Gout, RA, JIA

Question 1

Gout

Answer 1

• Disease that occurs in response to presence of mosodium urate (MSU) crystals in joints, bones, and soft tissue.
• It may result in acute arthritis and chronic arthropathy
• Characterized biochemically by serum or plasma urate concentration exceeding 6.8mg/dL

Question 2

Pathophysicologic mechanisms of gout

Answer 2

A number of interacting processes are responsible.

• Metabolic, genetic, and other factors that result in hyeruricemia
• Physiologic, metabolic, and other characterisitcs responsible for crystal formation
• Cellular and soluble inflammatory and innate immune processes and characterisitcs of MSU crystals themselves that promote the acute inflammatory response to MSU cystals
• Imuune mechanisms and other factors that mediate the resolution of acute inflammation
• Chronic inflammatory processes and the effects of crystals and immune cells on osteoclasts, osteoblasts, and chondrocytes that contribute to the formation of tophi and bony erosions, cartilage attrition, and joint injury

Question 3

Hyperuricemia and Gout

Answer 3

• Hyperuricemia is a necessary predisposing factor for gout. However, most people who have hyperuricemia will never develop gout.
• Hyperuricemia is due to impairment of renal urice acid excretion, overproduction of uric acid, and/or overconsumption of purine-rich foods metabolized to urate.
• Individual differences in the formation of crystals and/or in inflammatory responses to the crystals may determine if people with hyperuricemia wil develop gout.

Question 4

MSU Crystals

Answer 4

• Solubility of MSU is determined by its concentration along with factors that influence nucleation and growth of crystals. This helps to explain why hyperuricemua is necessary, but not sufficient for gout development.
  
  1. Urate concentration - urate concentration levels above its solubility (~7mg/dl) are associated with increase risk of gout.
  2. Temperature - Solubility of MSU falls rapidly with decreasing temperautre - since non-inflammted synovial fluid is cooler than serum, it means that even a low concentration of MSU could result in crystals.
  3. Nucleation and growth - nucleation rates and subsequant growth rates of MSU crystals are directly proportional to degree of MSU supersaturation.

Question 5

Inflammation and the development of gout

Answer 5

• Innate immune activation of MSU crystals are critical to development of gout.
• Phagocytosis of MSU crystals by neutrophils and other cells contribute to the inflammatory response.
• MSU crystal deposition in synovium results in initation of intese inflammatory response
  
  • ​Synovial linning in inflitrated by neutrophils, monocytes/macrophages, and lymphocytes
• Initiation of acute inflammatory reponse to MSU crystals is affected by properties of the crystals, ex. proteins coating the crystals, cell-mediated mechanisms, assembly and activation of inflammation, and release of multiple cytokines.

Question 6

Tophaceous Gout

Answer 6

• Tophi - depositis of MSU crystals surrounded by granulomatous inflammation. It is a complex chronic inflammatory tissue response to MSU crystals deposition, often results in destructive changes in surrounding connective tissue.
  
  • Both innate and adaptive immunity take part
  • Cyclical process of trophus inflammation, resolution, and tissue remodeling
• Tophi are most commonly found in proteoglycan-rich articular, periarticular, and subcutaneous areas of joints, bones, cartilage, tendons, and skin.
• They are of visible and/or palpable.

Question 7

Chronic Gouty Arthropathy

Answer 7

• When MSU crystal deposits result in the development of bone and cartilage erosions.
  
  • Tophi contribute to bone erosions and joint damage in gout.
  • Activated osteoclasts also play a role in erosion - MSU crystals don’t directly stimuate osteoclast formation, but may activate osteoclastogenesis.
  • Furthermore, MSU crystals cause negative effects on chondrocytes and cartilage viability and function - chondrocytes undergo increasing cell death in response to exposure to MSU crystals. Furthermore, chondrocyte production of cartilage matrix is also impaired by crystals.

