RA, AS, SLE, Sjogren's, SS, Vasculitis (Week 3--Weinreb) Flashcards
Rheumatoid arthritis (RA)
Chronic systemic autoimmune disease defined by presence of symmetric inflammatory polyarthritis that primarily affects small joints of the hands (PIP, MCP) and can have variable extraarticular involvement
Can be associated with significant morbidity and disability due to irreversible joint damage and increased mortality, but early treatment can result in significantly improved outcomes (early recognition is key!)
Prevalence of RA
Prevalance from 0.1-1.1%
Higher prevalence in populations of European descent and lower prevalence in populations of Asian descent
Native American populations have prevalence of 5-7% (so maybe caused by “New World” infection)
Associated with smoking especially in HLA-BRD1 allele
>20 candidate genes for susceptibility
Women have 2-3 times increased risk
Key pathophysiologic features of RA
Articular and systemic inflammation:
1) Pannus formation: synovial swelling, inflammation; cartilage loss and bone erosions; joint damage and loss of function
2) Osteoclast activation: bone erosions; periarticular osteopenia and joint damage
3) Extraarticular manifestations
Overall: swelling, bone erosions, joint damage
Other pathology you can see with RA
Hypertrophic villous synovium
Proliferation, inflammatory cell infiltration and lymphocytic clusters
Pannus causing (?) eroded cartilage
RA clinical presentation: history
Insidious with increasing symptoms over weeks to months that progress to characteristic chronic symmetrical polyarthritis
Fatigue, low grade fever, weakness, weight loss
Pain, swelling, stiffness (morning or after prolonged inactivity, >30 min to hours) of hands and to varying degrees of other small, intermediate, and large joints; tenosynovitis
Loss of function acutely secondary to pain and stiffness from active inflammation and chronically secondary to joint deformities associated with joint damage from progression of marginal bony erosions and joint space narrowing
Spontaneous remissions rare
RA clinical presentation: articular findings on exam
Symmetric synovitis (inflammatory arthritis) of PIP and MCP joints, not DIPs
Deformities: finger joint tendon weakening resulting in subluxations (swan-neck, boutonniere, ulnar deviation); severe deformity due to progressive bony erosions (arthritis mutilans); muscle atrophy from disuse
Rheumatoid nodules: granulomatous nodules at sites of pressure or friction (subcutaneous, tendons, bursae, less commonly in soft tissues); usually benign but may interfere with joint function and associated with more disease
Finger extensor tendon rupture: loss of extension due to tendon rupture from mechanical forces related to joint deformities, nodules, and/or tenosynovitis
Spine: cervical spine only, transverse ligament weakening and subluxation of C1 on C2 and risk of spinal cord impingement/compression by odontoid (dens) leading to extremity weakness or sensation loss; C1/2 joint synovitis can result in spinal cord impingement
Radiologic changes seen in RA
Marginal bony erosions associated with increased risk of deformities and further cartilage and bony destruction leading to loss of joint function!
Symmetrical joint space narrowing
What tests are associated with increased risk of erosive disease in RA?
Elevated CRP
Seropositivity (positive RF or anti-CCP (cyclic citrullinated antibody) titers)
RA deformities
Swan neck (extension of PIP, flexion of DIP)
Boutonniere (flexion of PIP, extension of DIP)
Ulnar deviation of fingers
Arthritis mutilans (feel like bag of bone)
Tendon rupture/nodules in RA
Swelling of tendon sheaths due to synovitis of lining synovium
Rupture of extensor tendons results in inability to extend fingers
Rheumatoid nodules on extensor tendons (nodules are monocytes, vascular inflammation, mostly not problem other than cosmetic, mostly occur on extensor surfaces; associated with more erosive RA)
RA clinical presentation: extraarticular findings
Muscle weakness: disuse atrophy, drug related, neuropathy, inflammatory (rare)
Bone: osteopenia secondary to inflammation, decreased activity, steroids
Eye: dry eyes common; “red eye RA”; episcleritis due to superficial scleral inflammation; scleritis due to deeper scleral inflammation; scleral thinning and/or perforation; keratitis or corneal inflammation (“corneal melt”) that can result in corneal destruction and loss of vision–medical emergency; infections secondary to treatment
Pulmonary: mild inflammatory (interstitial) lung disease, small airway obstruction; nodules; Caplan’s syndrome (nodulosis secondary to exposure to coal dust, seen in West Virginia, not much in CA…)
Cardiac: rarely pericarditis, myocarditis; increased risk of CAD
Hematologic: Felty’s syndrome characterized by splenomegaly and neutropenia; severe neutropenia (<1,000/mm3) associated with increased risk of infection
Malignancy: increased risk of B-cell lymphoma; less commonly large granular lymphocyte syndrome (T-cell/NK cell lymphoproliferative syndrome)
Rheumatoid scleritis vs. rheumatoid episcleritis
Rheumatoid scleritis: painful inflammation of deeper scleral layers; often associated with rheumatoid vasculitis
Rheumatoid episcleritis: painless or minimally painful inflammation of superficial scleral layers
How useful is RF in diagnosing RA?
