cardiovascular mortality, and occur primarily in
rheumatoid factor [RF]-positive patients.

Evaluation
Consider rheumatoid arthritis in patients with:
history of pain and stiffness in multiple joints with initial symptoms predominantly at one
location or a few scattered sites and prodromal anorexia, weakness, or fatigue
physical exam findings of boggy, tender, warm joints (but not erythematous), puffy hands,
atrophy of muscles near affected joints, weakness out of proportion to pain, joints held in
flexion, or positive squeeze test.
The most common presentation is the insidious development of arthralgia, arthritis, malaise, and
fatigue over several weeks, however, an acute polyarticular development over 1-2 days is
possible.
Morning stiffness (gelling) usually lasting > 2 hours is a common feature and its presence is an
indicator of increased disease activity.
 Suggested initial testing in patients suspected to have RA includes rheumatoid factor (RF),
anticyclic citrullinated peptide (anti-CCP) antibodies, erythrocyte sedimentation rate (ESR), C-
reactive protein (CRP), complete blood count (CBC) with differential, liver and renal function
tests, and x-rays of significantly involved joints.
RF positivity generally correlates with the disease severity and extra-articular
involvement but titers are not useful to monitor for disease progression and diagnostically
are false-negative in 30%-40% of RA patients who are early in their illness.
The presence of anti-CCP antibodies tends to correlate with erosive disease.
American College of Rheumatology/European League Against Rheumatism (ACR/EULAR)
diagnostic criteria may help guide therapy and predict progression of disease.
Clinical features and laboratory findings consistent with a diagnosis of rheumatoid arthritis
include:
multiple symmetric small joints that are swollen or tender for > 6 weeks
morning stiffness lasting > 1 hour
elevated rheumatoid factor (RF) or anti-CCP antibodies
elevation in either the ESR or CRP
x-ray of the wrists and hands demonstrate typical RA findings
Early rheumatoid arthritis should be distinguished from other conditions that can cause joint pain
and inflammation, so that treatment with disease modifying therapy can be started before
erosive joint destruction has begun.

Management
Early treat-to-target management decreases disease activity and improves physical function
and quality of life.
Disease-modifying antirheumatic drugs (DMARDs) are recommended as first-line therapy and
should be started early in the disease course (Strong recommendation).
Select initial therapy based on disease activity (as determined by a validated instrument
such as the Clinical Disease Activity Index) and presence of markers of poor prognosis.
In most patients, begin DMARD therapy with either methotrexate 2.5-25 mg once weekly
or leflunomide 10-20 mg/day orally.
Hydroxychloroquine 200-400 mg/day, minocycline 50-200 mg/day, or sulfasalazine 2-3
g/day are lower-toxicity DMARDs which can be used initially for patients with low disease
activity.
Biologic DMARDs such as tumor necrosis factor (TNF) inhibitors, abatacept, tocilizumab,
anakinra, and rituximab are expensive but generally recommended after failure of
nonbiologic DMARDs, especially in patients with high disease activity or poor prognostic
features.
Tofacitinib, an oral Janus kinase (JAK) inhibitor may be considered if the treatment with
methotrexate or biologic DMARDs fails or these therapies are contraindicated.
Additional DMARD considerations:
Immunize all patients starting or currently receiving DMARDs or biologic therapy.
For patients starting or currently on DMARDs or biologic therapy, give killed
pneumococcal, influenza (intramuscular), and hepatitis B vaccines (if applicable
risk factors), recombinant human papilloma virus vaccine.
Give live attenuated herpes zoster vaccine to patients starting or currently on
DMARDs and those starting biologic or tofacitinib therapy if ≥ 50 years old. Live
attenuated herpes zoster vaccine not recommended for patients currently
receiving biologic therapy.
Hepatitis B and C screening should be performed on patients at higher risk for these
diseases prior to initiating therapy with leflunomide, methotrexate, or any biologic
DMARD.
Monitor CBC, liver function tests, and creatinine every 2-4 weeks for 3 months with dose
changes and then every 8-12 weeks.
Screening for latent tuberculosis should be performed on patients prior to initiating
treatment with biologic DMARDs.
The American College of Rheumatology recommends performing retinal exams prior to
 starting and periodically after starting hydroxychloroquine, with the frequency of follow-up
exams determined by patient risk.
Adjunct medication therapy:
Nonsteroidal anti-inflammatory drugs (NSAIDs) orally or topically may help to control
symptoms but are not disease modifying.
Corticosteroids orally or intra-articularly may be used for symptom control. Early low-
dose steroids added to DMARD therapy may be used to reduce joint destruction and
increase clinical remission rates.
Nonpharmacologic patient management includes patient education, exercise, physical and
occupational therapies, and cognitive therapies.
Obtain complete blood count, creatinine, and liver transaminases prior to starting, resuming, or
significantly increasing pharmacologic therapy.
Periodic follow up for assessment of disease activity and monitoring for drug toxicity is
recommended, and may vary based on disease severity.

Related Summaries
Rheumatoid arthritis (list of topics)
Principles of management of rheumatoid arthritis
NSAIDs for rheumatoid arthritis
Corticosteroids for rheumatoid arthritis
Nonbiologic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis
Biologic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis
Combination therapies for rheumatoid arthritis
Physician Quality Reporting System Quality Measures

General Information
Description
systemic inflammatory disease characterized by symmetric, relapsing or chronic, destructive
synovitis, and sometimes multisystem involvement(2, 4, 5)

Definitions
European League Against Rheumatism (EULAR) definition of erosive disease
erosion (defined as cortical break) seen at ≥ 3 separate joints at any of following sites on
radiographs of both hands and feet
proximal interphalangeal (PIP) joints
metacarpophalangeal (MCP) joints
wrist (counted as one joint)
metatarsophalangeal (MTP) joints
2 joints counted if bilateral joints affected; 3 joints in the same joint group can fulfill
definition
Reference - Ann Rheum Dis 2013 Apr;72(4):479 full-text

Epidemiology
Who is most affected
 3 times more common in women(1, 2)
typical onset between 30-50 years old(5)
highest prevalence in women > 65 years old(1, 2)

