Postlethwaite

Question 1

List the 4 main seronegative spondyloarthropathies.

Answer 1

• Ankylosing spondylitis (AS)
• Enteropathic arthritis
• Reactive arthritis (Reiter’s syndrome)
• Psoriatic arthritis

Question 2

What are the common features of the spondyloarthropathies?

Answer 2

• Rheumatoid factor (-)
• HLA-B27 association
• Axial skeletal involvement: sacroiliitis, spondylitis
• Lg. joint asymmetric oligoarthritis (1-4 joints) -> lower extremities (mainly)
• Family history
• Absence of subcutaneous nodules and other extra-articular manifestations of RA
• Enthesitis (inflammation where tendons connect to bone) and dactylitis (hand inflammation)

Question 3

What is this?

Answer 3

Enthesitis: inflammation at the sites where tendons and ligaments attach to bone

Question 4

What is this?

Answer 4

Dactylitis: sausage-like digits (fingers or toes)

Question 5

What is HLA-B27?

Answer 5

• MHC class I molecule (think IC viruses/bacteria; present on all nucleated cells) that binds antigenic peptides and presents them to CD8+ T-cells
• Sensitive for AS, but NOT specific
  1. 90% of AS pts have it vs. 8% of general population (i.e., fairly common in the gen pop too)
  2. 2-6% of B27+ people have AS vs. 0.2-1.4% of the gen population
• Confers INC disease susceptibility and severity
  1. Pts. w/psoriasis or IBD who have it are more likely to devo axial (spinal) arthropathy
• 75% of pts with reactive arthritis have it

Question 6

Who does AS affect? Pathology?

Answer 6

• Who: adolescents to age 35 and male:female is 3:1
  1. Back pain that progresses to stiffness of the spine
• Pathology: inflammatory cell infilitrate, synovial inflam similar to RA, TNF-alpha excess
• Cause: unknown (may be some bacterial antigens involved, but unclear)

Question 7

What are the clinical features of AS?

Answer 7

• Sacroiliitis and spondylitis: insidious onset, chronic low back pain, back stiffness, symptoms gradually ascend up spine -> worse in AM & improve w/exercise
  1. Eventually, can’t move their heads
• Peripheral joint involvement (1/3 of pts): hips, ankles, knees, shoulders -> oligoarticular, often asymmetric
  1. Dactylitis: hand inflammation may occur
  2. Enthesitis: esp. achilles or plantar tendon insertions can cause heel pain

Question 8

What is going on here?

Answer 8

Inflammation of the spiny joints ->

bony fusion of the spine ->

DEC spine range of motion

Question 9

What are some of the extra-articular consequences of AS?

Answer 9

• Eye: anterior uveitis (25-30%) -> can precede, or occur intermittently during the disease
• Pulmonary: apical lung fibrosis, thoracic cage restriction (ankylosis of costovertebral joints of ribs)
• Cardiac: aneurysmal dilatation of ascending aorta (via inflam) with aortic regurgitation (3.5-10%), heart block (2.7-8.5%), pericarditis, ↑MI
  1. Aortic regurg/heart block 2x more common if peripheral joint involvement
• Always look for these things in pts with AS

Question 10

What are 6 of the important exam findings with AS?

Answer 10

• Sacroiliac tenderness
• Limited spine ROM in all directions
• Loss of lumbar lordosis + thoracic, cervical kyphosis
• Abnormal Schober’s test (<3cm): pt stands and bends forward at the waist
• Reduced chest expansion (<2.5cm): 4th ICS
• INC occiput to wall distance: head leaning forward
• NOTE: may devo flexion contractions in their hips due to their modified posture (head facing downward, but they still have to see in front of them)

Question 11

What is the difference b/t these two images?

Answer 11

• Left: normal sacroiliac joint
• Right: AS sacroiliac joint -> sacroiliitis (all fused together -> usually bilateral)

Question 12

What is a syndesmophyte?

Answer 12

• Bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints, leading to fusion of vertebrae
• Pathologically similar to osteophytes

Question 13

What do you see here?

Answer 13

• Ankylosing spondylitis in the image on the left (compared to normal on the right)
• “Squaring” of the vertebral bodies
• Syndesmophyte formation

Question 14

What are the x-ray findings with AS?

Answer 14

• Generalized spiny osteopenia (DEC bone mass)
• Eventual bony alkylosis
• Vertebral fractures can occur even after minimal trauma, due to spine rigidity and osteopenia
  1. If this happens, you are in trouble; if you get a high cervical lesion, you may die -> NO breathing
• Atlantoaxial joint and atlantooccipital subluxation, upward subluxation of axis
  1. Subluxation: partial dislocation; slight vertebral misalignment

Question 15

What are the general tx recommendations for AS (flow chart)?

Answer 15

Question 16

What is reactive arthritis?

Answer 16

• Aka, reiter’s syndrome: inflammatory arthritis after infectious process
• Classic triad: arthritis, urethritis, conjunctivitis -> more often, incomplete features
• Uncommon: 3-5 per 100,000; M:F 5:1
• 75% of pts HLA-B27 (+)
• More common in HIV/AIDS: more severe, resistant to therapy -> if either of these things are the case, think about HIV (he said they test everyone)

Question 17

What organisms are associatec with reactive arthritis?

Answer 17

• Salmonella
• Shigella
• C. diff
• See attached
• NOTE: can also get this from sexual contact (chlamydia?)

Question 18

What are the clinical features of reactive arthritis?

