Osteoarthritis/Gout
all components of joint affected by OA
- Cartilage is damaged, fibrillated - Chondrocyte efforts at repair lead to new bone formation (osteophytes) and subchondral sclerosis - Pro-inflammatory mediators produce low level synovitis - Disuse and inflammation lead to muscle atrophy and ligament degeneration
radiographs in gout
- marginal erosion w/overhanging edge - "rat bite"
synovial fluid in gout
*Crystal-induced arthritis and septic arthritis can be clinically indistinguishable and can coexist* *Particularly with acute, inflammatory monoarthritis, ALWAYS send a synovial fluid culture*
primary vs secondary OA
*primary/idiopathic OA* -- no predisposing condition; often associated w/aging *secondary OA* -- tends to affect younger individuals; end result of alt condition, including: - trauma - inflammatory arthritis (RA, psoriatic arthritis, JIA) - crystal arthropathy (gout, CPPD) - infection - metabolic disorders (hemochromatosis, alkaptonuria)
what is gout?
- *Metabolic disorder of purine metabolism leading to hyperuricemia* - Crystallized uric acid produces *inflammatory response* - Primary symptoms are musculoskeletal body hates the crystallization!
hyperuricemia DOES NOT EQUAL gout!!!
- 5% of asymptomatic adults are hyperuricemic - Uric acid level is sometimes normal in setting of acute gout - However, the risk of developing gout increases as uric acid increases: *uric acid > 9 mg/dL* --> 5% risk/yr *uric acid > 13 mg/dL* --> 50% risk/yr You never check a uric acid level in an acute guot setting. Usually inf response with crystals and uric acid can be high or low because in joint. Check in intercritical period when not in flare. Uric acid fluctuates. Uric acid over 13 you will get gout. Really important
classic acute gout
- Acute onset (hours) - Usually mono- or oligoarthritis - Red, hot, exquisitely painful joint - Any joint can be involved - *Podagra is classic* (great metatarsophalangeal joint) - Can have fever, leukocytosis - Will eventually resolve without treatment bedsheet on foot hurts!
stages of gout
- Asymptomatic hyperuricemia - Acute gouty arthritis - Intercritical gout (between 1 episode and the next) - Chronic tophaceous gout (large crystal deposits) - Extra-articular manifestations: tophi, renal disease
crystal arthritis -- key points
- Both disorders cause an acute arthritis that can mimic a septic joint - Gout is caused by disordered purine metabolism - Xanthine oxidase is critical in uric acid metabolism - Uric acid is primarily excreted in the kidney where urate transporters play an important role - The gold standard for diagnosis is demonstration of needle shaped, negatively birefringent crystal on polarizing microscopy. - Complications of gout include tophi, renal disease, chronic arthropathy - Treatment of acute gout is directed at reducing inflammation (NSAIDs, glucocorticoids, colchcine) - Urate lowering therapy is indicated for recurrent gout or complications of gout. - The goal of urate lowering therapy is to achieve a uric acid level < 6. - CPPD is caused by *abnormal calcium dihydrophosphate deposition* in the joint and surrounding tissues. - Several metabolic disorders are associated with CPPD - Familial CPPD (a genetic disorder) should be considered in a patient < 55 yrs of age with polyarticular disease - The gold standard for diagnosis involves demonstration of rhomboid shaped positively birefringent crystals on polarizing microscopy. - Treatment of CPPD focuses on anti-inflammatory therapies.
renal disease in gout
- Calculi - Renal interstitial deposition - Renal tubular deposition - Tophi in kidney This is an image of a kidney from a patient with gout who developed chronic urate nephropathy. There are pale, yellow-tan deposits in the medulla that are tophi.
causes of uric acid overproduction
- Congenital enzyme abnormalities (rare; young onset). Examples: - *Lesch-Nyhan syndrome*: hypoxanthine guanine phosphoribosyltransferase 1 (HGPRT) deficiency - *Phosphoribosylpyrophosphate (PRPP) synthetase overactivity* - Lymphoproliferative diseases - Hemolysis (rupturing RBCs) - Psoriasis - Glycogen storage diseases - Ethanol, hypoxia - *Idiopathic* Lesch-nyhan miss the HGPRT where children eat their fingers. Very specific, very rare. Huge overproduction of gout. Higher uric acid. Part of genetic abnormality they eat their fingers. Less severe PRPP. Gout at younger age but don't eat your fingers. Lymphomas, myelodisplastic disorders. Due to high cell turnover high purine synthesis. Psoriasis any inf disease. Inborne errors glycogen process. Any kind of stress. Also reasons we don't know.
