2 - Acute Arthritis and Urate Metabolism Crystal Arthritis Flashcards
1
Q
Acute Arthritis - “Acute”
A
Less than 6 weeks duration
2
Q
Acute Arthritis - “Arthritis”
A
Inflammation localized to the articular surfaces
Swelling (Synovitis and/or effusion), warmth, discomfort, redness
Distinct from arthralgia, peri-arthritis, tendinitis, bursitis, etc
3
Q
Acute Joint Complaints - Goals of the initial evaluation
A
Distinguish articular vs. non-articular pathology
Determine inflammatory vs. non-inflammatory features
Identify and triage musculoskeletal emergencies appropriately
Assess whether history, current symptoms and exam are consistent with a specific rheumatic disease
Obtain appropriate additional testing (imaging, labs, etc)
Establish short and long term treatment plans (when to refer)
4
Q
Acute Joint Complaints - Timing
A
Rapid Onset:
Trauma
Septic
Crystalline
Slow Onset:
Systemic Rheumatic Disease
Non-Inflammatory Process (Osteoarthritis)
5
Q
Acute Joint Complaints - Time of day the symptoms feel worst
A
AM:
Prolonged in systemic rheumatic disease
PM:
Sprain/strain/non-inflammatory
6
Q
Acute Joint Complaints - Worse with Activity or Rest
A
Worse with activity:
Tendinitis
Bursitis
Non-Inflammatory Process
Worse with rest:
Systemic rheumatic diseases
7
Q
Acute Joint Complaints - Time from no symptoms to maximal intensity
A
Rapid:
Trauma
Septic
Crystalline
8
Q
Arthralgia
A
Pain in the joint that doesn’t appear to be inflammatory
9
Q
Acute Joint Complaints - Confined to joints or inter-articular
A
Localized to joints:
Arthritis
Arthralgia
Inter-articular:
Diffuse pain syndromes
10
Q
Acute Joint Complaints - Mono vs oligo vs polyarticular
A
Polyarticular:
Less likely to be septic arthritis (however, polyarticular septic arthritis is still possible)
Monoarticular:
Can still be an early presentation of a systemic rheumatic disease
11
Q
Acute Joint Complaints - Pattern of joints affected
A
Small joint peripheral
vs.
Large joint
vs.
Axial involvement
These provide clues to the type of systemic rheumatic disease if presentation is polyarticular
12
Q
Acute Joint Complaints - Recent Trauma
A
Possible fracture
Sprain
Strain
Tendon/ligamentous rupture
Also acute attacts of CCPD are often preceded by traumz
13
Q
Acute Joint Complaints - Warmth & Swelling
A
Hot to touch:
Septic or crystalline
Cool:
Non-inflammatory
14
Q
Acute Joint Complaints - Intensity and quality of symptoms
A
0 - 10 pain scale, “touch me not”:
Highest often in septic or crystalline
Sore vs ache vs stiff vs stabbing/lancinating vs burning vs numbness/tingling
Stiff>pain:
Systemic rheumatic diseases
Vague deep ache:
Hyperparathyroidism
Osteomalacia
Bone lesions (night pain)
Burning/numbness/tingling:
Neurogenic
Claudication:
Vascular vs. spinal stenosis
15
Q
Acute Joint Complaints - Symmetry
A
Certain systemic rheumatic diseases
16
Q
Acute Joint Complaints - Constitutional/prodromal symptoms
A
Infection or systemic rheumatic diseases, occasionally crystalline
17
Q
Acute Joint Complaints - Prior similar episodes
A
Less likely to be infectious
Intercritical return to complete normality:
Crystalline arthritis
18
Q
Specific indicators of systemic rheumatic diseases
A
Cutaneous manifestations (Psoriasis, photosensitivity, purpura, skin thickening, erythema nodosum, nodules, etc) Swollen glands Raynaud's Oral/nasal ulcers Pleurisy/pericarditis Eye inflammation Nail changes Dry eyes/mouth Proximal muscle weakness Sinusitis Hearing loss
19
Q
Acute Joint Complaints - Physical Exam - Articular
A
Inspection
Range of motion
Palpation (warmth, erythema, swelling, effusion, tenderness, deformity, crepitus, stability)
20
Q
Acute Joint Complaints - Physical Exam - Extra-articular
A
Requires multi-system examination
21
Q
Distinguishing Exam Features - Symmetry
A
Probably - Systemic Rheumatic Disease
Maybe - Non-inflammatory
Probably not - Tendinitis/bursitis
22
Q
Distinguishing Exam Features - Inflammation
A
Tendinitis/bursitis - Over tendon/bursa
Systemic Rheumatic Disease - Common
