RA, AS, SLE, Sjogren's, SS, Vasculitis (Week 3--Weinreb)

Question 1

Rheumatoid arthritis (RA)

Answer 1

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!)

Question 2

Prevalence of RA

Answer 2

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

Question 3

Key pathophysiologic features of RA

Answer 3

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

Question 4

Other pathology you can see with RA

Answer 4

Hypertrophic villous synovium

Proliferation, inflammatory cell infiltration and lymphocytic clusters

Pannus causing (?) eroded cartilage

Question 5

RA clinical presentation: history

Answer 5

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

Question 6

RA clinical presentation: articular findings on exam

Answer 6

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

Question 7

Radiologic changes seen in RA

Answer 7

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

Question 8

What tests are associated with increased risk of erosive disease in RA?

Answer 8

Elevated CRP

Seropositivity (positive RF or anti-CCP (cyclic citrullinated antibody) titers)

Question 9

RA deformities

Answer 9

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)

Question 10

Tendon rupture/nodules in RA

Answer 10

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)

Question 11

RA clinical presentation: extraarticular findings

Answer 11

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)

Question 12

Rheumatoid scleritis vs. rheumatoid episcleritis

Answer 12

Rheumatoid scleritis: painful inflammation of deeper scleral layers; often associated with rheumatoid vasculitis

Rheumatoid episcleritis: painless or minimally painful inflammation of superficial scleral layers

Question 13

How useful is RF in diagnosing RA?

Answer 13

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

Question 14

Cyclic citrullinated peptide antibody (Anti-CCP)

Answer 14

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?)

Question 15

Diagnosis of RA

Answer 15

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

Question 16

Management of RA

Answer 16

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)

Question 17

Seronegative spondyloarthropathy (SpA)

Answer 17

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

Question 18

Ankylosing Spondylitis (AS) pathophysiology

Answer 18

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

Question 19

Prevalence of AS

Answer 19

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

Question 20

AS clinical presentation: axial

Answer 20

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

Question 21

AS clinical presentation: peripheral joint arthritis

Answer 21

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

Question 22

AS clinical presentation: extraarticular involvement

Answer 22

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

Question 23

Diagnosis of AS

Answer 23

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

Question 24

Reactive Arthritis

Answer 24

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

Question 25

Psoriatic Arthritis (PsA)

Answer 25

**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)

Question 26

Systemic lupus erythematosus (SLE)

Answer 26

**Systemic** autoimmune disease affecting multiple organ systems **Pathologic antibody** production Susceptibility genes and environmental factors (maybe UV light, poorly understood)

Question 27

Key pathophysiologic mechanisms in SLE

Answer 27

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)

Question 28

Different types of pathogenic antibodies in SLE

Answer 28

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

Question 29

Key inflammatory cytokine abnormality in SLE

Answer 29

Interferon-alpha is increased

Question 30

SLE epidemiology

Answer 30

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...)

Question 31

Clinical presentation of SLE

Answer 31

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

Question 32

1997 ACR criteria for SLE

Answer 32

Sensitive and specific clinical lab findings to **define** patients as having SLE (for reserach) and to **diagnose** SLE **Malar rash** ("**butterfly**" spares nasolabial folds), **discoid rash** (scaly erythematous rash w/**follicular** **plugs**, heals w/scaring), **photosensitivity**, **oral** **ulcers**, **arthritis**, **seorsitis**, **renal** disorder, **neurologic** disorder, **hematologic** disorder, **immunologic** disorder, antinuclear antibodies (**ANA**) If 4/11 of these are present, 98% specificity and 97% sensitivity for SLE! (good for research purposes)

Question 33

Subacute cutaneous lupus (SCLE)

Answer 33

Associated with **anti-SSA** (Rho) antibodies Papulosquamous or annular skin disease

Question 34

Lupus band test

Answer 34

Immunofluorescent staining for **IgG** and complement at the **dermoepidermal** **junction** Can involve affected and unaffected skin Not specific test

Question 35

Clinical pearl for SLE!

Answer 35

Painless oral ulcer May correlate with disease activity Check for **nasal** mucosal ulcers!