Question 8

Clinical Manifestations gout

Answer 8

• Recurrent flares of inflammatory arthritis (gout flare)
• A chronic arthropathy
• Accumulation of urate crystals in the form of tophaceous deposits
• Uric acid nephrolithiasis
• A chronic nephropathy that is most often due to comorbid states

Question 9

Stages of Gout

Answer 9

1. Gout flares
2. Intercritical gout
3. Chronic gouty arthritis and tophaceous gout

Question 10

Gout flares

Answer 10

• Typically monoarticular and intensely inflammatory, occuring in the lower extremities.
• Patients with gout who have sustained chronic hyperuremia may develop tissue deposits of solid urate with associated articular injury.
• Symptoms of gout flare: severe pain, redness, warmth, swelling, and disability (max severity in 12-24 hrs with reduction in days to weeks); onset more often overnight and in early morning; generally involve single joint in the lower extremity (often big toe); inflammation may appear to extend past the involved joint

Question 11

Risk factors for gout flares

Answer 11

• Trauma or surgery
• Fatty foods starvation, or dehydration
• Certain medications - thiazide and loop diuretics, aspirn, and allopurinal
  
  • Starting urate-lowering therapy in the short term can trigger a gout flare. Generally use a antiinflammatory prophylaxis
• Alcohol consumption

Question 12

Gout intercritical period

Answer 12

Once a gout flare has resloved, patient has entered an intercritical period. Most patients will have a second flare within a year, and almost all will have a second flare within 10 years. In untreated patients, this intercritical period tends to become increasing shorter with progressive flares. Furthermore, even within intercritical periods, there may still be continued deposition of tophaceous material resulting in bony erosions that an evolve into gouty arthropathy.

Question 13

Investigation gout

Answer 13

• Synovial fluid analysis
  
  • Presence of MSU crystals in synovial fluid
  • 10,000- 100,000 WBC (esp. neutrophils) in fluid
• Blood tests
  
  • During gout flare, blood tests may show nonspecific changes consistent with inflammation - neutriphilic leukocytosis, elevated ESR, elevated CRP
  • Urate may be high, low, or normal
• Imaging
  
  • Radiography or MRI - subcortical bone cysts can suggest tophi or erosions
  • Ultrasound - Hyperechoic linear density overlying the surface of joint cartilagel tophaceous-appearing deposits in joints or tendons,
  • Dual-energy computed tomography - can identify urate deposits in articular and periarticular locations and can distinguish urate from calcium deposition

Question 14

Gout Treatment

Answer 14

• Oral therapies - recommended for patients with established gout experiencing a flare
  
  • Oral glucocorticoids - good option for those who are not candiates for intraarticular glococorticoid injection and contraindications for NSAIDs. 30-40mg prednisone daily.
  • NSAIDs - naprocen or indomethacine. Particularly appropriate in younger patients (<60) who lack comorbidities
  • Colchicine - comparable to other agents when taken within 24hrs of onset of a flare
• Parenteral glucocorticoids - for patients with established gout who have typical flares in 1-2 joints + low risk of infection. Or, in patients unable to take oral medications
• Urate-lowering treatment (i.e., allopurinal - blocks enzyme xanthine oxidase, which is necessary for conversion of purine to uric acid) - has no direct benefit on treatment of a gout flare. Indicated for those who have topaceous gout.

Question 15

Rheumatoid Arthritis

Answer 15

• Most common inflammatory arthritis that affects ~1% of the population. Due to complex interaction between genes and the environment that results in immune intolerance and synovial inflammation in a characteristic symmetric pattern

Question 16

Pathophysiology of RA

Answer 16

• Environmental factors + Suspectible genes + Epigenetic modification can result in altered poster-transcriptional regulation causing self-protein citrullination (when amino acid arginine is converted into cirtullin) of type II collagen, vitmentin, and fibrigogen, etc.
• These modified proteins are no longer recongized by the immune system as self antigen. These proteins then get picked up ny antigen presenting cells which activate CD₄ T-helper cells. These T-cells stimulate B cells to proliderate and differentiate into plasma cells which produce specific antoantiboides against self-antigens
• At the joint space:
  
  • T-cells secrete cytokines interferon-y and interleukin-17 and recruit macrophages which secrete cytokines TNF-α, interleukin-1, an interleukin-6
  • Over time there is damage to the cartilage,soft-tissue, and bone (eroded through increase production of RANKL) and synvial cells are activated, which release proteases that break down cartilage.
• The most prominent genese involved are class II MHC, most notably HLA-DR.