Unusual in non-inflammatory
23
Q
Distinguishing Exam Features - Tenderness
A
Tendinitis/bursitis - Focal
Systemic rheumatic disease - Over entire joint space
24
Q
Distinguishing Exam Features - Locking
A
Tendinitis/bursitis - Unusual expect with tears
Noninflammatory - Possible, implies loose body or internal derangement
Uncommon in Systemic rheumatic disease
25
Acute Monoarthritis - Common Etiologies
```
Infection
Crystal-induced
Trauma
Hemarthrosis
Osteonecrosis
Early monoarticular presentations of polyarticular diseases
```
26
Acute Monoarthritis - Infection
Bacteria (Gonococcal vs. non-gonococcal)
Viruses (often polyarticular)
Fungi/spirochetes/mycobacteria (Coccidiodomycosis, spirotrichosis, blastomycosis, lyme, M. marinum)
27
Acute Monoarthritis - Crystal induced
```
Gout
Pseudogout (Calcium pyrophosphate deposition disease, CPPD)
```
28
Acute monoarthritis - Joint aspiration
IMPERATIVE to perform if septic joint ins suspected
Gout is a risk factor for septic arthritis
"If you think of it, do it"
Gram stain and culture should be performed prior to antibiotics
Warfarin is NOT a contraindication
29
Monoarthritis - Synovial fluid tests
Cell count & Differential:
Inflammatory WBC>2,000 or >75% PMN
Septic and crystal arthritis often much higher
Gram stain & culture:
Negative studies to not absolutely rule out septic joint
Aerobe, anaerobe, fungal, AFB and mycobacterial if clinically indicated
Crystal assessment using polarized light microscopy
Glucose, LDH, protein not very helpful
30
Inflammatory Joint Fluid (>2,000 WBC/μL)
```
Rheumatoid arthritis
Psoriatic arthritis
Spondyloarthropathies
Juvenile chronic arthritis
Gout
Pseudogout
Systemic lupus erythematosus
Septic arthritis
```
31
Non-Inflammatory Joint Fluid (
```
Osteoarthritis
Trauma
Charcot's joint
Pancreatitis
Hemochromatosis
Acromegaly
Glucocorticoid withdrawal
Hypertrophic osteoarthropathy
Avascular necrosis
Pigmented villonodular synovitis
Systemic lupus erythematosus
```
32
Monoarthritis - Additional testing
CBC
Blood cultures
Coagulation studies
Plain radiographs
Elevated uric acid level does not exclude septic arthritis
CT or MRI in specific situations (suspect osteomyelitis as focus, or soft tissue abscess
Specialized testing for specific pathogens (typically not sent initially)
33
Bacterial Septic Arthritis
Musculoskeletal EMERGENCY
```
Associated with:
Sepsis
Extensive joint damage
Mortality (10% overall, 19 - 33% in elderly or with comorbidities)
Permanent loss of joint function (40%)
```
34
Bacterial Septic Arthritis - Gonococcal
Incidence decreasing over past 2 decades
Typically sexually active young adults
Female > Male
Other clinical features (maybe, but not necessary):
Polyarthralgia can precede - monoarthritis in 50%, though
Constitutional symptoms
Tenosynovitis, especially wrist (68%)
Skin lesions (75%) - erythematous papules progress to vesicles or pustules on extremities and trunk
Anogenital infection often asymptomatic
35
Bacterial Septic Arthritis - Non-Gonococcal
```
Gram positives (80%):
Staph aureus predominates (60%)
```
```
Gram negatives (10 - 20%):
E. Coli
Proteus
Klebsiella
Enterobacter
Very young, elderly, injection drug use, immunocompromised
```
Diabetes is a risk factor
Prodrome of malaise and fever (fever is often mild and only presents in 30 - 40% with temperatures >39C)
Large joint predilection (knees/hips>shoulders>wrist/ankles)
Requires aggressive management
36
Bacterial Septic Arthritis - Management
Serial aspiration to dryness vs. open surgical drainage with lavage
Parenteral antibiotics
Splinting and physical therapy to prevent contractures and muscle atrophy
37
Staph Aureus Septic Arthritis
Pathogenesis dependent on pathogen virulence factors and host factors
Virulence factors:
Adhesins
Bio-film (evasion mechanism)
Enzymes and toxins)
Consequence is inflammatory cell infiltration, synovitis, damage to cartilage and bone, erosion, joint destruction
Experimental limitation of virulence factors results in less joint damage