Helpful when history and exam suggestive of RA
Sensitivity is 80% and specificity is 85%
Due to decreased specificity, should not be used as screening test for RA
RF positivity associated with increased risk of nodules and erosive disease
Changes in RF titer not associated with changes in disease activity
Cyclic citrullinated peptide antibody (Anti-CCP)
Antibody that recognizes peptide of protein fillagrin containing citrullinated arginine residue; associated with heavy tobacco use
Sensitivity 48% (less than RF); specificity 96% (more than RF)
Associated with increased risk of developing bony erosions
May be positive 3-4 years prior to onset of RA (role in early diagnosis?)
Diagnosis of RA
History and physical find symmetrical polyarthritis
Positive RF and/or anti-CCP support diagnosis but don’t rule in or out RA on their own
Symmetrical joint space narrowing, marginal erosions help assess severity but may be absent in early stage or not develop
MRI or ultrasound help detect subclinical synovitis or erosive changes not seen on plain X-rays
Management of RA
Determine severity of involvement
Control pain from inflammation and improve function
Prevent development or progression of bony erosions/joint damage
Treat extraarticular manifestations
Medication: NSAIDs, steroids, DMARDs (disease modifying antirheumatic drugs), biologics (antibodies or receptor antagonists targeting specific RA pathways–inflammation, erosions (anti-IL1, anti-TNF, anti-I16, anti-CD20, costim inhibition)
Seronegative spondyloarthropathy (SpA)
Group of inflammatory arthritic diseases that variably share similar pattern of asymmetric oligoarticular (2-4 joints) peripheral arthritis
Variably present with sacroiliitis, spondylitis, enthesitis, extraskeletal involvement (eye, bowel, lungs, heart)
Negative for RF (seronegative!!)
Axial involvement (spine, SI joints) typically associated with presence of Class I HLA-B27 allele
Ankylosing Spondylitis (AS) pathophysiology
Axial spondylarthritis: bilateral symmetric sacroiliitis (SI joint inflammation that progresses to erosion and widening then fusion (ankylosis))
Spondylitis to a variable extent: enthesitis of spinal ligaments and capsular attachments resulting in erosions (vertebral squaring, shiny corners) then ligament calcification (syndesmophytes–thin whispy calcification from one corner/margin to the other); progressive ligamentous calcification results in vertebral fusion (“bamboo” spine) from lumbar to cervical spine regions
Prevalence of AS
90% of disease susceptibility due to genetics with 90% contributed by HLA-B27 (+8 additional susceptibility genetic loci/genes); environmental factors unknown
More common in men, peak age of onset between 20 and 30
Ethnic differences because of population differences in HLA-B27 allele
AS clinical presentation: axial
Sacroiliitis: inflammatory back pain, variable morning pain and back stiffness (>30 min) improves with exercise and worse with rest, buttocks pain, nighttime pain while sleeping
Spondylitis: progressive spine fusion leads to loss of lumbar lordosis, decreased cervical spine ROM and cervical kyphosis, decreased chest expansion due to enthesitis of costovertebral joints; spine fusion results in extremely limited range of spinal motion and disability and stiff chalk-like spine increases risk of pseudofracture through fused segments
Costosternal/manubriosternal joints can get enthesitis and chest pain
AS clinical presentation: peripheral joint arthritis
15% of AS patients
Shoulder and hip arthritis are most common
Progressive hip joint arthritis is bad bc can lead to hip joint fusion and fixed flexion contractures; with fused spine, hip joint contractures result in forward bending which exacerbates disability
Enthesitis at elbow condyles, pelvis, spinous processes, patella, tibial tubercle, Achilles tendon, plantar fascia
AS clinical presentation: extraarticular involvement
Opthalmologic: acute anterior uveitis; unilateral and characterized by redness, pain, diminished visual acuity, photophobia; associated with HLA-B27
Cardiac: aortic inflammation can lead to aortic dilatation and aortic valve incompetence
Pulmonary: rarely interstitial lung disease (upper lobes)
GI: “cryptic” or asymptomatic colitis of ilium and/or colon