Question 17

Clinical Presentation RA

Answer 17

• Articular disease:
  
  • Disease onsent tends to be insidous with main symtpoms being pain, stiffness (morning), and swelling of many joints
  • Main joints affected are the MPC, PIPs, interphalangeal joints of the thumb, wrist joints, and MTPs. Later in disease course elbows, shoulbers, ankles, and knees, are also commonly affected
• Extraatricular involvement:
  
  • Aching, stiffness, symptoms of bilateral carpal tunnel syndrome, weight loss, depression, and fatigue

Question 18

Investigations RA

Answer 18

• Synvoial fluid - examination tneds to show an inflammatory effusion with leukoctye count between 1500 and 25,000 cubic mm characterized by predomiance of polymorphonuclear cells. Levels over 25,000 should alter to possibility of co-exisitng infection.
• Hematologic - anemia of chronic disease, thrombosyotsis, and sometimes mild leukocytosis.
• Autoantibodies - 75-80% of patients with RA test positive for RF (rheumatoid factor), ACPA (anti-citrullinated peptide/protein antibodies), or both. Patients who test positive for these antibodies are said to have seropositive RA.
• Acute phase response - Eythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CPR) and amount of elevation tends to corrleate with disease activity.

Question 19

Imaging RA

Answer 19

• Plain film radiography - progressive changes occur in affected joints of patients with active disease, including periatricular osteopenia, joint space narrowing, and bone erosions.
• MRI - More sensitive then X-rays for identifying bone erosions and may detect them earlier in disease course.
• Ultrasonography - Can be used to assess for inflammation within joints that are not tender or swollen on physical exam

Question 20

Clinical Course of RA

Answer 20

• Patterns of progression - most show fluctuation of disease activity over periods lasting weeks to months.
• Disease activity vs. structural damage - disease activity can vary - mainly as a result of therapeutic interventions where both flares and quiescense due to both beneficial effects of medications and withdrawal due to loss of efficacy or side effects. In contrast, structural damage is cumulative and irreversible. Damage is related to both inflmmation, but also with degeneration and repair.
• Remission - achieving remission does not entirely preclude development to further erosive changes. Very rare without the use of DMARDs

Question 21

Diagnostic Criteria RA

Answer 21

Presence of synovitis in at least one joint + absence of alternative diagnois that better explains synovitis + achievement of total score of at least 6:

• Number and site of involved joint:
  
  • 2-10 large joints = 1 point
  • 1-3 small joints - 2 points
  • 4-10 small joints = 3 points
  • >10 joints (including at least one small joint) =5 points
• Serological abnormality:
  
  • Low positive = 2 points
  • High positive = 3 points
• Elevated acute phase response (ESR or CRP) = 1 point
• Symptoms duration at least 6 weeks = 1 point

Question 22

Treatment RA

Answer 22

• Disease modifying antirheumatic disease (DMARDs) - generally start with a DMARD, usually methotrexate in order to suppress synovitis and prevent articular erosions and joint space narrowing. Should initiate as soon as possible.
  
  • Recommended to trial methotrexate alone before adding other DMARDS or trying a biological DMARD
  • Methotrexate serves as the anchor drug for most DMARD combinations.
    