Symptoms of OA
- Gradual onset and progression of symptoms - Pain with usage of joint - Improvement with rest - Mild (< 30 minutes) or no morning stiffness - Progression: Activity related pain --> Rest pain --> Night pain, instability
Most Common OA Locations
- Hand - CMC, PIP, *DIP* joints - Hip - Knee - Foot - Spine (cervical, lumbar) DIP uniquely affected in OA. DOES NOT affect MCP
elimination of uric acid
- Human tissues *do not contain uricase* and cannot degrade uric acid. - In plasma, uric acid exists primarily as Na+-urate. - Uric acid is eliminated through the gastrointestinal tract and kidney. birds have uricase, makes bird poop white. most is excreted via kidney.
radiographic features OA
- Joint space narrowing - Osteophyte formation - Subchondral sclerosis - Subchondral cysts Often *asymmetric involvement* between and within joints (for example, medial versus lateral compartment narrowing in knee)
epidemiology of gout
- Men > women, increases in women after menopause - Affects up to 3.9% of US adults - Prevalence increases with age - Severity and prevalance are increasing (Obesity, hypertension, chronic renal failure) - *Most common inflammatory arthritis* gout more in men! men pout (gout). estrogen is PROTECTIVE!! women can get it after menopause. Obesity hypoventilation syndrome (also known as *Pickwickian syndrome*) is a condition in which severely overweight people fail to breathe rapidly enough or deeply enough, resulting in low blood oxygen levels and high blood carbon dioxide (CO2) levels.
treatment of ACUTE gout
- NSAIDS - colchicine - intra-articular steroids - systemic steroids - analgesia *NOTE: this list does NOT contain allopurinol, febuxostat, probenicid* these are primarily medications which mediate the inflammatory response to uric acid *ACUTE gout will resolve eventually w/o treatment* Nsaids classic but need prescription doses. *Colchicine is antimicrotubule. Stabilizes inflammazone*, don't really know how it works. Give 1x/day or 2x/day acutely. Give it 1x per hour until profound diarrhea. You cant even walk because pain and then give med and cant move. Stopped doing that. Give 2x/day. Colchicine and NSAIDS all depend on renal function. Steroids give a burst to knock it out and deal with whether uric acid is elevated later. No drugs to treat hyperuricemia. Any time uric acid goes up and down risk for gout. *Get them over the flare and then decrease uric acid*!! It'll get better on its own. These meds have nothing to do with uric acid. ON TEST ACUTE DRUGS HAVE NOTHING TO DO WITH URIC ACID!!! get the inflammation down. then deal with uric acid later!!
CPPD: acute treatment options
- NSAIDs - Colchicine (not as effective as for gout) - Steroids (oral, intra-articular) - Analgesics - (Refractory disease: sometimes *hydroxychloroquine, methotrexate*) Pseudogout will resolve on its own with time.
CPPD pathogenesis
- Pathogenesis not well described - Avascular articular hyaline cartilage, menisci are susceptible to calcification - CPPD crystals deposit - Trigger inflammatory reaction in chondrocytes, intra-articular leukocytes, synoviocytes --> systemic inflammatory response; presumably similar mechanisms as in gout - Inflammatory response --> synovitis, cartilage damage *influenced ambient calcium, magnesium, pH, matrix composition*
causes of uric acid under-excretion
- Renal insufficiency - Diuretics (increase water excretion) - Low dose aspirin - Hypertension - Cyclosporine (an immunosuppressent -- affects purine metabolism) - Ketoacidosis - Lead nephropathy - Idiopathic *estrogen is uricosuric; thus premenopausal women are less likely to develop gout* note: Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma
common triggers for acute gout
- Surgery - Alcohol - Increased purines in diet - Fluctuation of uric acid level - initiation of therapy to lower uric acid level - diuretics (loop and thiazide) Beer. Uric acid rises and falls changes solubility and that's when these can form.
Physical Exam in OA
- Usually 1 or few joints - Typical locations - often asymmetric - Small effusions - Low level synovitis - Bony enlargement of joint - Pain on range of motion of joint - *Loss of active and passive range of motion* of joint - Crepitus on range of motion of joint - Deformity - Absence of extra-articular signs of disease
non-pharmacologic OA management
- Weight loss - Lifestyle modification - Physical therapy (eg, quad strengthening, gait retraining for knee OA) - Occupational therapy (hand OA) - Splinting and bracing - Assistive devices (cane, walker) - Tai chi (knee, hip OA) - Other physical exercise
Causes of Hyperuricema
- over-production of uric acid - under-excretion of uric acid (MORE COMMON)
what is hyperuricemia?
