Rheumatology Pearls for Primary Care

Report
Rheumatology Update:
Pearls for Primary Care
Greg Gardner, MD, FACP
Gilliland-Henderson Professor of
Medicine
Division of Rheumatology
University of Washington
Rheumatology Pearl #1

There are only 3 patterns to joint
pain:
 Inflammatory
 Mechanical
(non-inflammatory)
 Fibromyalgia

Inflammatory





Mechanical




AM stiffness > 30 min (often several hrs)
Improvement with activity
Swelling common
Rheumatoid arthritis, polymyalgia
rheumatica
10-15 minutes of AM stiffness
Pain worse with use
Osteoarthritis, tendonitis
Fibromyalgia




AM stiffness significant
Poor sleep quality
Afternoon pain and fatigue
Exercise intolerance i.e. feeling “wiped
out”
Patient History





A 45 y/o woman with a 5 year history of rheumatoid
arthritis reports 2 hrs of AM stiffness, pain with activity
especially in the left knee, and if she overdoes it she
can have diffuse joint pain for a day or two after.
Reports poor quality sleep.
Meds: Methotrexate 15 mg po/wk, etanercept 50 mg
sc/wk
Exam: No swelling of the small joints of the hands or
feet. Small effusion in the left knee. She has multiple
tender points of fibromyalgia.
Testing: X-ray diffuse loss of cartilage in the left knee;
CBC normal, CRP normal
WHICH PATTERNS?
Rheumatology Pearl #2
Occam Razor vs Hickman’s Dictum

William of Ockam



Entia non sunt multiplicanda
praeter neccessitatem
Entities should not be multiplied
beyond necessity i.e. the simplest
explanation is usually correct
John Hickam, MD

The patient can have as many
diseases as they D_ _ _ well
please
Pearl 3: Do I Really Want to Check an ANA?



44 y/o woman complains of 10 years of aches and
pains and fatigue. Her local care provider checked
an ANA and found it was 1:80 and told her she had
lupus and referred her to you. She complains of
several hours of morning stiffness and any
continuous level of activity causes increased diffuse
pain. She quit her job as an electronics assembler
due to her symptoms.
Examination is positive for diffuse tender points
otherwise negative. There is no rash, joint swelling,
weakness (Pt gives way with strength testing)
She wants to know what you are going to do about
ANA Pearls: The Pearl of Checking an ANA



The sensitivity and specificity of the ANA test along with
the rarity of CTDs like SLE mean that most positive ANAs
are really false positives!
Current gold standard, according to the ACR, is to do
ANA screen by IFA and give a pattern and titer and follow
with a panel of extractable nuclear antigens
Many labs will now only do multiplex method and skip IFA;
ANA is positive if ANY of the autoantibodies are detected

Multiplex method alone is less sensitive than ANA by IFA
and also less specific so higher false positive and negative
rates
Patterns of ANA by Indirect Immunofluorescence
(IFA)
Five basic ANA patterns representing antibodies to
specific groups of nuclear antigens by IFA:
• Homogeneous (SLE)
• Speckled (non-specific)
• Peripheral (SLE)
• Centromere (CREST)
• Nucleolar
(SLE/Scleroderma)
Homogeneous FANA Pattern
Screening for Antinuclear Antibodies by Indirect
Immunoflorescence Technique (IFA)
Step 1:
Ab
Y
Nucleus
Patient serum containing ANAs placed
on slide containing HEp-2 cells.
ANAs attach to cell nucleus
Anti-human IgG
Slide
Y
Fluorescein Tag
Y
Step 2:
The preparation is washed and fluorescent labelled antiimmunoglobulinis added. Preparation glows when viewed
under fluorescence microscope
Extractable Nuclear Antigens (ENA)
Dectected by Various Methods
Antigen
Abbreviation
Sjogren’s syndrome A (aka Ro) SSA (SLE/SS)
Sjogren’s syndrome B
(aka La)
SSB
(SS/SLE)
Double stranded DNA
DsDNA (SLE)
Smith antigen
Sm (SLE)
Ribonuclear protein
RNP (SLE/MCTD)
Scleroderma 70
SCL 70
Chromatin
(SLE)
Centromere
AB nuclear antigens
(CREST)
Saline
extractable
are targets of ANAs
that help characterize specific illnesses
Multiplexed Method for Detecting
Autoantibodies
1.
2.
3.
4.
5.
1.
Autoantigen is fused to colored micropheres
Pt serum is then incubated with microspheres; if
autoantibodies are present these will attach to the
autoantigen/sphere complex
Antihuman IgG/fluorochrome tag then added
Microsphere then placed in flow cytometry column that uses
two lasers, one to detect color of sphere and one to identify
the presence of the antibody/fluorochrome complex
Results reported as a number not titer
DsDNA
2. Spheres/Antigen + Pt’s serum
3. Fluorochrome tagged antihuman IgG
SSA
RNP
4.
Important Points for Primary Care