Incidence/Prevalence
Global

global prevalence of RA about 0.24%

based on systematic review
23 studies assessing incidence and prevalence data for RA from 10 countries in 6 world
regions reviewed
global prevalence of RA
0.24% (95% CI 0.23-0.25%) overall
0.35% (95% CI 0.34-0.37%) in women
0.13% (95% CI 0.12-0.13%) in men
Reference - Ann Rheum Dis 2014 Jul;73(7):1316
common in North America and Europe compared with rural West Africa(1)

United States

estimated incidence 0.6% in American adults aged > 18 years in 2005 (Arthritis Rheum 2008
Jan;58(1):15 full-text)
prevalence of RA 1.07% among adults aged > 35 years in Rochester, Minnesota in 1985
(Arthritis Rheum 1999 Mar;42(3):415 in Arthritis Rheum 2008 Jan;58(1):15 full-text)
higher incidence of RA in women in New England states compared to western United
States
based on prospective cohort study
83,546 women followed from 1976 to 2004
compared with women in western United States, women in New England states had
increased incidence of rheumatoid arthritis (rate ratio 1.42, 95% CI 1.1-1.82)
Reference - Arch Intern Med 2008 Aug 11;168(15):1664 full-text

United Kingdom

incidence 1.5 per 10,000 males and 3.6 per 10,000 females each year(4)

Likely risk factors

smoking
smoking associated with increased risk of rheumatoid arthritis
based on systematic review
systematic review of 16 observational studies evaluating association between
smoking history and risk of developing rheumatoid arthritis
increased risk of rheumatoid arthritis in
male smokers
ever (odds ratio [OR] 1.89, 95%CI 1.56-2.28)
current (OR 1.87, 95% CI 1.49-2.34)
past (OR 1.76, 95% CI 1.33-2.31)
rheumatoid factor-positive males
ever (OR 3.02, 95% CI 2.35-3.88)
current (OR 3.91, 95% CI 2.78-5.5)
past (OR 2.46, 95% CI 1.74-3.47)
males with ≥ 20 pack-years smoking history (OR 2.31, 95% CI 1.55-3.41)
female smokers
 ever (OR 1.27, 95% CI 1.12-1.44)
current (OR 1.31, 95% CI 1.12-1.54)
past (OR 1.22, 95% CI 1.06-1.4)
females with ≥ 20 pack-years smoking history (OR 1.75, 95% CI 1.52-2.02)
Reference - Ann Rheum Dis 2010 Jan;69(1):70

Possible risk factors

genetic predisposition
STAT4 gene and CD40 locus associated with increased risk for rheumatoid arthritis(3)
human leukocyte antigen (HLA) genes and gender may constitute about 60% genetic
risk of RA (Mayo Clin Proc 2006 Jan;81(1):94)
twin studies have reported inconsistent results
monozygotic twin concordance rate ranged from 10% to 18% (J Rheumatol 1994
Aug;21(8):1420)
15.4% monozygotic twin concordance rate and 3.6% dizygotic twin
concordance rate for rheumatoid arthritis
based on cohort study
91 monozygotic and 112 dizygotic pairs evaluated
Reference - Br J Rheumatol 1993 Oct;32(10):903
monozygotic twin concordance rate 0% in survey of 37,338 Danish twins with
85% response rate (BMJ 2002 Feb 2;324(7332):264), commentary can be found
in BMJ 2002 May 4;324(7345):1100, BMJ 2002 Aug 17;325(7360):391
interpretation of twin studies may be limited by 89% false-positive rate for self-
reported diagnosis of RA (Ann Rheum Dis 1992 May;51(5):588 PDF)
increased risk of rheumatoid arthritis observed among first-degree family
members of persons with systemic lupus erythematosus
based on population-based cohort study
23,658,577 persons from Taiwan National Health Insurance Research Database
registered in 2010 evaluated
18,283 (0.08%) had systemic lupus erythematosus (SLE)
increased risk of rheumatoid arthritis observed among first-degree family
members of persons with SLE (adjusted relative risk 2.66, 95% CI 2.28-3.11)
Reference - JAMA Intern Med 2015 Sep 1;175(9):1518
elevated rheumatoid factor associated with increased long-term risk of RA
based on prospective cohort study
9,712 white persons aged 20-100 years without rheumatoid arthritis were evaluated for
plasma immunoglobulin M (IgM) rheumatoid factor level and followed up to 28 years
plasma IgM rheumatoid factor levels at baseline
< 25 units/mL in 95.7%
25-50 units/mL in 1.8%
50.1-100 units/mL in 1.9%
> 100 units/mL in 0.6%
1.9% developed RA
compared to plasma IgM rheumatoid factor level < 25 units/mL, risk of RA increased with
rheumatoid factor level of (p < 0.0001 for trend)
25-50 units/mL (adjusted hazard ratio [HR] 3.6, 95% CI 1.7-7.3)
50.1-100 units/mL (adjusted HR 6, 95% CI 3.4-10)
> 100 units/mL (adjusted HR 26, 95% CI 15-46)
Reference - BMJ 2012 Sep 6;345:e5244 full-text, editorial can be found in BMJ 2012 Sep
6;345:e5841
elevated soluble tumor necrosis factor receptor II (sTNFRII) levels associated with
increased likelihood of subsequent development of rheumatoid arthritis
based on nested case-control study
57,744 patients in 2 prospective cohorts of women (Women's Health Study and Nurses'
Health Study) evaluated
blood samples obtained prior to symptom onset in women later diagnosed with
 rheumatoid arthritis (170 incident cases) compared with blood samples of 510 matched
controls
mean time from blood collection to rheumatoid arthritis symptom onset 5.2 years (range
0.3-12 years)
patients with increased sTNFRII levels associated with increased risk for subsequent
rheumatoid arthritis (relative risk 2, p = 0.004)
Reference - Arthritis Rheum 2009 Mar;60(3):641
coffee consumption
conflicting evidence for coffee consumption and increased risk for rheumatoid
factor (RF)-positive rheumatoid arthritis
based on cross-sectional study and prospective cohort study
6,809 persons without arthritis evaluated and prospective cohort of 18,981 men
and women who had no arthritis or history of it at baseline followed for 13 to 16
years
in cross-sectional study, increased number of cups of coffee daily not associated
with significant increased risk for RF positivity
in prospective cohort study
126 developed rheumatoid arthritis of whom 89 had positive RF
drinking ≥ 4 cups of coffee daily associated with increased risk for RF-
positive rheumatoid arthritis (relative risk 2.2 , 95% CI 1.13-4.27)
Reference - Ann Rheum Dis 2000 Aug;59(8):631 PDF, commentary can be found
in Ann Rheum Dis 2000 Dec;59(12):1000
decaffeinated coffee consumption but not caffeinated coffee or tea associated with
increased risk for rheumatoid arthritis
based on prospective cohort study
31,366 women aged 55-69 years followed for 11 years
158 developed rheumatoid arthritis
drinking > 3 cups of decaffeinated coffee per day associated with increased risk
for rheumatoid arthritis (relative risk [RR] 2.58, 95% CI 1.63-4.06)
drinking > 3 cups of tea per day had decreased risk (RR 0.24, 95% CI 0.06-0.98)
no association found between caffeinated coffee or daily caffeine intake and risk
for rheumatoid arthritis
Reference - Arthritis Rheum 2002 Jan;46(1):83 full-text
absence of hormonal replacement therapy may increase risk for progression to RA in
women with early arthritis who carry human leukocyte antigen (HLA) HLA-DRB1-01
and/or HLA-DRB1-04 alleles (level 2 [mid-level] evidence)
based on retrospective cohort analysis
568 women (mean age 47 years) with early arthritis and HLA-DRB1-01 and/or HLA-
DRB1-04 alleles were analyzed
in women with no hormonal replacement therapy, risk of RA increased (odds ratio [OR]
1.85, 95% CI 1.32-2.68
Reference - Ann Rheum Dis 2010 Sep;69(9):1683
effect of oral contraceptives on risk for rheumatoid arthritis uncertain (Curr Opin Rheumatol
2009 May;21(3):279 full-text)
low socioeconomic status and high birth weight may increase risk for rheumatoid arthritis (Curr
Opin Rheumatol 2009 May;21(3):279 full-text)

