2 - Acute Arthritis and Urate Metabolism Crystal Arthritis Flashcards
Acute Arthritis - “Acute”
Less than 6 weeks duration
Acute Arthritis - “Arthritis”
Inflammation localized to the articular surfaces
Swelling (Synovitis and/or effusion), warmth, discomfort, redness
Distinct from arthralgia, peri-arthritis, tendinitis, bursitis, etc
Acute Joint Complaints - Goals of the initial evaluation
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)
Acute Joint Complaints - Timing
Rapid Onset:
Trauma
Septic
Crystalline
Slow Onset:
Systemic Rheumatic Disease
Non-Inflammatory Process (Osteoarthritis)
Acute Joint Complaints - Time of day the symptoms feel worst
AM:
Prolonged in systemic rheumatic disease
PM:
Sprain/strain/non-inflammatory
Acute Joint Complaints - Worse with Activity or Rest
Worse with activity:
Tendinitis
Bursitis
Non-Inflammatory Process
Worse with rest:
Systemic rheumatic diseases
Acute Joint Complaints - Time from no symptoms to maximal intensity
Rapid:
Trauma
Septic
Crystalline
Arthralgia
Pain in the joint that doesn’t appear to be inflammatory
Acute Joint Complaints - Confined to joints or inter-articular
Localized to joints:
Arthritis
Arthralgia
Inter-articular:
Diffuse pain syndromes
Acute Joint Complaints - Mono vs oligo vs polyarticular
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
Acute Joint Complaints - Pattern of joints affected
Small joint peripheral
vs.
Large joint
vs.
Axial involvement
These provide clues to the type of systemic rheumatic disease if presentation is polyarticular
Acute Joint Complaints - Recent Trauma
Possible fracture
Sprain
Strain
Tendon/ligamentous rupture
Also acute attacts of CCPD are often preceded by traumz
Acute Joint Complaints - Warmth & Swelling
Hot to touch:
Septic or crystalline
Cool:
Non-inflammatory
Acute Joint Complaints - Intensity and quality of symptoms
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
Acute Joint Complaints - Symmetry
Certain systemic rheumatic diseases
Acute Joint Complaints - Constitutional/prodromal symptoms
Infection or systemic rheumatic diseases, occasionally crystalline
Acute Joint Complaints - Prior similar episodes
Less likely to be infectious
Intercritical return to complete normality:
Crystalline arthritis
Specific indicators of systemic rheumatic diseases
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
Acute Joint Complaints - Physical Exam - Articular
Inspection
Range of motion
Palpation (warmth, erythema, swelling, effusion, tenderness, deformity, crepitus, stability)
Acute Joint Complaints - Physical Exam - Extra-articular
Requires multi-system examination
Distinguishing Exam Features - Symmetry
Probably - Systemic Rheumatic Disease
Maybe - Non-inflammatory
Probably not - Tendinitis/bursitis
Distinguishing Exam Features - Inflammation
Tendinitis/bursitis - Over tendon/bursa
Systemic Rheumatic Disease - Common
Unusual in non-inflammatory
Distinguishing Exam Features - Tenderness
Tendinitis/bursitis - Focal
Systemic rheumatic disease - Over entire joint space
Distinguishing Exam Features - Locking
Tendinitis/bursitis - Unusual expect with tears
Noninflammatory - Possible, implies loose body or internal derangement
Uncommon in Systemic rheumatic disease
Acute Monoarthritis - Common Etiologies
Infection Crystal-induced Trauma Hemarthrosis Osteonecrosis Early monoarticular presentations of polyarticular diseases
Acute Monoarthritis - Infection
Bacteria (Gonococcal vs. non-gonococcal)
Viruses (often polyarticular)
Fungi/spirochetes/mycobacteria (Coccidiodomycosis, spirotrichosis, blastomycosis, lyme, M. marinum)
Acute Monoarthritis - Crystal induced
Gout Pseudogout (Calcium pyrophosphate deposition disease, CPPD)
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
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
Inflammatory Joint Fluid (>2,000 WBC/μL)
Rheumatoid arthritis Psoriatic arthritis Spondyloarthropathies Juvenile chronic arthritis Gout Pseudogout Systemic lupus erythematosus Septic arthritis
Non-Inflammatory Joint Fluid (
Osteoarthritis Trauma Charcot's joint Pancreatitis Hemochromatosis Acromegaly Glucocorticoid withdrawal Hypertrophic osteoarthropathy Avascular necrosis Pigmented villonodular synovitis Systemic lupus erythematosus
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)
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%)
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
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
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
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
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