Always order a reflexive panel
ANA particularly useful for Dx of 4 CTDs

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Negative ANA and negative SSA essentially rules out
SLE (sensitivity of doing both is 99% for Dx of SLE)


SLE
Scleroderma (Diffuse/CREST)
Sjogren’s syndrome
Mixed connective tissue disease
Rare Pt with mild SLE or Sjogren’s will be SSA only +
A low titer ANA ie 1:40 or 1:80 is generally clinically
irrelevant as is an isolated low level result by multiplex
assay

20-30% Nl blood donors have ANA at 1:40; 12% > 1:80
Important Points for Primary Care

ANA 1:160 or greater accompanied by other
disease characterizing antibodies means disease is
present or will be present


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SLE Pts can have SLE antibodies present prior to the
onset of clinical manifestations (mean 3.3 yrs range
up to 9 yrs)
Specific ENA help characterize disease
Pts with high titer ANA plus other autoantibodies
should be referred to rheumatology (other clues to
CTD?)
Other autoimmune diseases can be associated with
a positive ANA i.e. autoimmune thyroid diseases,
PBC, autoimmune hepatitis, RA
Other ANA Pearls

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Anti-DsDNA & anti-Sm (Smith) are generally specific for
SLE
 Anti-DsDNA goes up and down with disease activity
Referral to a community rheumatologist with + ANA and
no Dx – up to 50% will have a CTD Dx (approx 20%
SLE), and 10% may have autoimmune thyroid disease
Pts with isolated + ANA and no disease: 5.6% will come
to a Dx of CTD in 5 yrs (data reassuring)
Remember that the ANA has to make sense
Check an ANA when clinical symptoms and signs point
to possible CTD
Myckatyn J Rheum 2003;30:736
ANA Profiles
Patient 1
ANA 1:640 speckled
SSA
>100
SSB
30
DSDNA neg
Sm
neg
RNP
neg
RF
150
Sjogrens
Patient 2
ANA 1:320 homogeneous
SSA
>100
SSB
neg
DSDNA 632
Sm
neg
RNP
66
RF
neg
SLE
ANA Profiles
Patient 3
Patient 4
ANA 1:320 speckled
SSA
neg
ANA 1:320 Nucleolar
SSA
neg
SSB
SSB
DSDNA
neg
neg
Sm
RNP
neg
neg
SCL 70
>100
neg
DSDNA
Sm
RNP
neg
neg
> 100
RF
35
Mixed Connective Tissue Disease
Diffuse Scleroderma
ANA Profiles
Patient 5
ANA 1:160 speckled
SSA
neg
SSB
neg
DSDNA
neg
Patient 6
ANA 1:40 speckled
SSA
neg
SSB
neg
DSDNA
neg
Sm
RNP
RF
Sm
RNP
RF
neg
neg
neg
ANA in isolation
neg
neg
neg
Clinically insignificant ANA
References for ANA

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Waits JB. Rational use of laboratory testing in the
initial evaluation of soft tissue and joint complaints
Prim Care Clin Office Pract 2010;37:673–689
Arbuckle MR et al. Development of autoantibodies
before the clinical onset of systemic lupus
erythematosus. NEJM 2003;349:1526-1533
Shel WC, Jason M. The diagnostic associations of
patients with antinuclear antibodies referred to a
community rheumatologist. J Rheumatol
1989;16:782-785
American College of Rheumatology Position Paper
on ANA testing www.rheumatology.org
Pearl 3# Cold Hands or Raynaud’s
Phenomenon?



A 55 y/o woman complains of 6 months of her
hands being very uncomfortable in the cold. Notes
that her fingers of both hands turn white when in
cold. No report of skin changes in her fingers, joint
swelling,
difficulty swallowing, DOE,
nor family history of Raynaud’s
Her general examination
is normal
How would you evaluate this
patient?
Step 1: Is it Raynaud’s Phenomenon?

Maurice Raynaud first described the
manifestation that bears his name in 1862

Vasospasm involving the digits, ears, nose
with cold exposure OR emotional distress

Populations based survey: 12% report RP

Three phases:


Pallor related to initial vasoconstriction

Cyanosis due to severe flow restriction

Erythema due to rebound vasodilitation
Cold emersion test available when
uncertain
Step 2: Is it Primary or Secondary
Raynaud’s

Primary Raynaud’s Criteria

Vasospastic attacks precipitated by cold or emotion
Symmetric attacks involving both hands
Absence of tissue necrosis or gangrene
No examination findings of secondary Raynaud’s
Normal nail-fold capillary exam
Normal ESR

Negative serologic findings in particular ANA

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Median age of onset 14 yrs old; 27% onset after 40 yrs
old
2 yrs of PRP w/o manifestations of CTD; unlikely to be
SRP
Secondary Raynaud’s Phenomenon