    • Contraindications - women planning to become pregnant, pregnant women, patients with liver disease or excessive alcohol intake, patients with eGFR <30.
• NSAIDs - Should be used at full therapeutic antiinflammatory doses for patients with active RA unless contraindicated. Maximal analgesic and antiinflammatory effect is achieved within 10-14 days. Effective management with DMARDS should allow for discontinuation of daily full dose NSAID use.
• Glucocorticoids - Act to rapidly redue symptoms due to inflammatory synovitis in RA. Recommended to use to help control disease acitivty in initial treatment of severely active RA and in those where a trail of NSAIDs proved ineffective.
• Analgesics - Acetaminophen can also be used for pain relief. Try to avoid use of opioids.

Question 23

Nonarticular Manifestations of Rheumatoid Arthritis

Answer 23

• Systemic symptoms - generalized aching, stiffness, and constitutional symtpoms
• Osteopenia - may be systemic, periatricular, or focal
• Muscle weakness - due to synovial inflammation (reduced motion of joints results in atrophy of muscles serving these joints), myositis, vasculitis involving skeletal muscle vessels can result in acute pain in muscle bundles, while vasculities neuropathy can cause muscle weakness, drug induced
• Abnormal body composition - see increase in body fat and reduce lean body mass, even at normal BMI. This contributes to reduced physical function and cardiometabolic risk
• Skin disease
  
  • Rheumatoid nodules - palpable nodules. Common on pressure points (olecranon), but can form anywhere.
  • Skin ulcers
  • Neutrophilic dermatoses
• Eye involvement
  
  • Episcleritis - eye becomes actuely red and painful, without discharge
  • Sclerities - deep occular pain. Dark red discolouration.
• Lung disease
  
  • RA associated intersititial lung disease
  • Pleural disease - common in RA patients, but often subclinical
  • Rheumatoid lung nodules
• Cardiac Disease
  
  • Coronary artery disease​
  • Pericarditis and myocarditis - uncommon
  • Heart failure
• Vasculities
• Peripheral vascular disease
• Hematoligc abnormalities
  
  • Anemia of chronic disease (normocytic, hypochronic)
  • Felty’s syndrome - seropositve RA + neutropenia - may have associated anemia, thrombocytopenia, enlarged spleen, and leg ulcers.
  • Large granular lymphocyte syndrome
  • Lymphoproliferative disease

Question 24

Juvenile Idopathic Arthritis

Answer 24

• Juvenile Idiopathic Arthritis (JIA) refers to a heterogeneous group of diseases that share the common feature of arthritis of unknown origin occurring before the age of sixteen. JIA is an inflammatory disorder that primarily affects synovial joints.
• To be considered JIA, onset of the disease must take place before the age of sixteen, be characterized by inflammation in at least one joint, and last for at least six weeks.
• Includes: Systemic JIA, Oligoarthritis, Polyarthritis, Psoriatic arthritis, Enthesitis-related arthritis, and Undifferentiated arthritis

Question 25

Systemic JIA

Answer 25

• A autoinflammatory disease (involved innate immune system where there is unprovoked inflammation)
• Characterized by daily fever, rash, and arthritis
• 10-20% of all JIA cases

Question 26

Articular Manifestations of Systemic JIA

Answer 26

• Arthralgias are common in early disease course, ut arthritis is not always prominents
• Joints typically involved when arthritis becomes appearant include the wrists, kness, and ankles.
• May also affect the hands, hips, cervical spine, and temporomandibular joints.

Question 27

Extra-articular Manifestations of Systemic JIA

Answer 27

• Quotidian fever - daily fever spike of greater than or equal to 38.5⁰, with noral or subnormal temperature for teh rest of the 24hr period.
• Rash - round-oval, macular, salmon-pink rash. Slightly raised. Differ in size - smaller ones have slight plaaor surrounding, whereas larger ones have central pallor. Often found in axillaw and around the waist. Most prominents during fever. May be pruritic.
• Macrophage activation syndrome - severe complication of systemic JIA that can occur within first few days to weeks of disease onset. Life threatening emergency - Persistent fever; atypical rash; coagulopathy; decreasing WBCs, RBCS, and plateltes; hepatitis, hyperferritinemia
• Hepatomegaly, splenomegaly, and lymphadenopathy (increase suspicion of malignancy)
• Pericarditis
• Pulmonary manifestations such as pleural effusions
• Pharyngitis

Question 28

Laboratory Findings Systemic JIA

Answer 28

Some laboratory abnormalities are characteristic, but non are specific for the diagnosis.