Polyarthritis Differential - Infection
Gonococcal Meningococcal Lyme disease Rheumatic fever Bacterial endocarditis Viral - Rubella, parvovirus, HBV, HCV Fungal - Histoplasmosis, Disseminated Coccidiodomycosis Mycobacterial
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
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
Most common virus causing chronic polyarthralgia/arthritis
HCV
Common viruses causing self-limited polyarthralgia/arthritis
HBV
Parvovirus
Alphaviruses
Dengue
Viruses less likely to cause polyarthralgia/arthritis
EBV CMV Mumps Coxsackie HSV Adenovirus
Viral serologies if high suspicion
HCV
HBV
Parvovirus
Viral cultures form joints are difficult and rarely performed
Chikungunya - Locations
Caribbean
Parts of Africa
Mediterranean
Southeast Asia
Gout
Intense inflammatory arthritis
Destructive potential for the joint
Caused by immunoreactivity to precipitated uric acid crystals in individuals with hyperuricemia
Phases of gout
Acute:
Intermittent presentation
Chronic:
Episodic vs. persistent
Tophaceous vs. non-tophaceous
Tophi
Uric acid crystals under the skin
Accumulate in places that are cooler
Can develop sinus tracks that can drain
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
Acute Gout - Joint Predilection
1st Metatarsophalangeal (called podagra) Midfoot Ankle Knee Wrist Elbow Distal Interphalangeal
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
Gout - Radiograph
Preservation of the cortex around the erosion
Overhanging edge
“rat bite erosion”
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
Why is incidence of gout increasing?
Aging population
Increasing obesity
Treatment of cardiovascular risk factors (diuretics)
Improved longevity with CKD/Transplant
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)
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
Allantoin
Soluble and easy to excrete
Primary contributors to the urate level
Endogenous purine synthesis
Dietary purine load (less so)
Primary contributors to urate excretion
Renal excretion Gut excretion (less so)
Urate: Overproduction vs. Underexcretion
Underexcretion = 90% of gout patients Overproduction = 10% of gout patients
How much urate is excreted after passing through the proximal tubule?
7 - 12%
Urate exchanger at the proximal tubule
URAT1
Urate reabsorbed in order to trade and excrete lactate, nicotinate, pyrazinamide
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
Acute Gout - Hallmark Crystal Finding
Needle shaped
Intracellular
Negative birefringence with polarized light microscopy
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
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
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
Gout - Treatment
Acute attack:
Reduce inflammation, Pain
Chronic Gout:
Reduce hyperuricemia
Reduce the frequency/prevent flares
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
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
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
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
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
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
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
Chronic Gout - Xanthine Oxidase Inhibitors
Allopurinol
Febuxostat
Oxypurinol
Can be used in over-producers, under-excretors, and those with urate nephrolithiasis
Allopurinol
Requires renal function based on dosing adjustment
Toxicities (
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
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)
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
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
Chronic Gout - Uricase Replacement
Rasburicase PEGylated uricase (Pegloticase)
Rasburicase
Uricase replacement
Available for the prevention of tumor lysis syndrome
Immunogenicity prevents repeated infusions
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
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
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
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
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
CPPD Epidemiology
Prevalence unknown
There are hereditary forms
Associated with: Prior joint damage/injury Hemochromatosis Hyperparathyroidism Hypophosphatasia Hypomagnesemia Age
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
Hydroxyapatite Deposition Disease
Another crystal-induced arthritis
Intra-articular and periarticular hydroxyapatite deposition
Milwaukee shoulder
Predisposing factors - age, CPPD, dialysis, trauma