Host factors cause more damage than pathogen factors
38
Lyme Arthritis
Features dependent on phase of disease
Early disseminated lyme:
Polyarthralgia
ELISA may be negative very early
```
Late lyme:
Weeks to months after primary infection (ELISA positive, if lyme infected)
Mono, oligo, occasionally polyarthritis
Tends to be symmetric
Large/medium joint
Large effusion in a single knee in most
```
39
Polyarthritis Differential - Infection
```
Gonococcal
Meningococcal
Lyme disease
Rheumatic fever
Bacterial endocarditis
Viral - Rubella, parvovirus, HBV, HCV
Fungal - Histoplasmosis, Disseminated Coccidiodomycosis
Mycobacterial
```
40
Polyarthritis Differential - Systemic Rheumatic
```
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Sjogren's Syndrome
Reactive Arthritis
Psoriatic Arthritis
Polyarticular Gout
Sarcoid Arthritis
Vasculitis
Polymyalgia Rheumatica
Inflammatory myopathies
```
41
Viral Arthritis
Usually self-limited, requires no specific therapy
Direct invasion of synovium by virus
Immune complex mediated synovitis
Virus acting as an antigenic target for the immune system
42
Most common virus causing chronic polyarthralgia/arthritis
HCV
43
Common viruses causing self-limited polyarthralgia/arthritis
HBV
Parvovirus
Alphaviruses
Dengue
44
Viruses less likely to cause polyarthralgia/arthritis
```
EBV
CMV
Mumps
Coxsackie
HSV
Adenovirus
```
45
Viral serologies if high suspicion
HCV
HBV
Parvovirus
Viral cultures form joints are difficult and rarely performed
46
Chikungunya - Locations
Caribbean
Parts of Africa
Mediterranean
Southeast Asia
47
Gout
Intense inflammatory arthritis
Destructive potential for the joint
Caused by immunoreactivity to precipitated uric acid crystals in individuals with hyperuricemia
48
Phases of gout
Acute:
Intermittent presentation
Chronic:
Episodic vs. persistent
Tophaceous vs. non-tophaceous
49
Tophi
Uric acid crystals under the skin
Accumulate in places that are cooler
Can develop sinus tracks that can drain
50
Acute Gout - Cardinal signs and symptoms
```
Intense articular inflammation:
Calor
Dolor
Rubor
Tumor
```
Touch-me-not tenderness
Maximal symptoms in early morning after sleeping for hours
Inter-critical resolution of symptoms
51
Acute Gout - Joint Predilection
```
1st Metatarsophalangeal (called podagra)
Midfoot
Ankle
Knee
Wrist
Elbow
Distal Interphalangeal
```
52
Chronic Gout - Cardinal signs and symptoms
Features/presentation extremely variable
Attacks more frequent or continuous symptoms
Tophi
Articular damage, destruction, disability
Nephropathy/Nephrolithiasis
Cardiovascular risk
53
Gout - Radiograph
Preservation of the cortex around the erosion
Overhanging edge
"rat bite erosion"
54
Gout - Epidemiology
Most common inflammatory arthritis
Prevalence estimates vary
Tophaceous gout: ~75% of untreated chronic gout patients with disease > 20 years
M>F
Very uncommon in pre-menopausal women
Incidence in women goes up after menopause
55
Why is incidence of gout increasing?
Aging population
Increasing obesity
Treatment of cardiovascular risk factors (diuretics)
Improved longevity with CKD/Transplant
56
Risk factors for Incident Gout
Hyperuricemia (main risk factor, necessary but not sufficient)
Obesity
Hypertension
Medications (Diuretics, cyclosporine, tacrolimus, low dose aspirin)
Dietary (Red meat, shellfish, other fish, beer, liquor)
57
Urate Metabolism
Diet and cell breakdown
Purines
Hypoxanthine (broken down by Xanthine Oxidase)
Xanthine (broken down by Xanthine Oxidase)
Uric acid (broken down by Urate oxidase/Uricase)
Allantoin + CO2 + H2O
58
Allantoin
Soluble and easy to excrete
59
Primary contributors to the urate level
Endogenous purine synthesis
| Dietary purine load (less so)
60
Primary contributors to urate excretion
```
Renal excretion
Gut excretion (less so)
```
61
Urate: Overproduction vs. Underexcretion
```
Underexcretion = 90% of gout patients
Overproduction = 10% of gout patients
```
62
How much urate is excreted after passing through the proximal tubule?