posttraumatic stress disorder (PTSD) associated with increased risk of adult-onset

rheumatoid arthritis
based on cohort study
3,143 male twin pairs who served active military duty during Vietnam War era had PTSD
assessed in 1987 and diagnosis of rheumatoid arthritis (RA) obtained in 1991 as part of
follow-up survey
prevalence of RA 1.9%
mean PTSD symptom level 25.5 (scale range 15-60)
statistical adjustments made for age, education, body mass index (BMI), smoking status,
combat exposure, and depression
increased prevalence of RA among patients in highest quartile of PTSD symptoms vs.
 lowest quartile (adjusted odds ratio 3.8, 95% CI 2.1-6.1)
Reference - Psychosom Med 2010 Jun;72(5):481

Factors not associated with increased risk

silicone breast implants do not appear to be associated with development of rheumatoid
arthritis
based on systematic review and meta-analysis
systematic review of 9 cohort studies, 9 case-control studies, and two cross-sectional
studies
no association found for increased risk of
rheumatoid arthritis
systemic lupus erythematosus
scleroderma or systemic sclerosis
Sjogren syndrome
Reference - N Engl J Med 2000 Mar 16;342(11):781 full-text
vitamin D intake does not appear to be associated with altered risk for development of
RA
based on cohort study
29,368 women without history of RA aged 55-69 years followed for 11 years
152 (0.5%) developed RA
intake of vitamin D (food and supplement) not associated with altered risk for
development of RA
Reference - Arthritis Rheum 2004 Jan;50(1):72
occupational exposure to mineral oil (cutting oil, motor oil, form oil, hydraulic oil, or
asphalt) does not appear to be associated with increased risk of RA
based on case-control study
1, 419 RA patients and 1,674 controls from Swedish population aged 18-70 years
evaluated
occupational exposure to mineral oil not associated with increased risk RA
Reference - Arthritis Research & Therapy 2005 Sep 23;7(6):R1296
postmenopausal hormone therapy does not appear to be associated with risk for
rheumatoid arthritis
based on cohort study
27,347 women who were part of Women's Health Initiative trials followed for > 5 years
hormone therapy not associated with reduction in risk for rheumatoid arthritis
Reference - Arthritis Rheum 2008 Feb 29;59(3):302 full-text
single episode of monoarthritis does not appear to increase risk for rheumatoid arthritis
based on cohort study
270 patients with undiagnosed arthritis < 1 year duration classified as 1 of 3 patient types
patients with single episode of monarthritis
patients with monoarthritis and history of patient-reported arthritis
patients with polyarthritis
at 3 years no patient in single episode group had developed rheumatoid arthritis
Reference - J Rheumatol 2007 Dec;34(12):2351
factors which may be associated with decreased risk for rheumatoid arthritis
alcohol consumption associated with decreased risk of rheumatoid arthritis
based on systematic review of observational studies and additional cohort study
systematic review of 6 case-control studies and 3 cohort studies evaluating
association between drinking alcohol and risk of developing rheumatoid arthritis in
96,906 persons
drinking alcohol associated with reduced risk of rheumatoid arthritis in
overall meta-analysis (odds ratio 0.78, 95% CI 0.63-0.96) (results limited
by significant heterogeneity)
significant association found in analysis of case-control studies but not in
analysis of cohort studies
Reference - Rheumatology (Oxford) 2013 May;52(5):856
 prospective cohort study of 34,141 women aged 54-89 years in Sweden followed
for 7 years
197 incident cases of rheumatoid arthritis occurred
reduced risk of rheumatoid arthritis with
drinking > 4 glasses of alcohol (1 glass equivalent to ethanol 15 g)
per week vs. < 1 glass per week or never drinking alcohol (relative
risk 0.63, 95% CI 0.42-0.96)
long-term alcohol consumption (> 3 glasses of alcohol per week at
time points 10 years apart) vs. never drinking alcohol (relative risk
0.48, 95% CI 0.24-0.98)
Reference - BMJ 2012 Jul 10;345:e4230 full-text
long-term breastfeeding might be associated with reduced risk for rheumatoid
arthritis in mother
based on case-control study
136 women with rheumatoid arthritis were matched to 544 controls without
rheumatoid arthritis
lifestyle factors evaluated via self-administered questionnaire
compared to never breastfeeding, breastfeeding for ≥ 13 months associated with
reduced risk for rheumatoid arthritis (OR 0.46, 95% CI 0.24-0.91)
Reference - Ann Rheum Dis 2009 Apr;68(4):526
lower incidence of rheumatoid arthritis in patients with schizophrenia (Acta Psychiatr
Scand 2007 Nov;116(5):317)