Features that suggest secondary Raynaud’s:

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RP after age > 30 yrs
Severe episodes that lead to ischemia
Nail fold capillary abnormalities
Positive ANA/disease-related antibodies
Clinical features of the below diseases
Diseases to consider:


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Scleroderma specturm disease
Mixed connective tissue disease
Systemic lupus erythematosus
Dermatomyositis
Polymyositis
Features of Secondary
Raynaud’s

ANA features suggesting
CTD
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High titer ANA
Nucleolar pattern
Centromere pattern
High titer RNP
Elevated DsDNA
Nailfold
Capillaroscopy
Normal
Dilatation
Dropout
Dilatation
Bizarre
Loops
Can also use ophthalmoscope
Step 3: Evaluation for Secondary Raynaud’s

Careful history and
exam

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Medications & RP

Nail fold exam (has
the highest positive
predictive value)
Laboratory studies

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CBC, ESR
TSH
ANA reflexive panel
Consider SPEP,
cryoglobulins, CPK

Interferon, estrogen
nicotine, tobacco,
narcotics, cyclosporine,
cocaine, ergotamines,
clonidine, B blockers
sympathomimetics
Environment & RP

Previous frostbite,
repetitive vibration
exposure, hypothenar
hammer syndrome
Step 4: Treatment of Raynaud’s
Phenomenon

Mild PRP only may
require exposure
intervention
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Avoidance behavior
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Central warmth
Windblock gloves
Good handwarmers
Crazy thermabands
Nicotine
Caffeine
Meds that worsen
Biofeedback?

Medications

Ca channel blockers

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Not verapamil
Losartan
Prazosin
Topical NTG
SSRIs
LD ASA with Ca
blockers
2 g/day of α-linoleic acid
Take home primary care pearls
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Primary Raynaud’s is common
Secondary disease is rare but common enough that
with recent onset Raynaud’s, CTD should be
considered
Unilateral Raynaud’s requires vascular evaluation
Treatment should begin with physical measures and
avoidance of medications that can make disease
worse
Referral for:
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Evaluation suggests secondary Raynaud’s
Severe disease not responsive to usual therapy
Acute digit threatening ischemia
Raynaud’s References
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Wigley F. Raynaud’s Phenomenon. N Engl J Med
2002;347:1001-1008
LeRoy EC, Medsger TA Jr. Raynaud’s
phenomenon: a proposal for classification. Clin Exp
Rheumatol 1992;10:485-8.
M. García-Carrasco et al. Treatment of Raynaud’s
Phenomenon. Autoimmunity Reviews 2008;8:62–
68
Pearl 5: Hyperuricemia: More than Just Gout

A 55 y/o male with a history of hypertension, type 2
DM, and CRI develops an acute left 1st MTP pain.
Pain is so severe that he is unable to walk on it and
even the bed sheets are painful. In the ED noted to
have a red painful left 1st MTP and resists you trying
to move the joint.

Laboratory tests show a normal CBC, creatinine is
1.9 mg/dl, uric acid is “normal” at 7.5 mg/dl, CRP is
elevated at 20 mg/L

DDx?
Treasure Chest of Gout Pearls


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Most common form of inflammatory arthritis
in men over 40; > 5 million affected; rare in
women pre-menopause
A serum uric acid above 6.8 mg/dl is
abnormal even if your lab says 8.5 mg/dl is
normal!
Uric acid level may go down to normal during
attack
Certain groups i.e. Pacific Islanders have
genetic predisposition to gout
Very rarely other diseases produce podraga


Small joints of the hands and feet are
RARELY septic unless directly invaded
Do I really need to aspirate that 1st MTP??
Acute Urate Gout
Interval
Hyperuricemia
Tophaceous Gout
Step 1: Treat the Acute Attack

NSAIDs


Oral Steroids



Need 30-40 mg with 5-10 day taper to affect
inflammation
IM/IA steroids
Colchicine


Potent short acting agent ie indomethocin
Start within 24 hrs; 1.2 mg followed 1hr by 0.6 mg –
done
Anakinra

IL-1 inhibitor works like miracle for complex
hospitalized patients who can’t take standard
What causes the tiny crystals to cause so
much pain? Answer: the innate immune
system

Uric acid
supersaturates,
crystallizes and is
recognized by
inflammatory cells via
Toll-like receptors

Inflammatory
mediators, in
particular IL-1,
produced and lead to
rubor, calor, dolor
Step 2: Modify Risk Factors
1.
Avoid certain
•
•
medications
2.
Medications to avoid
•
•
Avoid beer/ale
•
3.
•
Encourage slow wt loss
•
4.
Discuss a low purine diet
and one low in fructose
Diuretics
Niacin
Calcinurin inhibitors
LD ASA
Laxatives in excess
“Medications” that help
•
•
•
•
Vitamin C
Losartan
Statins
Dairy products
Step 3: Decisions Regarding Hypouricemic
Therapy