Neurologic: secondary to nerve impingement from spinal disease; cord impingement secondary pseudofractures and formation of unstable pseudoarthrosis
Diagnosis of AS
History of inflammatory back pain, limited spinal ROM, enthesitis, radiologic findings
>95% of patients with AS are HLA-B27 positive but only 5% of carriers of HLA-B27 develop AS, so not a good screening test
Positive HLA-B27 with strong history, exam, X-ray supports AS diagnosis
Negative HLA-B27 with weak history, exam, X-ray rules out AS diagnosis
But negative result does NOT rule out AS if clinical findings are strong
Reactive Arthritis
Oligoarticular arthritis develops 1-4 weeks after infection (may be subclinical but usually is GI, GU (STDs like chlamydia), URI)
Peripheral arthritis: acute, asymmetric, oligoarticular; erosive in 10-15%, chronic in 15-50%
Axial skeletal involvement: asymmetric sacroiliitis in 20% and asymmetric spondylitis
Tenosynovitis and enthesitis: digital tendon sheath and enthesial inflammation can result in dactylitis which appears as sausage-like swelling of the digit
Extraacticular: conjunctivitis, urethritis, oral ulcers, genital ulcers, circinate balanitis (rash on glans of penis), hyperkeratotic vesicular psoriasis-like rash on palms and soles called keratoderma blennorrhagica
HLA-B27: (less impt than in AS); 60-80% positive, associated with more severe arthritis, sacroiliitis and spondylitis, extraarticular manifestations, more chronic disease course
Psoriatic Arthritis (PsA)
Inflammatory arthritis of variable joint involvement associated with psoriasis (prevalence: 7-40% with psoriasis) but rarely occurs without psoriasis
Variable presentation: arthralgias, true synovitis, enthesitis, dactylitis (sausage fingers)
Variable patterns of joint involvement: distal arthritis (DIPs), asymmetric oligoarthritis, symmetric polyarthritis (similar to RA but with DIP involvement), arthritis mutilans, spondylarthritis
Variable characteristic peripheral radiologic findings: normal, enthesitis, erosive arthritis, “pencil in cup”, joint fusion (ankylosis)
Variable axial radiologic findings: normal, asymmetric sacroiliitis, asymmetric spondylitis (axial involvement more likely in HLA-B27+ individuals)
Systemic lupus erythematosus (SLE)
Systemic autoimmune disease affecting multiple organ systems
Pathologic antibody production
Susceptibility genes and environmental factors (maybe UV light, poorly understood)
Key pathophysiologic mechanisms in SLE
1) Impaired apoptosis leading to secondary necrosis, intracellular antigen exposure, innate immune system inflammation
2) Loss of tolerance and immune system dysregulation –> increased production of pathogenic autoantibodies
3) Increased formation and impaired clearance of immune complexes
4) Inflammation and tissue damage from immune complex complement activation, other autoantibodies and the effects of altered cytokine production (ex: increased production of INF-alpha)
Different types of pathogenic antibodies in SLE
1) Depleting or neutralizing antibodies: directed against plasma protein or cells that results in loss of function; can form immune complexes
2) Cytotoxic (antibody dependent cellular cytotoxicity (ADCC)): against self-antigens on cells leading to cell death
3) Agonistic/Activating antibodies: specifically stimulate a cell receptor or plasma protein leading to activation of cell/protein
4) Inhibitory antibodies: bind cell receptor and inhibit a cellular function
Key inflammatory cytokine abnormality in SLE
Interferon-alpha is increased
SLE epidemiology
51/100,000 prevalence or 2-8/100,000 per year
Female 9x more likely to get it than male, and might be due to sex hormones
Disease onset between 16-55 for the most part
Prevalence and severity of disease higher in AA and hispanics (however, prob due to socioeconomic status, not pathophysiology…)
Clinical presentation of SLE
Systemic autoimmune inflammation involving multiple organ systems
Varying symptoms, and can be mild (“rodeo drive lupus”) or life-threatening
Chronic medical problems secondary to end-organ damage
“I’M DAMN SHARP”
Immunoglobulins
Malar rash
Discoid rash
ANA
Mucositis (oral ulcers)
Neurologic disorders
Serositis (pleuritis, pericarditis)
Hematologic disorders
Arthritis
Renal disorders
Photosensitivity