Associated conditions
Sjogren syndrome
Felty syndrome
Caplan syndrome (Occup Med (Lond) 2004 Aug;54(5):304)
rheumatoid arthritis associated with mildly increased risk of metabolic syndrome
based on systematic review of observational studies
systematic review of 12 case-control or cross-sectional studies evaluating association
between rheumatoid arthritis and risk of metabolic syndrome in 6,686 patients
rheumatoid arthritis associated with increased risk of metabolic syndrome (odds ratio
1.24, 95% CI 1.03-1.5) in analysis of 11 studies, results limited by significant
heterogeneity
stratified results suggest larger magnitude of association in studies in United States
compared to studies in Asia and Europe
Reference - PLoS One 2013;8(10):e78151 full-text

RA associated with increased risk of squamous cell and basal cell cancer, with higher
risk in patients treated with TNF inhibitors
based on population-based cohort study
58,967 patients with RA in Sweden were matched by age, sex, and county of residence
to 379,666 general population controls
among patients with RA, 78.7% were naive to biologics and 21.3% were treated with
tumor necrosis factor (TNF) inhibitors
compared to general population, RA naive to biologics associated with increased risk of
squamous cell cancer (adjusted hazard ratio [HR] 1.88, 95% CI 1.74-2.03)
basal cell cancer (adjusted HR 1.22, 95% CI 1.07-1.41)
compared to RA naive to biologics, RA treated with TNF inhibitors associated with
increased risk of squamous cell cancer (adjusted HR 1.3, 95% CI 1.1-1.55)
nonsignificant increase in risk of basal cell cancer (adjusted HR 1.14, 95% CI
0.98-1.33)
Reference - BMJ 2016 Jan 28;352:i262 full-text
6.8% prevalence of hypothyroidism in women with rheumatoid arthritis and
hypothyroidism associated with increased risk for cardiovascular disease
based on subgroup analysis of cohort study
 236 women (out of 358 total patients) with rheumatoid arthritis were tested for
hypothyroidism and cardiovascular disease
16 women (6.8%) had clinical hypothyroidism
6 women (2.5%) had subclinical hypothyroidism
cardiovascular disease defined as verified medical history of coronary, cerebral, or
peripheral arterial disease
6 of 16 (37.5%) hypothyroid women had cardiovascular disease
compared to euthyroid patients, women with hypothyroidism had increased risk for
cardiovascular disease (adjusted odds ratio 4.1, 95% CI 1.2-14.3)
Reference - Ann Rheum Dis 2008 Feb;67(2):229
RA activity over time, but not RA duration, associated with increased risk of
cardiovascular disease
based on cohort study
855 patients (mean age 54 years) with RA plus > 6 months follow-up and no history of
cardiovascular disease before RA diagnosis were analyzed
154 cardiovascular events occurred during 9,959 patient-years of follow-up
disease activity measured with 28-joint Disease Activity Score (DAS28)
increased time-averaged DAS28 associated with increased risk of cardiovascular
disease (p = 0.002)
disease duration < 10 years and disease duration > 10 years not associated with no
significantly different risk of cardiovascular disease
Reference - Ann Rheum Dis 2015 Jun;74(6):998

Etiology and Pathogenesis

Causes
complex interplay between environmental and genetic factors(3)
50% of risk attributable to genetic factors(1, 3)
initial event inciting inflammatory response unknown(5)

Pathogenesis
unclear if arthritis begins as primary bone or joint problem(1)
initial triggering event (possibly autoimmune or infectious) stimulates proliferation of synovial
macrophages and fibroblasts(3, 5)
lymphocytes infiltrate perivascular regions and endothelial cells proliferate causing
neovascularization
blood vessels in affected joint become occluded with small clots or inflammatory cells
inflamed synovial tissue begins to grow irregularly, forming pannus tissue which invades
and destroys cartilage and bone
multiple cytokines (including tumor necrosis factor), interleukins (including interleukin-6),
proteinases, and growth factors are released, causing further joint destruction and
development of systemic complications

History and Physical

History
Chief concern (CC)

pain and stiffness in multiple joints (common)(2, 5)

 initial symptoms at one location or few scattered sites in 33%(5)
prodromal anorexia, weakness, or fatigue common(2, 5)

History of present illness (HPI)

symptoms must be present ≥ 6 weeks for clear diagnosis (Best Pract Res Clin Rheumatol 2005
Feb;19(1):55)
variable onset(5)
most common onset is insidious development of symptoms over several weeks
stiffness and swelling prior to pain
may present with symmetric joint involvement(2, 5)
multiple joints commonly involved(3, 5)
explosive acute polyarticular onset evolving over several days can occur(5)
slowly progressive or variable course, flares common(5)
morning stiffness lasting ≥ 45 minutes after initiating movement is common(5)

Social history (SH)

ask about history of smoking

ask about functional impact including limitations in ability to work, meet family responsibilities, or
enjoy leisure time
ask about impending pregnancies

Review of systems (ROS)

hoarseness with patient report of laryngeal pain may suggest cricoarytenoid joint
inflammation(5)

Physical
General physical

may have fever and weight loss(2)

Skin

subcutaneous (rheumatoid) nodules

present in up to 30% of patients with advanced disease
about 1-2 cm
usually found at pressure points - elbow, knuckles, ischial spines, occiput, extensor
forearm, Achilles tendon
also seen in rheumatic fever or gout (but gouty tophi tend to develop insidiously)
Reference - Best Pract Res Clin Rheumatol 2007 Oct;21(5):907
may have prominent epitrochlear, axillary, and cervical lymph nodes(5)

