275

Gout

Gout

NEJM 2003 349:17

CAUSES

INVESTIGATIONS (CONT’D)

DECREASED URATE EXCRETION (90%)

w3Cw (Cell count with diff,
Culture and Gram stain, Crystal, for gout, sens
85%, spc 100%)
SPECIAL

 RENAL DISEASE

wCAN’T LEAPw Cyclosporine, Alcohol,
Nicotinic Acid, Thiazides, Loop diuretics, Etham
butol, ASA (low dose), Pyrazinamide
INCREASED URATE PRODUCTION (10%)
 METABOLIC SYNDROME obesity, hyperlipidemia,
hypertension
 INCREASED METABOLISM alcohol, hemolytic ane
mia, psoriasis, Lesch Nyhan syndrome
 NEOPLASTIC myeloproliferative disease, lym
phoproliferative disease, chemotherapy

 DRUGS

PATHOPHYSIOLOGY

IMBALANCE decreased urate excretion and/or
increased urate production ! uric acid crystals
deposited in joints, skin, and kidneys ! arthritis,
tophi, and renal failure. Gout almost never occurs in
pre menopausal women
PRECIPITANTS surgery, dehydration, fasting,
binge eating, binge drinking, exercise, trauma

 ARTHROCENTESIS

 TOPHI ASPIRATION

DIAGNOSTIC ISSUES

SERUM URIC ACID LEVELS may be falsely lowered
in an acute attack
JOINT X RAY soft tissue swelling, normal joint
space, erosions ( ‘punched out’’ and sclerotic lesions
with overhanging edge)
JOINT FLUID ALWAYS confirm diagnosis with a
synovial fluid tap if possible. Microscopy shows pre
dominantly neutrophilic infiltrate with some intracel
lular monosodium urate crystals (needle shaped,
negative birefringence, i.e. yellow when parallel to
plane of polarized light)
MANAGEMENT


 LABS

ACUTE NSAIDs (first line, avoid if renal/hepatic
failure; naproxen 375 500 mg PO BID Â3 days, then
250 375 mg PO BID Â4 7 days; sulindac 150 200 mg
PO BID Â7 10 days; indomethacin 25 50 mg PO TID
Â3 days, then 100 mg PO div BID QID Â4 7 days;
celecoxib 200 mg PO BID Â1 day, then 100 mg PO BID
Â6 10 days). Systemic corticosteroids (avoid if
joint sepsis not excluded; prednisone 30 60 mg PO
daily Â3 days, then # 10 15 mg daily Â3 days until
discontinuation, triamcinolone 50 mg IM Â1 dose).
Intra articular corticosteroids (for mono and oli
goarthritis only. Methylprednisolone 100 150 mg
intra articularly once). Colchicine 0.6 mg PO daily
BID during acute attack (avoid the approach of giving
colchicine q1h until development of diarrhea)
LONG TERM MANAGEMENT purine restricted
diet (# red meats, # seafood, " low fat dairy products,
" fruit and veges). Allopurinol 50 300 mg PO daily
(first line, xanthine oxidase inhibitor, renal correction
required, do not give in acute attack; however,
continue allopurinol if already on it prior to acute
attack). Probenecid 250 1000 mg PO BID (first line,
# renal urate reabsorption. Ensure normal renal func
tion). Sulfinpyrazone 50 200 mg PO BID. Colchicine
0.6 mg PO BID Â6 months (for prophylaxis against
recurrent attacks only. Do not give colchicine IV)




LONG TERM THERAPY consider if patients have
frequent attacks (!3/year, tophaceous deposits,

CLINICAL FEATURES

SYMPTOMS
mono/oligo and asymmetric, espe
cially first MTP joint. Podagra, inflammation
of the first MTP joint, is the presenting symptom
in 75% of gout patients. However, the first MTP
is also commonly affected in pseudogout, psor
iatic arthritis, sarcoidosis, osteoarthritis, and
trauma
TOPHI yellowish white nodular urate crystals col
lection in subcutaneous tissues (particularly colder
extremities such as ear, fingers, olecranon bursa,
ulnar aspect of forearm), bone, tendons (Achilles),
cartilage, and joints. Generally painless but may
lead to erosions
KIDNEYS urolithiasis (radiolucent), uric acid
nephropathy (reversible acute renal failure sec
ondary to acute lysis), urate nephropathy
(chronic renal failure secondary to interstitial
deposits)