7 - 12%
63
Urate exchanger at the proximal tubule
URAT1
Urate reabsorbed in order to trade and excrete lactate, nicotinate, pyrazinamide
64
Genetics of hyperuricemia
Mutations in hypoxanthine guanine phosphoribosyltransferase (HPRT) and phosphoribosyl pyrophosphatase synthetase (PRPSI):
Early onset gout
Lesch-Nyhan Syndrome
Idiopathic hyperuricemia:
Likely polygenic
Polymorphisms in URAT1 and other urate transport proteins are likely contributors
65
Acute Gout - Hallmark Crystal Finding
Needle shaped
Intracellular
Negative birefringence with polarized light microscopy
66
How do the crystals trigger inflammation?
Crystals bind TLRs on macrophages
TLRs signal the NALP3 Inflammasome (IL-1, TNF-α, IL-18)
```
Cytokine cascade:
Endothelial priming
Neutrophil influx
Leukotriene production
Bradykinin generation
```
67
Neutrophil Extracellular Traps (NETs)
```
Neutrophils die and extrude their DNA
This forms a net
This aggregates inflammatory cytokines and chemokines
This breaks the inflammatory cascade
Resolves acute gouty inflammation
```
68
Gout - Diagnostic Pearls
Demonstration of uric acid crystals should be attempted in all patients.
Asymptomatic joints often demonstrate uric acid crystals
Serum uric acid levels can be low or normal during an acute attack
Acute gout and septic arthritis can coexist
Gout and rheumatoid arthritis are rarely seen together
Rapidity of onset, intensity of symptoms, intercritical resolution of symptoms distinguish gout from other inflammatory arthritidies
69
Gout - Treatment
Acute attack:
Reduce inflammation, Pain
Chronic Gout:
Reduce hyperuricemia
Reduce the frequency/prevent flares
70
Acute Gout - Treatment
```
Colchicine
NSAIDs
Intra-articular steroids (preferred)
Systemic corticosteroids/ACTH
Analgesics
Ice
Investigational - Systemic anti-IL-1 therapy and other anti-cytokine biologics
```
71
Acute Gout - Colchicine
Used for decades, but only one clinical trial
Mechanism unknown
Likely interferes with PMN chemotaxis
Best outcome when used early (first 12 - 24 hours of attack)
Toxicities:
Diarrhea
Myopathy (especially in those with renal/hepatic insufficency, those on HMG-CoA reductase inhibitors, cyclosporine)
Bone marrow suppression
Low dose colchicine plus lower doses 1 hour later is as effective as a higher dose regimen
72
Acute Gout - NSAIDS
Well established
Little studied
All NSAIDs are likely effective
Indomethacin traditionally used (but risk of GI toxicity)
COX-2 inhibitors appear to be as effective as non-selective NSAIDs
Etoricoxib is as effective as indomethacin in a randomized, double blind clinical trial
73
Acute Gout - Corticosteroids
Intra-articular corticosteroids = treatment of choice for acute mono/oligo articular gout
Refractory to NSAIDs/colchicine
Contraindications to NSAIDs/colchicine
May be associated with rebound flares when used without NSAIDs/colchicine
Side effect profile often an issue for those with gout and multiple comorbidities
Intramuscular corticotropin an option, but not seen often
74
Acute Gout - Cytokine Inhibition
IL-1 antagonism
Pain after acute flare is lower for Canakinumab compared to intramuscular Triamcinolone
It is for patients are unable to take NSAIDs or colchicine
Can't hold a candle to NSAIDs/colchicine
75
Gout Flare Prophylaxis - Cytokine Inhibition
IL-1 antagonism
Acute flares lower in patients treated with Canakinumab compared to colchicine
Acute flares after starting allopurinol reduced patients treated with rilonacept compared to placebo
Not compared against colchicine
Not FDA approved for this indication
76
Chronic Gout - Management
Reduce/Eliminate Flares by lowering Urate
Reduce exogenous purines
Reduce endogenous purines
Facilitate urate handling
Prophylax against flares (important during lowering of urate)