Lungs

rales (crackles) may suggest interstitial fibrosis(5)

Abdomen

splenomegaly may indicate Felty syndrome

Extremities
 joint findings(2, 5)
joints with highest ratio of synovium to articular cartilage most commonly affected
wrists, proximal interphalangeal and metacarpophalangeal joints commonly
affected
distal interphalangeal joints and sacroiliac joints usually not affected
foot and ankle
metatarsophalangeal (MTP) joint involvement is early sign of RA (Eur J
Radiol 1998 May;27 Suppl 1:S18)
valgus deformities and flat foot frequently seen in later stages (Eur J Radiol
1998 May;27 Suppl 1:S18)
affected joints typically boggy, tender and warm, but usually not erythematous
may have “puffy” hands secondary to increased blood flow to inflamed areas
muscles near inflamed joints often atrophy(5)
weakness commonly out of proportion to pain(5)
patients often hold joints in flexion to minimize painful distension of joint capsules(5)
low-grade fever, fatigue, malaise, and other systemic complaints may arise, especially in an
acute presentation(2, 5)
squeeze test (compression pain in metacarpophalangeal [MCP] and MTP joints)(2, 5)
ulnar deviation, as well as swan neck and bouttoniere deformities, are more common as
complications of longstanding disease, but may occur early in disease course(2, 5) I506277.jpg
I506276.jpg

Diagnosis
Making the diagnosis
American College of Rheumatology/European League Against Rheumatism (ACR/EULAR)
2010 criteria for diagnosis
≥ 1 joint with definite clinical synovitis not explained by another disease plus 1 of the
following
presence of long-standing disease previously satisfying classification criteria
presence of ≥ 2 typical periarticular erosions
score > 6 on following criteria
joint involvement (0-5)
1 medium-to-large joint - 0
2-10 medium-to-large joints - 1
1-3 small joints (large joints not counted) - 2
4-10 small joints (large joints not counted) - 3
> 10 joints (> 1 small joint) - 5
serology (0-3)
negative rheumatoid factor (RF) and anticitrullinated protein
antibody (ACPA) - 0
low positive RF or low positive ACPA - 2
high positive RF or high positive ACPA - 3
acute phase reactants (0-2)
normal C-reactive protein and normal erythrocyte sedimentation
rate (ESR) - 0
abnormal C-reactive protein or abnormal ESR - 2
duration of symptoms (0-1)
< 6 weeks - 0
> 6 weeks - 1
goal is to identify patients with rheumatoid arthritis as early as possible to allow for
therapy before erosive changes have begun
 Reference - Ann Rheum Dis 2010 Sep;69(9):1580, correction can be found in Ann
Rheum Dis. 2010 Oct;69(10):1892, commentary can be found in Ann Rheum Dis 2010
Sep;69(9):1575

Differential diagnosis
other causes of arthritis include(3)
systemic lupus erythematosus
psoriatic arthritis
scleroderma
polymyalgia rheumatica
sarcoidosis
spondyloarthropathy
viral process (such as parvovirus B19 arthropathy)
gout
calcium pyrophosphate deposition disease
fibromyalgia
adult-onset Still disease
remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome
case series of 12 patients can be found in Mayo Clin Proc 2007 Dec;82(12):1510
case series of 10 patients can be found in JAMA 1985 Nov 15;254(19):2763
Jaccoud's arthropathy case report in Lancet 2013 Jun 15;381(9883):2108

Testing overview
refer patients with suspected rheumatoid arthritis to rheumatologist as soon as possible, without
performing blood tests or imaging due to reduced chance of drug-free remission and increased
risk for progressive joint damage if delay in treatment > 12 weeks(2)
initial testing in patients with suspected RA includes
rheumatoid factor (RF)(2, 5)
anticyclic citrullinated peptide (anti-CCP) antibodies(2, 5)
complete blood count with differential(2, 5)
erythrocyte sedimentation rate (ESR)(2, 5)
C-reactive protein (CRP)(2, 5)
liver function tests(5)
imaging
x-ray
magnetic resonance imaging
ultrasound
aspiration of synovial fluid or synovial biopsy if infection or crystal-induced disease
suspected(2)
American College of Rheumatology recommendations for testing when starting, resuming, or
significantly increasing pharmacological therapy
complete blood count
liver transaminase levels
serum creatinine
if considering leflunomide or methotrexate, screen for hepatitis B and C if patient history
suggests higher risk
if considering hydroxychloroquine, perform retinal exam
perform every 5 years if patient is low risk (no liver disease, no concomitant retinal
disease, < 60 years old)
perform annually if higher risk patient
if considering biologic disease-modifying antirheumatic drug, screen for latent
tuberculosis
 assess for risk factors
screen regardless of history of bacillus Calmette-Guérin (BCG) vaccination
false-negative tests more likely in RA patients than non-RA patients
References
Arthritis Rheum 2008 Jun 15;59(6):762 full-text (endorsed in 2015 guideline
update)
Arthritis Rheum 2002 Feb;46(2):328
Japan College of Rheumatology recommends patients taking tocilizumab should have the
following laboratory findings to avoid opportunistic infections
white blood cells count ≥ 4,000 per mcL (4 × 109 leukocytes/L)
peripheral blood lymphocyte count ≥ 1,000 per mcL (1 × 109 lymphocytes/L)
negative serum 1, 3-beta-D-glucan assay
Reference - Mod Rheumatol 2009;19(4):351
consider x-ray neck in flexion to rule out odontoid ligament laxity
arthrocentesis with synovial fluid analysis should be considered to rule out calcium
pyrophosphate dihydrate deposition disease or gout (Cleve Clin J Med 2008 Jul;75 Suppl
5:S17 full-text)