Question 36

Nephritis in SLE

Answer 36

Deposition/formation of **immune complexes** (IC) and **complement** binding in the **kidney** --\> inflammation and lupus nephritis Location of ICs associated with different types of nephritis: 1,2 (subepithelial), 3 (subendothelial), 4 (mesangial) Find **anti-dsDNA** antibodies

Question 37

Classification of SLE nephritis

Answer 37

Class I: minimal mesangial Class II: mesangial proliferative Class III: focal proliferative glomerulonephritis (GN) Class IV: diffuse proliferative GN Class V: membranous nephritis Class VI: advanced sclerotic nephritis Note: glomerulonephritis is inflammation involving glomerulus and resulting in damage and renal dysfunction

Question 38

Clinical presentation of SLE nephritis

Answer 38

Varying degrees of **renal** **failure**, **hematuria**, **pyuria**, **proteinuria**; increased **morbidity and mortality** Active renal involvement associated with **increased anti-dsDNA antibodies** and **low** **complement** **C3/C4** (bc consumed by ICs! However, not always because you're producing more C3/C4 also)

Question 39

Neurospychiatric SLE

Answer 39

Many neuropsychiatric manifestations of SLE (NPSLE) Many mechanisms: for example, **agonistic** antibody can **activate NMDA receptor** on neurons

Question 40

ANA test for SLE

Answer 40

ANA test to detect antinuclear antibodies **Titer** and **pattern** **of staining** is reported Also, level of antibodies to **specific** nuclear antigens are determined to provide increased sensitivity and specificity for SLE and other conditions **99% sensitivity**: less than 1% of people **with lupus** will **have positive ANA** But low specificity

Question 41

What rheumatic diseases is ANA useful for?

Answer 41

SLE (99% sensitivity) Drug-induced lupus (95-100%)

Question 42

ANA is not very specific, so what other non-rheumatic conditions is it elevated in?

Answer 42

Liver disease, pulmonary disease, chronic infections, hematologic conditions, malignancies, other

Question 43

Patterns of ANA reactivity

Answer 43

Peripheral Speckled Homogeneous Nucleolar

Question 44

Antinuclear antibody associations

Answer 44

**dsDNA**: high sensitivity and **specificity**, helpful **diagnostically** for SLE, correlates with disease **activity** (esp **nephritis**) **Histones**: **drug**-**induced** lupus **Ro(SS-A)** and **La(SS-B)**: **neonatal** **lupus** (subacute cutaneous lupus for Ro(SS-A) **Sm**: high **specificity** for SLE (low sensitivity), helpful **diagnostically** but no SLE associations (**ANA**: high **sensitivity** (good for **screening**), low specificity)

Question 45

Activation of thrombosis by antiphospholipid (aPL) antibodies in SLE

Answer 45

Increased prevalence of **aPL antibodies** in SLE patients (20-50%) aPL antibody binding results in release of tissue factor (TF) and other inflammatory mediators, promoting a **prothrombotic** state (**activating** antibody)

Question 46

What can antiphospholipid (aPL) antibodies cause?

Answer 46

Central retinal artery occlusion Cerebral infarct Recurrent miscarriage Deep vein thrombosis Digital ischemia Livedo reticularis

Question 47

Clinical use of ANA and antinuclear antibody subsets in SLE

Answer 47

+ANA only helpful if SLE clinically suspected Not a useful screening test ANA titer doesn't correlate with SLE disease activity ANA sensitivity for SLE (99%) so **negative test means SLE very unlikely** **anti-dsDNA** and **anti-Sm** very specific for SLE

Question 48

Drug-induced lupus

Answer 48

Strong association with **hydralazine, isoniazid, minocycline, anti-TNFalpha** More **abrupt** **onset** and **less severe manifestations** of SLE (fever, rash, arthralgias/arthritis, serositis) Positive ANA and anti-histone antinuclear antibodies Symptoms resolve after stopping medication Treat just with NSAIDs, steroids for symptoms Mechanism of disease unclear

Question 49

Management of SLE

Answer 49

Treat early and aggressively to **prevent end-organ damage** Prevent flares (hydroxychloroquine) NSAIDs, steroids, antimalarials, immunosuppressives

Question 50

Sjogren's Syndrome

Answer 50

**Autoimmune** **lymphocytic** (primarily CD4+ and B-cell) infiltration of **exocrine** **glands** resulting in glandular damage and subsequent dysfunction/loss of funtion Extraglandular involvement: arthritis, lymphocytic infiltration of various organs, lymphoma

Question 51

Can antibodies be used to diagnose Sjogren's syndrome?