- usually *>7.5-8mg/dL* - at 37 degrees celsius, solubility of urate in plasma is 7mg/dL (solubility decreases as temp decreases) gout affects more DISTAL joints! temp lower.
moving away from gout... on to CPPD
= calcium pyrophosphate deposition disease Square + rhomboid. Buzzword. Looks like gout but see extra Ca deposits all along bone. Get concerned. Presents like gout.
histopathology of the tophus
A: Amorphous fibrillary crystalline tissue deposits of tophaceous gout in formalin-fixed tissue represent the proteinaceous matrix that surrounds dissolved crystals (H&E). B: Agranulomatous reaction palisades around a gouty tophus (H&E). Cut it off and look under scope. Crystalline tissue deposits. Dissolved crystals. Granulomatous but not quite perfect. Cells trying to wall off crystals
Calcium Pyrophosphate Deposition Disease (CPPD): Clinical Presentations
Acute CPPD "Pseudogout" - Acute onset of mono, oligo or polyarthritis - Red, hot tender joint(s) - May have fever - Triggers: surgery, fluid shifts Most commonly involved joints - Knee, shoulder, wrist, pubic symphysis chronic CPPD "pseudogout" - mimic RA
what is CPPD?
An acute or chronic joint disease caused by the deposition of calcium pyrophosphate dihydrate (CPPD) crystals.
surgical intervention for OA
Arthroscopy? (to look within joint) - Used for loose bodies, meniscal tears - not specifically for OA Osteotomy - Reserved for malaligned knee or hip joint (e.g., severe genu varum "bow leg deformity") - Wedge of bone removed to restore alignment Arthroplasty - Removal of joint surface, replacement with prosthetic joint
spectrum of CPPD
Asymptomatic - Radiographically apparent chondrocalcinosis without inflammatory arthritis - May contribute to development of osteoarthritis Acute CPPD Chronic CPPD
familial CPPD
Autosomal dominant familial CPPD - *Mutations in ANKH* - gene that encodes a PP transporter Suspect in younger person (<55 years) with polyarticular disease
other crystals
Be aware that there are other crystal deposition diseases; we just covered the two that are by far the most common ones: gout and CPPD.
CPPD: radiographic features
Chondrocalcinosis--calcification of cartilage - menisci of knees - triangulofibrocartilage of wrists - pubic symphysis - shoulder See changes of osteoarthritis (CPPD causes secondary osteoarthritis)
hand changes -- what are they called??
In hand OA, the DIP and PIP joints are enlarged due to bony changes., known as "Bouchard nodes" at PIPs and "Heberden nodes" at DIPs. Note that *MCPs are spared*. B then H alphabetical
treatment of CHRONIC gout
Indications for *urate lowering therapy* - recurrent acute gout - chronic polyarthropathy - renal stones - tophi Goal = uric acid < 6 mg/dL
OA epidemiology
Most common form of arthritis - Affects > 20 million people in U.S. - Increases with age 65 yrs and older: > 50% have radiographic OA 75 yrs and older: 100% have radiographic OA - Most common cause of adult disability in U.S. - Affects both genders and all ethnic groups - The prevalence of OA is increasing The question here is just cause you have OA doesn't mean you're symptomatic from it. Affects everyone everywhere
renal elimination of uric acid
Most of uric acid is reabsorbed and 8-12% are excreted. URAT I and Glut9 important transporters. New drugs that target the transporters. Most reabsorbed in prox tubule and the rest is excreted in the urine.
GOUT medications (KNOW!)
NSAID/colchicine/probenecid contraindicated in renal insufficiency allopurinol: renal dosing in renal insufficiency *important interactions: azathioprine and mercaptopurine are inactivated by xanthine oxidase, levels of these can become toxic if these drugs are used together*
CPPD epidemiology
Not well understood Primarily based upon radiographic findings Prevalence increases with age - Up to 4.5% of patients age > 40 years have radiographic chondrocalcinosis - Up to 40% of patients > 80 years have radiographic chondrocalcinosis
CPPD: Diagnosis
Observation in synovial fluid (ideally inside leukocyte): calcium pyrophosphate dihydrate crystals CPPD crystals are - rhomboid - positively birefringent KNOW THIS
treatment options OA
goals: - alleviate pain - improve functional status - future: prevent progression of disease treatment options: - non pharmacologic - pharmacologic - surgical
OA of DIP joints
note the joint space narrowing, sclerosis, formation of new bone (osteophytes)
OA of CMC joint of thumb
note the narrowing of the joint space, sclerosis of bony margins, osteophytes, subchondral cysts
normal vs osteoarthritic cartilage
ragged, holes, mess
risk factors for OA
realize that RA and inf arthritis can lead to OA
normal hand vs OA?
seagull
factors leading to OA
seagull change
what is OA?