Clinical prediction rules

modified predictive rule (using duration of morning stiffness instead of severity)
predicts progression to rheumatoid arthritis in patients with undifferentiated arthritis
(level 1 [likely reliable] evidence)
based on revised derivation of predictive rule and validation in 3 independent cohorts
morning stiffness duration not as predictive as severity but used because duration data
was available in validation cohorts
prediction score 0-14 derived from 9 factors
age in years × 0.02
female gender - add 1 point
distribution of involved joints
add 0.5 points if small joints of hands and feet
add 0.5 points if symmetric
add 1 point if upper extremities
add 1.5 points if upper and lower extremities
morning stiffness duration
add 1 point if 30-59 minutes
add 2 points if ≥ 60 minutes
number of tender joints
add 0.5 points if 4-10
add 1 point if ≥ 11
number of swollen joints
add 0.5 points if 4-10
add 1 point if ≥ 11
C-reactive protein level
add 0.5 points if 5-50 mg/L
add 1.5 points if > 50 mg/L
rheumatoid factor - add 1 point if positive
anticyclic citrullinated peptide (anti-CCP) antibodies - add 2 points if positive
score rounded to nearest integer
in derivation cohort of 570 patients
335 of 388 patients (86%) with score ≤ 6 did not have rheumatoid arthritis
86 of 114 patients (75%) with score ≥ 8 had rheumatoid arthritis
60 patients (10.5%) with score 6.5-7.5 were in intermediate range
in British validation cohort of 99 patients
54 of 65 patients (83%) with score ≤ 6 did not have rheumatoid arthritis
7 of 7 patients (100%) with score ≥ 8 had rheumatoid arthritis
 27 patients (27%) with score 6.5-7.5 were in intermediate range
in German validation cohort of 155 patients
78 of 94 patients (83%) with score ≤ 6 did not have rheumatoid arthritis
25 of 27 patients (93%) with score ≥ 8 had rheumatoid arthritis
34 patients (22%) with score 6.5-7.5 were in intermediate range
in Dutch validation cohort of 34 patients
18 of 21 patients (86%) with score ≤ 6 did not have rheumatoid arthritis
5 of 5 patients (100%) with score ≥ 8 had rheumatoid arthritis
8 patients (24%) with score 6.5-7.5 were in intermediate range
in 3 validation cohorts combined with 288 patients
150 of 180 patients (83%) with score ≤ 6 did not have rheumatoid arthritis
37 of 39 patients (97%) with score ≥ 8 had rheumatoid arthritis
69 patients (24%) with score 6.5-7.5 were in intermediate range
Reference - Arthritis Rheum 2008 Aug;58(8):2241 full-text

Blood tests
Rheumatoid factor (RF)

RF generally correlates with disease severity and extra-articular involvement(6)

most commonly immunoglobulin M (IgM) RF(6)
tests for other classes of RF (immunoglobulin G, immunoglobulin A) not widely used(6)
titers not useful to monitor disease progression(6)
low specificity in general population(6)
false-negative in 30%-40% of patients early in illness(5, 6)
false-positives associated with(6)
advancing age - prevalence in healthy elderly may be as high as 10%, generally with titer
≤ 1:40
chronic bacterial infections
infective endocarditis
tuberculosis
syphilis
Chronic hepatitis C infection (Medicine (Baltimore) 2000 Jan;79(1):47)
viral diseases
mumps
rubella
influenza
parasitic diseases
other inflammatory conditions
Sjogren syndrome
systemic lupus erythematosus (SLE)
scleroderma
mixed connective tissue disease
cryoglobulinemia
pulmonary disease
sarcoidosis
pulmonary fibrosis
silicosis
asbestosis
neoplastic disease, especially
leukemia
colon carcinoma
liver disease
primary biliary cirrhosis
Anticyclic citrullinated peptide antibodies (anti-CCP)

also called anticitrullinated protein antibody (ACPA)

tends to correlate with disease progression(4, 5)