Answer 51

Only if clinical findings suggestive, because antibodies are not sensitive or specific ANA, anti-SSA, anti-SSB, RF

Question 52

What is the gold standard for diagnosis of Sjogren's syndrome?

Answer 52

Biopsy shows **lymphocytic infiltration** and **salivary gland destruction** Do minor salivary gland biopsy from inner lip

Question 53

Clinical features of Sjogren's syndrome

Answer 53

**Dry mouth** (xerostomia --\> leads to dental **cavities** (carries) **Dry eyes** (xeroophthalmia) **Dry tracheobronchial mucosa** (xerotrachea) **Dry skin** (xerosis) and **vaginal mucosa** **Major salivary gland enlargement** **Pancreatic** **exocrine** **dysfunction** and **hypochlorhydria** Extraglandular: **constitutional** (fatigue, low grade fever, myalgias), **arthritis/arthralgias**

Question 54

Sicca (dry eyes and mouth together) related findings in Sjogren's syndrome

Answer 54

Xerostomia Dental decay Parotid enlargement Keratoconjunctiva sicca: rose bengal staining showing corneal abrasions (abrasions happen because of dryness) (STEP 1 says: dry eyes, dry mouth, nasal and vaginal dryness, chronic bronchitis, reflux esophagitis, NO arthritis)

Question 55

Neonatal lupus

Answer 55

Subacute cutaneous SLE (SCLE) Anti-SSA (Rho) antibodies These antibodies can react and lead to a range of cardiac electrical abnormalities (cytotoxic effect of anti-SSA)

Question 56

Systemic sclerosis (Scleroderma)

Answer 56

Complex **systemic** disease characterized by excessive **extracellular matrix deposition** that is caused by underlying **autoimmunity**, **vasculopathy** and tissue **fibrosis** Interaction between genes and environment More prevalent in women, increased susceptibility of AAs Can be limited or diffuse cutaneous sclerosis

Question 57

Proposed environmental triggers for systemic sclerosis

Answer 57

Infection Drugs Chemical exposures (vinyl chloride, silica) Maternal lymphocyte exposure in fetus or felat lymphocyte exposure in mother causing graft vs. host reaction that progresses to SS However, not clear

Question 58

Early and late phases of SS

Answer 58

**Early**: (1) **immunologic** and **inflammatory** (T and B cell activation, monocytes, autoantibodies, cytokines, growth factors); (2) **vascular** (endothelial cell damage and apoptosis, increased vascular reactivity, vascular smooth muscle cell and pericyte proliferation leading to increased vessel wall thickness, ROS, hypoxemia, vascular loss) **Late**: **fibrotic** (fibroblast activation and differentiation to myofibroblasts (contractile cells), collagen overproduction, increased deposition, remodeling in blood vessel walls and other tissues)

Question 59

Limited sclerosis vs. diffuse sclerosis

Answer 59

Clinical subgroups defined by **extent** of skin thickening and tightening; limited and diffuse have overlapping systemic features **Limited sclerosis**: 60% of cases; only involves **distal** **extremities** (up to elbows and/or knees), face and neck but **NOT the trunk**; longstanding Raynaud's that may preceed onset; no tendon friction rubs; isolated **pulmonary** **HTN**, **anticentromere** antibodies (60-90%); more **gradual** and less extensive skin involvement **Diffuse sclerosis**: 30% of cases; involves **entire** **extremities**, face, neck and **trunk**; Raynaud's associated with skin changes or later; tendon friction rubs; more widespread and extensive internal organ involvement (**renal disease, ILD (fibrosis), severe and diffuse GI disease, cardiac**); **anti-Scl-70** antibodies (20-30%); more **rapid** and extensive skin involvement