structural or functional failure of a joint due to loss of cartilage and other joint tissues which is evident on radiographs and causes discomfort or decreased function
pharmacologic management of OA
topical - capsaicin - NSAID oral - acetaminophen - NSAID - tramadol (remember: -adol = opioid agonist/antagonist) - narcotics intra-articular - GCC - viscosupplementation with hyaluronic acid no clear benefit of glucosamine chondroitin! NO DRUGS that retard/rev progression of OA...
normal, varus, valgus
varus = bow-legged - more stress on medial compartment from OA valgus = knock-kneed - more stress on lateral compartment from OA
knee OA deformity
varus defomity of R knee and R knee effusion
OA pathophysiology
we see... - progressive loss of articular cartilage - new formation of subchondral bone - new bone and cartilage formation at joint margins - low level synovitis
differentiating OA from RA CHART KNOW THIS
no osteophytes in RA
chronic tophaceous gout
Frequent attacks of acute gouty arthritis Bone destruction and degenerative arthritis -- common in advanced cases Polyarthropathy -- can mimic rheumatoid arthritis
inflammazone
Huge cytokine storm of inflammazone all inf produced due to 1 crystal formed and that's what causes all the pain. Hard for us to break it down. Don't need to know enzymes
conditions associated w/CPPD
Hyperparathyroidism Hypothyroidism Chronic renal insufficiency Hypophosphatemia Hypomagnesemia Lymphoproliferative disorders Hemochromatosis (too much iron) Hemosiderosis (too much iron) increased PTH. increased bone resorption, Ca2+ in blood.
production of uric acid
REQUIRES *xanthine oxidase* imp bc that's how we block it
chronic tophaceous gout: clinical features
Tophi are deposits of urate crystals in tissue Common tophi sites: - synovium - subchondral bone - olecranon bursae - infrapatellar tendon - Achilles tendon - ear pinnae
CPPD: treatment approach
Treatment is geared at reducing inflammation No definitive preventive treatment Goals in managing acute attacks - Reduce symptoms - Diagnose and treat any associated or triggering illnesses
OA: the "joint organ"
We see pain. Patients complain about pain not LOF. Change behavior before complaining about LOF. #1 cause joint replacement. What we don't understand is any of the underlying nonclinical stuff of OA. Any cause inevitably leads to the same result. Same thing in the end but don't know how it gets there. We don't know how to stop it, fix it. Only treat it supportively. No FDA drugs approved for OA
normal cartilage
composition - collage (type II) - proteoglycans (aggrecan) - matrix - chondrocytes limited vascular supply/innervation balance of injury/repair
what things in diet exacerbate/reduce gout?
exacerbate: - alcohol - shellfish - organ meats - purine rich foods - fructose may reduce gout - dairy - fruits (cherries)
IMPORTANT: Urate lowering therapy
f possible, stop diuretics Allopurinol and febuxostat can cause transient increase in uric acid and risk of flare (not used in acute gout, often prescribe "prophylactic" colchicine when starting).
acute gout pics
Distal joints because colder. Pathognomonic. They smile. This is painful this is not that. Really unique pain
flow chart of gout
Eat food. Ideally some protein in it. Make proteins, DNA. Have uric acid level and it goes out. Either make too mch or don't pee it out in blood saturates crystallizes gout
laboratory tests in OA
Exclude other causes - inflammatory arthritis, metabolic disorders (RA, hemochromatosis, CPPD, etc.) Inflammatory markers usually *normal* for age No autoantibody or other diagnostic laboratory test for OA Synovial fluid with low WBC *Usually WBC is 200-2000 cells/mm3*
flow chart
Crystal nucleates and gets enveloped. Inf reaction. Change of pH lactic acid. Inflammatory cells that envelop crystal. Gets angry and makes inflammazone where you get gout inflammation
differential diagnosis
Septic joint Rheumatoid arthritis Spondyloarthropathies Other inflammatory arthropathies *Remember: always order a culture on synovial fluid*
intercritical gout
Symptom-free period between episodes of acute gout (may be months or years) If untreated, episodes of acute gouty arthritis become more frequent, last longer, and often involve more joints (polyarticular) When you want to check uric acid. In between gout flares. Unique for chronic inf arthritis. RA is persistent, additive, chronic inf. Don't treat? Gets better on its own. They may do fine then flare again. Unique disease. Truly have high uric acid. Gout flares closer and closer. Patients with gou for years not treated looks like RA chronically inflammed joints chronic uric acid.
diagnosis of gout
Synovial fluid showing needle-shaped negatively birefringent crystals (ideally inside leukocytes) on polarizing microscopy Inflammatory synovial fluid