• Elevated WBCs with granulocytes predominate
• Marked reactive thrombocyotsis (rapid drop in platelets may indicate macrophage activation syndrome)
• Elevated ESR
• Hyperferritinemia
• Minor elevations of AST, ALT
• Hypoalbuminemia
• Increase globulin levels
• Low grade D-dimer positivity
• Anemia
• Antinuclear antibodies (ANA) an rheumatoid factors are almost always negative

Question 29

Diagnosis of systemic JIA

Answer 29

• sJIA is a diagnosis of exclusion.
• Must have quotidian fevers for at least 2 weeks and arthritis for at least 6 weeks to make daignosis.
  
  • Should do a workup to exclude infectious casue of fever.
• Differential - bacterial bone and joint infection, viral and postinfection arthritis, other autoimmune and autoinflammatory disease, malignancy, and malaria.

Question 30

Polyarthritis

Answer 30

• Polyarticular JIA is further divided based on present on absence of rheumatoid factor.
• It is more frequent in females than males
• It has a bimodal distribution of the age at onset - first peak is 2-5years and second is 10-14 years.
• Autoimmune process which is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance.
  *

Question 31

Clinical Presentation Polyarthritis

Answer 31

Presentation is varied, although it tends to fall into patterns based upon the age.

• Children <10 - tends to begins with 1-2 joints affected and tends to stay indolent until infection precipitates dramatic increase in symptoms. Disease then becomes relentlessly preogressive, spreading to involve 5 or more joints within the first 6 months of disease onset. Joint involvement is symmetric with knees, wrists, and ankles more frequently affected.
• Older children - Patients have relatively rapid onset of inflammation in multiple joints, including involvement of many small joints of hands and feet, within 2-3 months of disease onset. Pain in small joints is a common manifestation and may be greater than inflammation and stiffness.

Question 32

Laboratory Finding Polyarthritis

Answer 32

No diagnostic lab findings, but the following may be present:

• Elevated ESR, anemia, and hypergammaglobulinemia
• Many younger children ara ANA positive, however, it is unlrealted to severity
• Positive RF is uncommon in children <10. After age 10, people are divided based on presence or absence of RF. Older children with RF are more likely to be female and have more severe disease.

Question 33

Diagnosis of Polyarthritis

Answer 33

• Diagnosis requries development of arthritis in more than 4 joints during the first 6 months of disease.
• Differential - reactive arthritis, Psoriatic JIA, enthesitis, adult-type rheumatoid arthritis, systemic JIA, SLE, systemic vasculitis, sactcoidosis, IBS, malgiancy, etc.

Question 34

Complications Polyarthritis

Answer 34

• MSK
  
  • Bony erosions and joint destruction
  • osteopenia and osteoporosis
  • TMJ joint involvement
  • mobility issues
• Occular
  
  • Uveitis can occur in polyarticular JIA (more common in oligoarticular). Uveitis is usually isolated to anterior chamber and is symptomatic.
• Visceral
  
  • Internal organ involvement is rare, but can have chronic anemia and malaise.

Question 35

Oligoarthritis

Answer 35

• Understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells.
• Further divided into 2 groups:
  
  • Persistent - children with 1-4 joints affected duing the first 6 months of disease who do not develop arthritis in additional involved joints over time.
  • Extended - children with 1-4 joint affected during the first 6 months of disease who subsequently experience involvement of more than 4 joints.
• Most common subgroup of JIA
• Effects females more than males
• Peak incidence at age 2-3. Less common >5, and rarely >10.