Question 60

Other types of sclerosis

Answer 60

Don't need to know these Scleroderma sine scleroderma: systemic disease without skin involvement, rare Overlap syndromes: association of findings with other autoimmune diseases

Question 61

Systemic sclerosis: cutaneous

Answer 61

On skin biopsy, see **denser collagen**, **loss of skin appendages** (hair follicles), focus of **inflammation** Early finding is **edema** of hands (immune/inflammatory) **Skin thickening** on hands and neck **Sclerodactyly**: tightened skin (shiny, loss of creases) and tethered of tendons resulting in fixed flexion **contractures**; can be severe causing significant disability (fibrotic) Tightening of skin over **face** and **mouth** resulting in diminished oral aperture (fibrotic) **Furrowing** of skin around mouth secondary to skin tightening (fibrotic) Cutaneous **calcinosis** and subcutaneous calcinosis (immune or vascular?) Facial and inner lip **telengictasia** (vascular) **Capillary loop dilation** and capillary dropout/loss **Raynaud**'s phenomenon (vascular) Digital tip **ulcerations** secondary to ischemia (vascular), cause digital **pits/scars** after they heal Digital **gangrene** secondary to severe vasculopathy (vessel constriction and obliteration) Digital phalangeal **tuft resorption (bone resorption)** (vascular)

Question 62

Systemic sclerosis: vasculopathy

Answer 62

**Vasoconstriction**, impaired relaxation Over time, get vascular wall **remodeling** (proliferation of smooth muscle cells, then fibrosis) Vascular obliteration and tissue **hypoxia** (which contributes to fibrosis)

Question 63

Raynaud's Phenomenon

Answer 63

Characteristic sequence of **white**, **blue**, **red** in fingers (and other extremities) First in response to cold, get constriction of arterioles and white blanching (**constriction**) --\> then because of decreased blood flow to fingers and decreased outflow so get blue (**congestion**) --\> then get increased inflow again and become red (**hyperemia**) Note: Raynaud's symptoms can occur in the absence of any underlying disease

Question 64

Systemic sclerosis: fibrosis

Answer 64

**Collagen** production, deposition; matrix **contracture**, remodeling Tissue **fibrosis**; organ dysfunction

Question 65

Systemic sclerosis: pulmonary disease

Answer 65

Primary cause of **morbidity** and **mortality** in systemic sclerosis Spectrum of pulmonary infolvement: 1) isolated pulmonary arterial hypertension (PAH) 2) Interstitial lung disease/pulmonary fibrosis 3) Combined presentation

Question 66

Systemic scleorsis: pulmonary disease--PAH

Answer 66

Isolated pulmonary hypertension (PAH): More often in **limited** **sclerosis** Secondary to vasoconstriction/impaired vascular relaxation Characteristic history of **dyspnea** on exertion; **O2 desaturation with exertion** Can result in right sided heart failure (**cor pulmonale**) Treatment with arterial **vasodilators** can improve symptoms and survival

Question 67

Systemic sclerosis: pulmonary disease--ILD

Answer 67

Interstitial lung disease/pulmonary fibrosis: More frequent and extensive in **systemic sclerosis** Secondary to **fibrosis** Presents with **chronic dry cough** and worsening dyspnea; **hypoxemia** Both lung **inflammation** (alveolitis) and **fibrosis** result in destruction and irreversible loss of lung tissue Usually progressive, resulting in increased mortality **No treatments** to reverse process; cytotoxic therapy may slow/prevent progression **Honeycombing** seen on CT (?), characteristic of fibrosis

Question 68

Systemic sclerosis: cardiac

Answer 68

Symptomatic cardiac involvement also associated with increased mortality Most common type of involvement is **right heart failure secondary to PAH** Less commonly, primary involvement due to **vasculopathy** (ischemia and arrhythmias) and/or **fibrosis** (**heart failure** and **arrhythmias**) can occur

Question 69

Systemic sclerosis: renal

Answer 69

Scleroderma renal crisis: More commonly associated with **diffuse sclerosis** Usually occurs within first five years of disease Characterized by **acute** **renal failure** and severe **hypertension** Used to be major cause of mortality until **ACE inhibitors** found to be effective See **pruning** and **loss of vasculature** on angiogram See onion skin appearance of glomerulus on renal biopsy from patient with scleroderma renal crisis