Reasons to consider hypouricemic therapy

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Hypouricemic agents

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> 2 attacks/year, tophi, kidney stones, chronic persistent
gout
CKD, CAD??
Allopurinol - 100-800 mg/d; rash, hypersensitivity
syndrome; reduce dose of azathioprine to 1/4
Febuxistat - 40-80 mg/d; liver toxicity, azathioprine issue
Probenecid - 250-1000 mg BID; use with meals and
hydration; decrease elimination of meds ie PCN
Lowering uric acid INCREASES risk of gouty attack


Use colchicine prophylaxis where possible 0.6-1.2 mg/day
If unable to use provide Pt with as need use predisone,
2012 ACR Guidelines for the Treatment of Gout
1.
2.
3.
4.
5.
6.
7.
Educate patient on diet, lifestyle, and treatment
objectives
Xanthine oxidase inhibitors are first line therapy
Treat to target ie < 6 mg/dl (< 5 if tophi present)
Starting dose of allopurinol should e no greater that 100
mg/day and less than 100 mg/day in Pts with CKD; slow
upward titration that could exceed 300 mg/day even in
CKD
Screen for HLA B5801allele in Koreans with CKD and
all Pts of Thai and Han Chinese descent BEFORE
starting allopurinol due to risk of severe hypersensitivity
Can combine uricosuric agent with XOI
(Pegloticase (pegolated uricase) can be used in severe
1984 Hande guidelines for renal dosing of
allopurinol based on concern for drug
hypersensitivity not renal toxicity
Creatinine
Clearance
Allopurinol
Dosing
0 ml/min
100 mg/3
days
10 ml/min
100 mg/2
days
20 ml/min
100 mg/day
40 ml/min
150 mg/day
60 ml/min
200 mg/day
80 ml/min
250 mg/day
>100 ml/min
300 mg/day
 Severe hypersensitivity reactions
are not dose dependent; may not
correlate with oxypurinol levels.
Puig. J. Rheumatol 16:842-844, 1989
 No increase in allopurinol SE in
pts receiving higher than Hande
recommended doses. VazquezMellado. Ann Rheum Dis 60:981-983, 2001
 Following Hande guidelines led to
suboptimal control of
hyperuricemia & did not prevent
hypersensitivity Dalbeth. J Rheumatol
2006;33: 1646-1650
 Gardner’s guideline: Go low go
slow and treat to SUA level
Gouty Tophi
Bad Tophaceous Gout
Tophi + Allopurinol + Patience = Success
Summary of Some of the Recent Information
on Uric Acid and Inflammation
Xanthine Oxidase is a superoxide producing enzyme;
allopurinol inhibits XO and thus has antioxidant properties
by preventing generation of free radicals
Filiopoulos et al Renal Failure 2012
Hyperuricemia and CKD/CAD

Emerging literature on the role of hyperuricemia and
progression in CKD



Control of hyperuricemia can improve BP
Control of hyperuricemia slows/halts progression of
CKD
Uric acid level is an independent risk factor for
all cause mortality in men and women with a
known history of CAD as well as an independent
risk factor for CHF

Hyperuricemia affect may be more pronounced in
African Americans
Outcome of BP/Creatinine at 12 mo using
allopurinol to normalize hyperuricemia in Pts with
CKD
Siu et al. Am J Kidney Dis 2006;47:51-59



54 pts randomized and followed for 12 months.
Initial UA in Rx group 9.75 & trial end 5.88; control group 9.92 vs 10.08
84% Rx group stable renal function vs 53% control group
Hyperuricemia and Mortality 2013

1054 Pts with
known CAD
followed > 3 yrs
and all cause
mortality
evaluated by
quartiles of UA



79% male
Mean age 65
yrs
Unadjusted and
adjusted
mortality
evaluated
Lin et al. J Cardiology 2013
Take Home Points




More reasons for gouty Pts to lower uric acid level
than just gout
Role of xanthine oxidase inhibitors and CKD/CAD to
be further elucidated
Not quite ready to lower UA primarily to address
CKD/CVD but certainly do for pts with gout
Old thinking about simply treating gouty attacks until
tophi appear then instituting hypouricemic therapy is
out of date and not in Pts best interest
References for Hyperuricemia and Gout



Terkeltaub R. Update on gout: new therapeutic
strategies and options. Nat Rev Rheumatol
2010;6:30-38
Filiopoulos V, et al. New insights into Uric acid
effects on the progression and prognosis of chronic
kidney disease. Renal Failure 2012;34:510-520.
Bhole V Krishnan E. Gout and the heart. Rheum Dis
Clin NA 2014;40:125-143.

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