 ARTHRITIS






INVESTIGATIONS

BASIC
CBCD, lytes, urea, Cr, uric acid (sens 75%),
AST, ALT, ALP, bilirubin, TSH, urinalysis, 24 h
urine uric acid collection (<800 mg/day sug
gests # excretion)
IMAGING joint XR

TREATMENT ISSUES


276

Polyarticular Joint Pain and Fever

TREATMENT ISSUES (CONT’D)

SPECIFIC ENTITIES (CONT’D)

overproduction of uric acid, or continued cyclospor
ine treatment)
ALLOPURINOL TREATMENT remember to start
colchicine or NSAIDs prior to allopurinol and to over
lap therapy to prevent precipitating flare. Allopurinol
alone can cause an abrupt decrease in serum uric acid
! breakdown and release of synovial urate crystal

deposits ! inflammation. Aim to decrease serum
uric acid level below 300 mmol/L [5.1 mg/dL]. Do
not start or stop allopurinol during an acute attack
SPECIFIC ENTITIES

CALCIUM PYROPHOSPHATE DEPOSITION DIS
EASE (CPPD, pseudogout) associated with normal
urate levels and chondrocalcinosis that are visible
radiographically. Crystals appear rhomboid and

have positive birefringence (blue when parallel
to polarized light, yellow when perpendicular). Risk
factors include old age, advanced osteoarthritis,
neuropathic joint, gout, hyperparathyroidism, hemo
chromatosis, diabetes, hypothyroidism, hypomagne
semia, trauma, and symptoms
BASIC CALCIUM PHOSPHATE CRYSTALS (BCPC)
crystals appear snowball like with Alizarin red S stain.
Implicated in bursitis, inflammation superimposed on
osteoarthritis, and calcinosis cutis in systemic sclerosis
and CREST
DIALYSIS PATIENTS develop destructive arthritis
and tendonitis from calcium oxalate, monosodium
urate, calcium pyrophosphate, and basic calcium
phosphate crystals. Amyloidosis may also contribute
to arthritis

Polyarticular Joint Pain and Fever

NEJM 1994 330:11


DIFFERENTIAL DIAGNOSIS

CLINICAL FEATURES (CONT’D)

wRICEw
RHEUMATOLOGIC
 SEROPOSITIVE SLE, rheumatoid arthritis
 SERONEGATIVE psoriatic arthritis, enteric arthri
tis, reactive arthritis
 VASCULITIS polymyalgia rheumatica, Wegener’s
granulomatosis, Behcet’s disease, Still’s disease
INFECTIONS
 BACTERIAL septic (Gonococci), meningococci,
endocarditis, Lyme disease, Whipple’s disease,
mycobacteria
 VIRAL Parvovirus, rubella, HBV, HCV, HIV, EBV






 PAIN DISPROPORTIONATELY GREATER THAN EFFUSION

rheumatic fever, Familial Mediterranean fever,
acute leukemia, AIDS

 FUNGAL


-

/

enteric infections,
genitourinary infections, rheumatic fever,
inflammatory bowel disease
CRYSTAL INDUCED gout, pseudogout
ETC
 MALIGNANCIES acute leukemia
 SARCOIDOSIS Lofgren’s syndrome
 FAMILIAL MEDITERRANEAN FEVER
 POST INFECTIOUS REACTIVE

 EFFUSION DISPROPORTIONATELY GREATER THAN PAIN




 POLYMYALGIA RHEUMATICA

DISORDERS dermatomyositis,
erythema nodosum, erythema multiforme, pyo
derma gangrenosum, pustular psoriasis