Urate therapy recommended for 2+ significant attacks per year, tophi or radiographic damage
77
Chronic Gout - Xanthine Oxidase Inhibitors
Allopurinol
Febuxostat
Oxypurinol
Can be used in over-producers, under-excretors, and those with urate nephrolithiasis
78
Allopurinol
Requires renal function based on dosing adjustment
Toxicities (
79
Febuxostat
Non-purine selective inhibitor of xanthine oxidase
Less toxicity in patients with chronic kidney disease
No cross-reactivity in patients with allopurinol hypersensitivity
Flares common with initiation - colchicine prophylaxis recommended
80
Chronic Gout - Uricosurics
Less commonly used
May precipitate nephrolithiasis in uric acid over-excretors or patients with a history of renal calculi
Probenecid
Benzbromarone/Sulfinpyrazone (not available in the USA)
Combining with Allopurinol is an option (requiring CAREFUL monitoring)
81
Probenecid
Molecular target: Renal URAT1 exchanger
Common clinical utility in patients refractory or intolerant to allopurinol (eg allopurinol hypersensitivity)
Ineffective in conjunction with low-dose aspirin
Ineffective in chronic kidney disease
82
Chronic Gout - "Surprise" uricosurics
Losartan (other ARBs)?
Blocks URAT1 exchanger in proximal renal tubule
```
Fenofibrates
Statins (maybe?)
Vitamin C
Cherries/Cherry extract
Low fat dairy products
```
83
Chronic Gout - Uricase Replacement
```
Rasburicase
PEGylated uricase (Pegloticase)
```
84
Rasburicase
Uricase replacement
Available for the prevention of tumor lysis syndrome
Immunogenicity prevents repeated infusions
85
PEGylated Uricase (Pegloticase)
Less immunogenic than Rasburicase
Shows promise for rapid resorption of tophi
Long-term safety unknown
FDA approved for refractory gout (appropriate for
86
Chronic Gout - Concomitant Management
Diet:
Less red meat, shellfish, fatty fish, alcohol, sugar, sweetened soda
More water, low fat dairy
Weight Loss
Treat other risk factors:
Hypertension, psoriasis, chronic dehydration
Consider alternates to diuretics
87
Acute Gout Prophylaxis during Urate Lowering Therapy - Rules of thumb
Do not start urate lowering therapy during an acute attack
Do not discontinue urate lowering therapy if an attack occurs
Prophylax with colchicine (0.6mg BID) or NSAIDs (colchicine preferred) for the first months of urate therapy
Acute attacks more likely when rapid uric acid shifts occur
If the patient is prone to attacks, stat low and slowly titrate urate lowering therapy
88
Acute Gout Prophylaxis during Urate Lowering Therapy - Typical timeframes
4 to 12 months to normalize serum uric acid levels
| 12 to 24 months for noticeable tophi reduction
89
Calcium Pyrophosphate Deposition Disease (CPDD) - Multiple Presentations
Asymptomatic Chondrocalcinosis:
In isolation or in conjunction with osteoarthritis
Acute CPPD inflammatory arthritis
Chronic CPPD inflammatory arthritis:
Can be mono-, oligo- or polyarticular
Rarely can resemble rheumatoid arthritis
Knee usually involved, especially in acute pseudogout
Hip, wrist and shoulder often involved, especially in chronic pyrophosphate-related osteoarthritis
90
CPPD Epidemiology
Prevalence unknown
There are hereditary forms
```
Associated with:
Prior joint damage/injury
Hemochromatosis
Hyperparathyroidism
Hypophosphatasia
Hypomagnesemia
Age
```
91
CPPD - Pathophysiologic Mechanism
ANKH gene linked to chondrocalcinosis
Gain of function mutations associated with increased extracellular inorganic pyrophosphate (ePPi)
Higher ePPi associated with CPPD deposition in chondrocytes
92
Hydroxyapatite Deposition Disease
Another crystal-induced arthritis
Intra-articular and periarticular hydroxyapatite deposition
Milwaukee shoulder
Predisposing factors - age, CPPD, dialysis, trauma