Question 70

Systemic sclerosis: GI

Answer 70

**Diminished oral aperture** may contribute to poor oral intake **Early esophageal dysmotility** (vascular): poor peristalsis and impaired lower sphincter function can result in sensation of food getting stuck in chest (dysphagia) and GERD; see dilated distal esophagus on imaging **Late esophageal dysmotility** (fibrotic): poor peristalsis results in dilated esophagus with associated dyphagia; chronic GERD can result in distal esophageal stricture and obstruction **GI bleeding** from colonic **telengiectasia** and gastric telengiectasia (severe GI bleeding, also watermelon stomach (vascular)) **Intestinal dilatation** (vascular and fibrotic): slow transit, constipation and ileus (functional obstruction)

Question 71

Diagnosis of systemic sclerosis

Answer 71

Presence of characteristic **cutaneous findings** in conjunction with other findings of **systemic** involvement Early in disease, systemic features subclinical and need special testing to identify Skin findings of other fibrosing conditions may seem similar to systemic sclerosis; but systemic nature of scleroderma is distinguishing

Question 72

Treatment of systemic sclerosis

Answer 72

Treatment for symptoms, **directed at involved systems** In general, treatment of complications due to vasculopathy has been more susccessful than treatment of those due to fibrosis (no great therapy for fibrotic manifestations)

Question 73

Vasculitis

Answer 73

**Inflammation**/**autoimmunity** targeted to the wall of a **blood vessel** that results in injury to the vessel wall with subsequent **occlusion** of the vessel due to thrombosis and/or loss of vessel integrity Usually systemic and clinical manifestations primarily due to **ischemia** from vascular occlusion or loss of vascular wall integrity Main mechanisms include **immune complex deposition**, **ADCC**, **direct immune cell cytotoxicity** Clinical manifestations reflective of size and distribution of **affected vasculature**

Question 74

Classification of vasculitis

Answer 74

**Large** vessel: aorta and branches **Medium** vessel: small and medium sized arteries **Small** vessel: vessels smaller than arteries such as capillaries and venules Note: small vessel vasculitis can either be (1) **immune complexes** in vessels, or (2) **paucity** of vascular Ig (often with **ANCA**)

Question 75

General clinical features of small vessel vasculitis

Answer 75

**Non-blanching palpable purpuric** lesions due to RBC **extravasation** from damaged vessels in small vessel vasculitis Immune cell infiltration of small vessel supplying a nerve (vasa nervorum) results in **neuropathy** RBC **cast** due to vasculitis involving glomeruli (**glomerulonephritis**)

Question 76

General clinical features of medium vessel vasculitis

Answer 76

Immune cell infiltration with destruction of medium vessel wall and obliteration of lumen **Skin ulcer** secondary to occlusion of medium sized arteriole Celiac artery anneurysmal dilatations with areas of **stenosis** of medium sized mesenteric arteries resulting in **abdominal pain after meals**, **GI bleeding** and possible **perforation** with severe ischemia

Question 77

General clinical features of large vessel vasculitis

Answer 77

**Giant cell arteritis**: disrupted internal elastic membrane, thickened temporal artery, stenoses of subclavian and axillary arteries that can cause **ischemic pain with exertion** in the **arm** (limb claudication) **Takayasu's arteritis**: large vessel stenoses (limb claudication), thickening and narrowing of the carotid arteries

Question 78

Antineutrophil cytoplasmic antibodies (ANCA)

Answer 78

Antibodies directed against **cytoplasmic** antigens in **neutrophils** Two types of reactivity: **cytoplasmic** (C) and **perinuclear** (P) **C-ANCA**: antibodies against serine proteinase-3 (PR3) **P-ANCA**: antibodies against myeloperoxidase (MPO), lactoferrin, and others Antibodies may play a pathogenic role by **activating neutrophils** Play a role in **non-immune complex** types of **small vessel vasculitis**

Question 79

Are anti-dsDNA and anti-Sm antibodies specific for SLE?

Answer 79

YES! (but ANA is NOT specific for SLE, it is sensitive)