 MUCOCUTANEOUS

CLINICAL FEATURES

DISTINGUISHING FEATURES

 TEMPERATURE >408C [>1048F]
bacterial arthritis, SLE

viral arthritis, Lyme
disease, reactive arthritis, Still’s disease, bacterial
endocarditis
MORNING STIFFNESS RA, polymyalgia rheumatica,
Still’s disease, some viral/reactive arthritis
MIGRATORY ARTHRITIS rheumatic fever, gonococ
cemia, meningococcemia, viral arthritis, SLE, acute
leukemia, Whipple’s disease
EPISODIC RECURRENCE palindromic rheumatism, Lyme
disease, crystal induced arthritis, IBD, Whipple’s dis
ease, Familial Mediterranean fever, Still’s disease, SLE

 FEVER PRECEDING ARTHRITIS




tuberculosis arthritis, bacterial endocarditis, IBD,
giant cell arteritis, Lyme disease
SYMMETRIC SMALL JOINT SYNOVITIS RA, SLE, viral
arthritis
9
LEUKOCYTOSIS (>15x10 /L) bacterial arthritis,
bacterial endocarditis, Still’s disease, systemic vas
culitis, acute leukemia
LEUKOPENIA SLE, viral arthritis
POSITIVE RHEUMATOID FACTOR RA, viral arthritis,

tuberculoses arthritis, bacterial endocarditis, SLE,
sarcoidosis, systemic vasculitis
INVESTIGATIONS

Still’s disease,

BASIC
CBCD, lytes, urea, Cr, AST, ALT, ALP,
bilirubin, uric acid, TSH, ESR, CRP, RF, anti CCP,

 LABS


277

Rheumatoid Arthritis

INVESTIGATIONS (CONT’D)

ANA, serologies (Borrelia burgdorferi, Strepto
cocci, Parvovirus, HBV, HCV, HIV), c ANCA,
urinalysis
 IMAGING CXR, X rays of affected joints
SPECIAL
 ARTHROCENTESIS w3Cw (Cell count with diff
[>2000 WBC/mm3], Culture and Gram stain,
Crystal)

SPECIFIC ENTITIES


STILL’S DISEASE
unknown. Most consider this
as a diagnosis of exclusion
DIAGNOSIS major criteria include fever !398C
[!102.28F] (quotidian vs. diquotidian), salmon
color maculopapular rash, arthralgia/arthritis !2
weeks, leukocytosis. Minor criteria include pharyn
gitis, lymphadenopathy, abnormal liver enzymes,
hepatomegaly/splenomegaly, negative ANA, and
RF. Need at least 2 major criteria and 3 minor criteria
to make diagnosis (sens 93%). Important to exclude
infections, malignancy, and acute rheumatologic
disease. Significantly elevated serum ferritin
TREATMENTS NSAIDs, corticosteroids, methotrex
ate, recombinant IL 1 receptor antagonist (anakinra)

 PATHOPHYSIOLOGY


MANAGEMENT

TREAT UNDERLYING CAUSE
SYMPTOM CONTROL


Rheumatoid Arthritis
DIFFERENTIAL DIAGNOSIS OF POLYARTHRITIS

wRICEw
RHEUMATOLOGIC (>6 weeks)

 SEROPOSITIVE wPSSRw Polymyositis, Palindro
mic rheumatism, SLE, Scleroderma, Sjogren’s
syndrome, Rheumatoid arthritis
 SERONEGATIVE
wPEARw Psoriatic arthritis,
Enteric arthritis, Ankylosing spondylitis, Reactive
arthritis, undifferentiated
 VASCULITIS polymyalgia rheumatica, Wegener’s
granulomatosis, Behcet’s disease, Still’s disease
INFECTIONS (<6 weeks)
 BACTERIAL sepsis, endocarditis, Lyme disease,
Whipple’s disease, mycobacteria
 VIRAL Parvovirus, rubella, HBV, HCV, HIV
 FUNGAL