absence of anti-CCP2 antibody may rule out rheumatoid arthritis in patients with early
symptoms (level 2 [mid-level] evidence)
based on systematic review of mostly low-quality studies
systematic review of 151 cohort, case-control, and cross-sectional studies evaluating
anti-CCP antibody assays for diagnosis of rheumatoid arthritis in patients with early
symptoms
results limited by heterogeneity
predictive performance of anti-CCP assays
sensitivity ranged from 12% to 93%
specificity ranged from 63% to 100%
pooled predictive performance of second generation anticyclic citrullinated peptide (anti-
CCP2) antibodies in patients with rheumatoid arthritis for < 2 years in analysis of 15
cohort studies
sensitivity 57% (95% CI 51%-63%)
specificity 96% (95% CI 93%-97%)
positive likelihood ratio 12.7 (95% CI 7.8-20.9)
negative likelihood ratio 0.45 (95% CI 0.39-0.52)
Reference - Ann Intern Med 2010 Apr 6;152(7):456
anti-CCP antibodies appear more specific than rheumatoid factor for rheumatoid
arthritis (level 2 [mid-level] evidence)
based on systematic review of studies with methodologic limitations
systematic review of 37 studies of anti-CCP antibody and 50 studies of rheumatoid factor
(RF) for diagnosis of rheumatoid arthritis
many studies had methodologic limitations, studies of RF were heterogeneous
pooled results for anti-CCP antibody had 67% sensitivity, 95% specificity, positive
likelihood ratio 12.46, and negative likelihood ratio 0.36
pooled results for IgM RF had 69% sensitivity, 85% specificity, positive likelihood ratio
4.86, and negative likelihood ratio 0.38
positive anti-CCP antibody associated with higher risk for radiographic progression than
positive IgM RF in 3 of 4 studies
Reference - Ann Intern Med 2007 Jun 5;146(11):797, editorial can be found in Ann Intern
Med 2007 Jun 5;146(11):816, commentary can be found in ACP J Club 2007 Nov-
Dec;147(3):78, Ann Intern Med 2008 Mar 4;148(5):403
similar conclusions supported by diagnostic case-control study with 155 patients with RA,
178 patients with other rheumatic diseases, and 100 blood donors (BMC Musculoskelet
Disord 2007 Apr 20;8:37 full-text)
combined detection of antibodies against citrulline-containing epitopes not associated
with greater accuracy in diagnosing rheumatoid arthritis than anticyclic citrullinated
peptide (anti-CCP) antibodies alone
based on cohort study
551 patients with arthritic disorders (rheumatoid arthritis in 55%) evaluated with enzyme-
linked immunosorbent assay (ELISA) and indirect immunofluorescence assay
accuracy of anti-CCP antibodies in diagnosing rheumatoid arthritis
sensitivity 76.2%
specificity 96%
accuracy of combination anti-CCP, antikeratin antibodies, and antiperinuclear factor
positivity in diagnosing rheumatoid arthritis
sensitivity 100%
specificity 28.3%
Reference - J Rheumatol 2010 Dec;37(12):2462
anti-CCP antibodies associated with joint erosions
based on cohort study without clinical outcomes
 681 patients with swelling in ≥ 2 joints for ≥ 4 weeks were evaluated from 2 subsets of
Norfolk Arthritis Register (NOAR) inception cohort
among 254 consecutive patients who had baseline radiography (recruited after 2000)
88 patients (34.6%) were anti-CCP positive
71 patients (28%) were RF positive
121 (48%) had erosions on baseline radiography
anti-CCP antibodies had 45.5% sensitivity, 75.2% specificity, 62.5% positive
predictive value, and 60.2% negative predictive value for erosions (positive
likelihood ratio 1.8)
anti-RF antibodies had 33% sensitivity, 76.7% specificity, 56.3% positive
predictive value, and 55.7% negative predictive value for erosions (positive
likelihood ratio 1.4)
among 427 consecutive patients who had baseline serum sample (1990-1994) and
radiograph at 5 years
125 patients (29.3%) were anti-CCP positive
113 patients (26.5%) were RF positive
181 (42.4%) had erosions on radiography at 5 years
anti-CCP antibodies had 54.7% sensitivity, 89.4% specificity, 79% positive
predictive value, and 73% negative predictive value for erosions (positive
likelihood ratio 6)
anti-RF antibodies had 41% sensitivity, 85.2% specificity, 63% positive predictive
value, and 66% negative predictive value for erosions (positive likelihood ratio 2.4)
Reference - Arthritis Rheum 2007 Sep;56(9):2929 full-text
combination of positive anti-CCP antibody and positive rheumatoid factor may predict
both diagnosis and persistence of rheumatoid arthritis
based on cohort study
96 patients with early inflammatory arthritis followed for up 72 weeks
for diagnosis of RA, combination of positive anti-CCP antibody and positive rheumatoid
factor had
sensitivity 100%
specificity 58%
positive predictive value 100%
negative predictive value 88%
for prediction of persistent RA, combination of positive anti-CCP antibody and positive
rheumatoid factor had
sensitivity 63%
specificity 97%
positive predictive value 86%
negative predictive value 91%
Reference - J Rheumatol 2005 Feb;32(2):231
anti-CCP antibody may predict progression to rheumatoid arthritis
based on small cohort study
61 patients with palindromic rheumatism followed for mean 5.4 years
29 (48%) developed rheumatoid arthritis
For Prediction of Development of Rheumatoid Arthritis:
Sensitivity Specificity PPV NPV LR+ LR-
Anti-CCP
83% 68% 71% 81% 2.6 0.12
antibody
Rheumatoid
67% 61% 60% 61% 1.7 0.54
factor
Both (positive
anti-CCP
antibody and
77% 84% 81% 81% 4.8 0.27
positive
rheumatoid
factor)
 Abbreviations: LR+, positive likelihood ratio; LR-, negative likelihood ratio; NPV,
negative predictive value; PPV, positive predictive value.
Reference - J Rheumatol 2006 Jul;33(7):1240, editorial can be found in J Rheumatol
2006 Jul;33(7):1216
lower anti-CCP antibody threshold associated with higher sensitivity for predicting