Question 36

Clinical Presentation Oligoarthritis

Answer 36

• Typical presentation is a toddler who is limping without complaint, often in th morning, and appear fine later in the day. In many cases child does not complain of pain, and family seeks medication advice only because knee is swollen.
• Tends to affect large joints - knees, ankles, occassionally wrists and elbow. Rarely the hips.
  
  • Joints tends to be swollen, tender, and warm
• Systemic manifestation - other than uveitis, tend to be absent

Question 37

Laboratory Findings Oligoarthritis

Answer 37

• No diagnostic laboratory tests
• Antinuclear antibodies (ANA) are frequently present and are associated with increased risk of uveitis
• Presence of anemia or an elevated ESR or CRP is associated with increased risk of progression to extended oligoarthritis or polyarticular disease.

Question 38

Diagnosis Oligoarthritis

Answer 38

• Presence of arthritis in ≤4 joints during the first 6 months of disease after ruling out other causes
  
  • Persistent - does not affect more than 4 joints throughout disease course
  • Extended - affects more than 4 joints after first 6 months of disease
• Exclusions
  
  • Psoriasis or family history in first degree relative
  • Arthritis in HLA-B37 positive male beginning after 6th birthday
  • Ankylosing spondylitis
  • Enthesitis related arthritis
  • Presence of IgM rheumatoid factor on at least 2 occasional 3 months apart
  • Presence of sJIA
• Differential - polyarticular JIA, psoriatic JIA, enthesitis-related arthritis, lyme disease, IBD, pigmented villonodual synvoitis, malignancy, other inflammatory and infectious disorders

Question 39

Course and Prognosis of Oligoarthritis

Answer 39

• 25-35% of children with oligoarticular JIA will go on to develop extended oligoarthritis
• Children with persistent typical oligoarticular have a better chance of achieving remission - 69% vs. 37%

Question 40

Management Oligoarthritis

Answer 40

• Initial therapy
  
  • Low disease activity, no poor prognosis risk factors - NSAIDs, intra-articular glucocorticoid injections, or a combination
    
    • Intra-articular injections - provide relief within days. Must exclude infectious cause.
    • NSAIDs - provide relieft within 2 weeks. If patients respond to NSAIDs they are continued until there has been a minimum of 6 months of disease inactivity
  • Moderate to high disease activity - use intra-articular glococorticoid injections with NSAIDs as needed. Methotrexate (DMARDs) is part of initial treatment in patients with high disease activity and risk factors for poor prognosis.
• Escalation of therapy:
  
  • Intra-articular injections shoudl improve arthritis for at least 4 months
  • Trial of DMARDS, usually methrotrexate, is recommended in those with severe disease activity, poor prognosis, and does not respond to joint injections.
  • Methotrexate should also be used in those who develop extended oligoarthritis
  • Patients are moved to biologics (TNF inhibitors) if they continue to have moderate-high disease acitivty after 3 months of a nonbiologic DMARD and have poor prognostic features, or after 6 months of nonbiologic DMARDs, without poor prognostic features.
• Infliximal and adalimumab are commonly used to treat uveitis.

Question 41

Complications of Oligoarticular JIA

Answer 41

• Arthritis of TMJ
• Uveitis - most serious complication of oligoarticular JIA. Occurs in 20-25%. Uveitis is typically isolated to anterior chamber and is completely asymptomatic. Periodic slit-lamp ophthalmic examination is required for screenign and detection
  
  • ANA positive = higher risk
  • Usually treated with topical glucocorticoids, methotrexate, and biologics.
  • 1/3rd of patients with uveitis will have occular complications - cataracts, synechiae, glaucoma, band keratopathy, macular edema
• Leg length discrepancy - there can be significant asymmetric bony overgorwth in bone length and widdth when a single knee is involved.
• Short stature - growth retardation is more liekly in children who requried treatment with DMaRDS then those who were treated with intra-articular glucocorticoid injections alone - likely due to disease severity rather than medication use.