-

/

enteric infections,
genitourinary infections, rheumatic fever,
inflammatory bowel disease
CRYSTAL gout, pseudogout, hydroxyapatite,
basic calcium phosphate
ETC
 MALIGNANCIES leukemia
 SARCOIDOSIS Lofgren’s syndrome
 FAMILIAL MEDITERRANEAN FEVER
 MUCOCUTANEOUS DISORDERS dermatomyositis,
erythema nodosum, erythema multiforme, pyo

derma gangrenosum, pustular psoriasis poly
myalgia rheumatica
 POST INFECTIOUS REACTIVE

PATHOPHYSIOLOGY

CLASSIFICATION OF ARTHRITIS
 MONOARTHRITIS 1 joint involved

PATHOPHYSIOLOGY (CONT’D)

2 4 joints involved
!5 joints involved
DESTRUCTION OF CARTILAGE T helper 1
mediated process ! proteases produced by synovial
cells destroy proteoglycans in the articular cartilage
! irreversible damage 6 months to 1 year from
disease onset
POSSIBLE TRIGGERS viruses (Parvovirus, EBV,
HTLV), super antigens (from bacteria/viruses), auto
antigens (QKRAA)
RISK FACTORS age >50, female (3:1), first degree
relative with rheumatoid arthritis, smoking, low level
of education
 OLIGOARTHRITIS
 POLYARTHRITIS

CLINICAL FEATURES

JOINT SYMPTOMS symmetric polyarthritis with

joint pain, swelling, redness, morning stiffness
(>1 h), and dysfunction
 HANDS MCP, PIP, and wrist joints most commonly
involved. Deformities include Boutonniere, swan
neck, Z (thumb), ulnar deviation at MCP joint, volar
subluxation of proximal phalanx from MCP head,
radial deviation of carpus, compression of the car
pal bones, subluxation at the wrist
 FEET MTP joint involved. Deformities include val
gus of the ankle and hindfoot, pes planus, forefoot
varus and hallux valgus, cock up toes
 LEGS knees (80%), ankles (80%), hips (50%)
 ARMS shoulders (60%), elbows (50%), acromio
clavicular (50%)
 ATLANTOAXIAL subluxation may lead to spinal cord
(cervical myelopathy with hand weakness/numbness)
 TEMPOROMANDIBULAR (30%)


278

Rheumatoid Arthritis

CLINICAL FEATURES (CONT’D)

related disorders include Baker cyst,
tenosynovitis, carpal tunnel syndrome

 OTHERS


Related Topics
Gout (p. 275)
Inflammatory Myositis (p. 281)
Lupus (p. 280)
Scleroderma (p. 281)
EXTRA ARTICULAR MANIFESTATIONS only in
rheumatoid factor seropositive patients
 RHEUMATOID NODULES (20%)
 PULMONARY pleural effusion (exudates, low glu
cose), pulmonary nodules (Caplan’s syndrome),
acute interstitial pneumonitis, bronchiolitis
obliterans
 CARDIAC valvular
abnormalities, myocarditis,
pericardial effusion, constrictive pericarditis
 GI elevated transaminases (especially ALP),
nodular hyperplasia (portal hypertension,
hypersplenism)
 HEMATOLOGIC anemia of chronic disease, Felty
syndrome (triad of seropositive rheumatoid
arthritis, neutropenia often associated with ane
mia and thrombocytopenia and splenomegaly.
Patients at risk of life threatening bacterial infec
tions). Large granular lymphocyte leukemia,
lymphoma
 NEUROLOGIC peripheral sensory neuropathy (not
motor), myelopathy from cervical vertebral
subluxation
 OPHTHALMIC keratoconjunctivitis sicca (Sjogren’s
syndrome), scleritis, episcleritis

 DERMATOLOGIC vasculitis (digital arteritis, cuta
neous ulceration, visceral arteritis)
 OTHERS amyloidosis
CONSTITUTIONAL SYMPTOMS fatigue (40%),
fever (low grade), sweats, weight loss, myalgia