development of rheumatoid arthritis

based on nested case-control study from prospective cohort study
93 women with incident RA and 297 matched controls from Nurses' Health Study cohorts
were analyzed
association of anti-CCP positivity with rheumatoid arthritis at threshold
> 5 units/mL had sensitivity 28% and specificity 100%
> 2 units/mL had sensitivity 51% and specificity 80%
Reference - J Rheumatol 2009 Apr;36(4):706, editorial can be found in J Rheumatol
2009 Apr;36(4):663
repeat anti-CCP antibody measurement at 2 years reported to have low seroconversion
rate in patients with RA
based on cohort study
775 patients (mean age 48 years and 77% female) with early undifferentiated arthritis
(mean symptom duration 3.4 months) had serial anti-CCP and rheumatoid factor
antibodies measured by automated second-generation assays once every 6 months for 2
years
at baseline
79.2% met American College of Rheumatology/European League Against
Rheumatism 2010 classification criteria for RA
41% were positive for anti-CCP antibody and 23.4% were positive for rheumatoid
factor antibody
at 2 years
12 anti-CCP-negative patients seroconverted toward positive (2.6%)
21 anti-CCP-positive patients seroconverted toward negative (6.6%)
Reference - J Rheumatol 2014 Jan;41(1):41
C-reactive protein levels not associated with risk of incident rheumatoid arthritis
based on prospective cohort study
27,939 women followed for mean 9.9 years
398 developed rheumatoid arthritis
no significant association between C-reactive protein levels and risk of development of
rheumatoid arthritis
Reference - Arch Intern Med 2006 Dec 11;166(22):2490, commentary can be found in
Arch Intern Med 2007 Jul 23;167(14):1552
other ACPA antibodies and non-ACPA antibodies
absence of combinations of anticitrullinated peptides/protein antibody assays may
rule out rheumatoid arthritis in patients with early arthritis (level 2 [mid-level]
evidence)
based on diagnostic cohort study with high loss to follow-up
813 treatment-naive adults (mean age 48 years) with undifferentiated early
arthritis (< 6 months duration) were assessed for anticitrullinated peptides/protein
antibody (ACPA) serum levels
ACPA assays included anticyclic citrullinated peptide (anti-CCP2), and
antimutated citrullinated vimentin (anti-MCV), and antihuman citrullinated
fibrinogen (AhFibA)
reference standard for diagnosis of RA was 1987 American College of
Rheumatology (ACR) criteria
RA diagnosed in 592 (86.7%) of 685 patients who had 2-year follow-up,
497 patients diagnosed at baseline
95 patients diagnosed at 2-year follow-up (51% of 188 patients without
diagnosis at baseline)
cutoffs for ACPA assays
anti-CCP2 > 40 Units/mL
 anti-MCV > 35 Units/mL
AhFibA > 0.199 optical density
for prediction of RA at 2 years in analysis of 188 patients without RA at baseline,
positive result on ≥ 2 ACPA assays had
sensitivity ranging from 27% to 28%
specificity ranging from 94% to 95%
positive predictive values ranged from 82% to 84%
positive predictive values for individual ACPA assays ranged from 73% to 80%
Reference - Ann Rheum Dis 2013 Mar;72(3):357
combination of anti-CCP2 with anti-MCV or rheumatoid factor assays does not
significantly improve diagnostic accuracy versus anti-CCP2 alone (level 2 [mid-
level] evidence)
based on diagnostic case-control study
198 patients with early RA (< 1 year duration), 112 with other rheumatic diseases,
and 60 healthy controls had serum concentration of anti-CCP2, rheumatoid factor,
and anti-MCV antibodies measured by ELISA
cutoffs were reported as optimized, but details not provided
for diagnosis of early rheumatoid arthritis using assay combinations
anti-CCP2 antibody and RF antibody had
sensitivity 80.3%
specificity 95.9%
positive likelihood ratio 20
anti-CCP2 antibody and anti-Sa antibody had
sensitivity 50%
specificity 99.42%
positive likelihood ratio 86
for diagnosis of early RA using single assays
anti-CCP2 antibodies alone had sensitivity 80.8% and specificity 94.2%
RF antibody alone had sensitivity 89.4% and specificity 70.3%
anti-MCV antibodies alone had sensitivity 50% and specificity 98.8%
Reference - J Rheumatol 2012 Aug;39(8):1506
antibodies against genetically modified citrullinated vimentin (anti-MCV) appear to
have moderate diagnostic accuracy for rheumatoid arthritis
based on 3 cohort studies
469 patients with various rheumatic diseases, including 164 with rheumatoid
arthritis were evaluated
anti-MCV ELISA had 69.5% sensitivity and 90.8% specificity
anti-CCP2 had 70.1% sensitivity and 98.7% specificity
Reference - Arthritis Res Ther 2006;8(4):R119 full-text
273 patients with rheumatoid arthritis and 100 healthy controls evaluated
anti-MCV ELISA had 70.7% sensitivity, 95% specificity
anti-CCP2 had 57.9% sensitivity, 96% specificity
Reference - Arthritis Rheum 2008 Jan;58(1):36 full-text
119 patients with RA and 118 controls (including patients with other rheumatic
diseases and healthy subjects) evaluated
anti-MCV antibodies had 75.6% sensitivity and 91.5% specificity
anti-CCP2 had 66.4% sensitivity and 98.3% specificity
Reference - J Rheumatol 2007 Aug;34(8):1658
anti-MCV may predict early rheumatoid arthritis (level 2 [mid-level] evidence)
based on cohort study
170 patients with early rheumatoid arthritis (RA) and 136 controls (including
patients with other rheumatic and infectious diseases and healthy subjects)
evaluated
for diagnosis of early RA
anti-MCV ELISA had 78.2% sensitivity, 93.4% specificity, 93.7% positive
predictive value, 77.4% negative predictive value
anti-CCP2 had 61.8% sensitivity, 96.3% specificity, 95.5% positive
predictive value, 66.8% negative predictive value
 rheumatoid factor had 72.4% sensitivity, 80.1% specificity, 82% positive
predictive value, 69.9% negative predictive value
Reference - J Rheumatol 2009 Jun;36(6):1136
anti-Sa antibodies may predict persistence of early polyarthritis (but not
rheumatoid arthritis)
based on prospective cohort study
260 adults with synovitis of at least 3 joints for 1 to 12 months and no definite
diagnosis evaluated and followed for 30 months
165 patients completed follow-up
149 [90%] were alive and completed final assessment)
68 (41%) had rheumatoid factor (RF), 53 (33%) had anti-CCP, 46 (28%) had anti-
Sa
persistent arthritis defined as presence of at least 1 joint with synovitis and/or
current use of disease-modifying antirheumatic drugs (DMARDs) or at least 10 mg
of prednisone equivalent per day
RF had 47% sensitivity, 91.7% specificity, and positive likelihood ratio 5.69
for persistent arthritis at 30 months
anti-CCP had 39% sensitivity, 91.7% specificity, and positive likelihood ratio
4.7 for persistent arthritis at 30 months
anti-Sa had 34% sensitivity, 95.8% specificity, and positive likelihood ratio
8.26 for persistent arthritis at 30 months
diagnosis of rheumatoid arthritis required ≥ 4 American College of Rheumatology
(ACR) criteria
RF had 57% sensitivity, 63% specificity, and positive likelihood ratio 1.53
for RA at 30 months
anti-CCP had 39% sensitivity, 67% specificity, and positive likelihood ratio
1.19 for RA at 30 months
anti-Sa had 39% sensitivity, 73% specificity, and positive likelihood ratio
1.44 for RA at 30 months
Reference - Arthritis Res Ther 2005;7(3):R592 full-text
antibodies against collagen II modified by reactive oxygen species may help
diagnose early rheumatoid arthritis (level 2 [mid-level] evidence)
based on diagnostic case-control study
85 patients with early RA (< 12 months duration) and 158 controls assessed for
antibodies against collagen II modified by reactive oxygen species (anti-ROS-CII)
using ELISA
patients with early RA were diagnosed with 1987 ACR criteria and had no
prior treatment with disease-modifying antirheumatic drugs
controls included 58 patients with arthralgia but no synovitis, 49 patients
with knee osteoarthritis, and 51 healthy individuals
cutoff for positive antibody assay was mean plus 3 standard deviations of ELISA
optical density from healthy individuals
diagnostic perform

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~ Heather

Heather Marie Mathis | Medical Assistant

HMathis@dilworthderm.com
Office Phone: (704) 376-9849 Ext. 4
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