DISTINGUISHING FEATURES BETWEEN
INFLAMMATORY AND NON INFLAMMATORY
ARTHRITIS
Inflammatory Non
inflammatory
Classic example
RA
OA
Morning stiffness >1 h
+/
Resting
Worsens
Improves
Activity
Improves
Worsens
Synovitis, redness +
Fever, weight loss +
ESR, CRP,
"
No change
platelets

INVESTIGATIONS


BASIC
CBCD, lytes, urea, Cr, AST, ALT, ALP, bilir
ubin, ESR, CRP, RF (IgM), anti CCP (more speci
fic), ANA, urinalysis
 IMAGING X rays of affected joints (particularly
hands, knees, and ankles; soft tissue swelling,
periarticular osteopenia, narrowing of joint
space, marginal bony erosions, subluxation,
joint destruction, bony ankylosis)
SPECIAL
 INFECTIOUS
WORKUP serologies (Parvovirus,
HBV, HCV, EBV, CMV, Borrelia burgdorferi)
 ARTHROCENTESIS w3Cw (Cell count with diff
[>2000 WBC/mm3], Culture and Gram stain,
Crystal. Cannot make definite diagnosis of rheu
matoid arthritis from arthrocentesis)
 LABS

DIAGNOSTIC AND PROGNOSTIC ISSUES

ACR DIAGNOSTIC CRITERIA FOR RHEUMATOID
ARTHRITIS morning stiffness (>1 h), arthritis of
!3 joint areas (either side of PIP, MCP, wrist, elbow,
knee, ankle, and MTP), arthritis of hand joints (PIP,
MCP), symmetric arthritis by area, subcutaneous
rheumatoid nodules, positive rheumatoid factor,
radiographic changes (hand and wrist X ray with
erosion of joints or unequivocal demineralization

around joints). Need 4 of 7 criteria to make diagnosis,
with first 4 criteria for at least 6 weeks
PROGNOSIS increased number of joints involved,
presence of rheumatoid nodules and seropositivity all
suggest more severe disease
MANAGEMENT

SYMPTOM CONTROL physical therapy, diet (O 3
and O 6 fatty acids). Joint protection (range of
motion exercises, orthotics, splints). NSAIDs (anti
inflammatory dose). Intraarticular steroid injec
tions (if severe pain). Patient education
DISEASE MODIFYING AGENTS OF RHEUMATOID
DISEASE (DMARDs) single agent (methotrexate
with folic acid, sulfasalazine, hydroxychloroquine,
minocycline, cyclosporine, azathioprine, gold). Com
bination triple therapy (methotrexate plus sulfasa
lazine plus hydroxychloroquine). Selective pyrimi
dine synthesis inhibitor (leflunomide). TNFa
inhibitors (infliximab, etanercept, adalimumab). B
cell inhibitor (rituximab, an anti CD20 monoclonal
antibody). T lymphocyte activation inhibitor (aba
tacept). Surgical intervention
SPECIFIC ENTITIES

PALINDROMIC RHEUMATISM episodic arthritis
with one or more joints being affected sequentially
for hours to days, and symptom free periods in



279

Systemic Lupus Erythematosus

SPECIFIC ENTITIES (CONT’D)

between for days to months. May be anti CCP posi
tive and occasionally progresses to other rheumatic
disorders (RA, SLE). Treatment with hydroxychloro
quine can be useful
SJOGREN’S SYNDROME (KERATOCONJUNCTIVITIS
SICCA)
 PATHOPHYSIOLOGY CD4 lymphocytic infiltration of
salivary and lacrimal glands
 CAUSES primary (sicca plus episodic, non deform
ing polyarthritis), secondary (RA, SLE, scleroderma,
polyarteritis nodosa, polymyositis, HIV)
 CLINICAL FEATURES sicca (dry eyes and dry mouth,
along with impaired taste, parotid gland enlarge
ment, dental caries), dyspareunia, arthralgia,
arthritis, and constitutional symptoms. May be
associated with Raynaud’s phenomenon, cuta
neous vasculitis, cerebritis, CNS vasculitis, stroke,
and peripheral neuropathy
 INVESTIGATIONS quantitative Ig (polyclonal IgG),
RF, ANA, ENA (SS A, SS B). Check for secondary
causes
 TREATMENTS symptomatic (artificial tears, pilocar
pine 5 mg PO QID), hydroxychloroquine
LOFGREN’S SYNDROME a benign self limited

form of sarcoidosis. Tetrad of erythema nodosum,
hilar lymphadenopathy, arthritis (ankles and some
times knees), and uveitis

SPECIFIC ENTITIES (CONT’D)

RESPIRATORY DISEASES IN RHEUMATOID
ARTHRITIS
 AIRWAY cricoarytenoid arthritis with central
airway obstruction, bronchiectasis, obliterative
bronchiolitis, chronic small airway obstruction
 PARENCHYMA pneumonia
(particularly with
immunosuppression), interstitial fibrosis, bronch
iolitis obliterans with organizing pneumonia, rheu
matoid nodules, rheumatoid pneumoconiosis,
apical fibrobullous disease, drug related pneumo
nitis and fibrosis (methotrexate, gold, penicilla
mine, NSAIDs, cyclophosphamide, azathioprine,
sulfasalazine)
 VASCULAR pulmonary hypertension, vasculitis
 PLEURAL pleuritis,
pleural effusion, pleural
thickening
UNDIFFERENTIATED CONNECTIVE TISSUE DIS
EASE overlap syndrome with clinical features of
two or more rheumatologic disorders (RA, SLE, Sjog
ren’s syndrome, scleroderma, inflammatory myopa
thies) but does not fit the diagnostic criteria for any
specific disorder

MIXED CONNECTIVE TISSUE DISEASE a specific
overlap syndrome with clinical features of SLE, scler
oderma, polymyositis, and antibodies to RNP. Char
acteristically, Raynaud’s phenomenon, myositis, and
synovitis are present

Systemic Lupus Erythematosus
PATHOPHYSIOLOGY

POPULATION typically affects women aged 15 45
AUTOIMMUNE
REACTION antibody immune
complex deposition in kidneys (glomerulonephri
tis), autoantibodies against cell surface antigens
on hematopoietic progenitor cells (anemia, neutro
penia, thrombocytopenia), antiphospholipid anti
bodies (thrombosis)
ACR DIAGNOSTIC CRITERIA w4 RASHESw
 4 rashes malar rash, discoid rash, oral ulcers,
photosensitivity
 Renal proteinuria >0.5 g/day or !3+, or cellular
casts)
 Arthritis !2 peripheral joints, non erosive
 Serositis pleuritis, pericarditis
 Hematologic hemolytic anemia, leukopenia <4.0
Â109/L, lymphopenia <1.5x109/L, thrombocytope
nia <100x109/L
 Excitation seizures, psychosis
 Serology ANA, anti dsDNA, anti Smith, antipho
spholipid antibodies, false positive VDRL


PATHOPHYSIOLOGY (CONT’D)

Need !4 of 11 criteria (each rash counts as one
criterion and ANA as a separate criterium) to make
diagnosis. Note that many patients may not ever fulfill
four criteria until several years into their disease course
CLINICAL FEATURES

JOINT SYMPTOMS symmetric non erosive polyar
thritis with joint pain, swelling, redness, morning
stiffness (>1 h), and dysfunction. Sens 88%
 HANDS Jaccoud’s arthritis (joint deformities are
unusual). Fingers and wrists may be involved
 LEGS knees more commonly affected
 AVASCULAR NECROSIS hip, shoulder, and knee may
be affected
EXTRA ARTICULAR MANIFESTATIONS
 PULMONARY pleuritis (sens 50%), pulmonary
hypertension, PE, shrinking lung syndrome (dys
pnea, pleuritic chest pain, progressive reduction in
lung volume, elevated diaphragms)
 CARDIAC pericarditis (sens 30%), myocarditis, Lib
man Sacks endocarditis