Answer 18

• Arthritis: asymmetric oligoarthritis, dactylitis, axial disease (sacroiliitis and spondylitis)
• Enthesitis: achilles, plantar fascia, symphysis p., ribs
• Urethritis: sterile, mucopurulent discharge, GI or GU trigger
• Oral ulcerations
• Circinate balanitis: ulcerations around penis glands
• Conjunctivitis (uveitis and keratitis also possible)
• Skin: keratoderma blennorrhagica (see attached)
• Nails: onycholysis (reminiscent of fungal infection; see attached)

Question 19

What is this?

Answer 19

• Keratoderma blennorrhagica: a skin manifestation of reactive arthritis
• Vesico-pustular waxy lesion w/yellow brown colour
• May join together to form larger crusty plaques with desquamating edges
• May resemble psoriasis; can also spread to palms, scrotum, scalp, and trunk

Question 20

What do you see?

Answer 20

• Onycholysis: nails feature of reactive arthritis
• Detachment of nail from nail bed, usually starting at tip and/or sides
• On hands, said to occur esp. on ring finger, but can occur on any of the fingernails
• May also happen to toenails
• Reminiscent of a fungal infection
• Most common cause is psoriasis

Question 21

What do you see here?

Answer 21

• Oral ulcerations characteristic of reactive arthritis

Question 22

What lab testing should you do for a patient with reactive arthritis?

Answer 22

• Inflammatory markers (ESR, CRP)
• Culture (unusual to be +)
  1. Serology for potential pathogens if indicated
• Consider HIV: test everyone
• HLA B27

Question 23

How should you follow-up with pts with reactive arthritis?

Answer 23

• Follow-up/observe for at least 2-3 months
• Recurrences are common
• 20-50% of patients devo a chronic course

Question 24

What are the key points for psoriatic arthritis?

Answer 24

• Suspect in pt w/asymmetric joint distribution pattern, and maybe add’l clinical features -> dactylitis, enthesitis, inflam back pain, (-) for rheumatoid factor
• Progressive disease: 47% of pts devo erosions w/in 2 yrs of dx -> polyarticular disease and elevated ESR are markers of poor outcome
• INC in vascularity of synovial fluid and neutrophils help distinguish spondyloarthropathy from rheumatoid arthritis; change in synovial CD3+ T cell infiltration might correlate with clinical response to treatment
• PA may originate at entheseal inserions b/c MRI shows prominent entheseal involvement w/bone marrow edema at entheseal insertions
• CD8+ T cells, innate immune may be involved
• Paucity of evidence for efficacy of disease-modifying anti-rheumatic drugs, but TNF inhibitors have proved effective for skin and joint disease
• DIP involvement is characteristic

Question 25

What is this?

Answer 25

Plaque psoriasis (psoriasis vulgaris)

Question 26

What do you see here?

Answer 26

• Nail features of psoriatic arthritis (nail dystrophic changes)

A. Nail pitting

B. Onycholysis: nail detachment from bed (reminiscent of fungal infection)

C. Severe destructive change with nail loss and pustule formation

Question 27

What is the immunopathology of psoriatic arthritis?

Answer 27

• Elevated plasma levels of immunoglobulins
• T-cells express:
  1. HLA-DR molecules
  2. Receptors for IL-2 and adhesion molecules
  3. Secrete IL-6 and o/pro-inflammatory cytokines
• Fibroblasts from skin and synovium proliferate and secrete IL-1 beta, IL-6, and PDGF
• Synovial cytokine profile similar to that of RA: TNF-alpha, IL-1, IL-6, IL-8, IL-18
• Serum cytokines upregulated: IL-10, IL-13, IFN-alpha, VEGF, IL-18, and FGF

Question 28

Why is IL-18 important in the immunopathogenesis of psoriatic arthritis?

Answer 28

• Increased levels of IL-18 in serum and synovial tissue
• Member of the IL-1 superfamily
  1. Stimulates angiogenesis
  2. Up-regulates chemokine expression on synovial fibroblasts
  3. Increases mononuclear cell recruitment

Question 29

How do the cytokine profiles differ in RA and PA?

Answer 29

• PsA synovial samples produce:
  1. More TNF-alpha, IL-1 beta, IL-2, IL-10, and INF gamma
  2. Less IL-4 and IL-5
• PsA synovium has less lining layer thickness and more vascularity

Question 30

What are the patterns of psoriatic arthritis?

Answer 30

• Polyarticular pattern (> 4 joints, RA-like)
• Oligoarticular pattern (< 4 joints, asymmetric)
• DIP involvement pattern
• Arthritis Mutilans (severe, destructive)
• Axial involvement (sacroiliitis and spondylitis, B27+)

Question 31

What is this?

Answer 31

Arthritis mutilans: characteristic of psoriatic arthritis

Question 32

What do you see here?

Answer 32

• X-ray of hand of psoriatic arthritis patient
• DIP involvement
• “Pencil in a cup” appearance

Question 33

What are some of the radiological manifestations of PA?

Answer 33

• DIP involvement: “pencil in a cup” appearance
• Periositis: inflammation of the periosteum
• Bony ankylosis: abnormal stiffening and immobility of a joint due to fusion of the bones
• Erosive and proliferative
• Axial disease resembles AS

Question 34

What’s up with this pt?

Answer 34

Psoriatic arthritis, but…

Significant improvements in skin lesions bc he was treated with Infliximab (10mg/kg infusion; anti-TNF)

Question 35

What’s going on here?

Answer 35

• Improvement in psoriatic arthritis patient after treatment (before on the left and after on the right)

Question 36

What are the key points for enteropathic arteritis?

Answer 36

• Gut wall is a leaky barrier exposed to commensal and pathogenic microorganisms
  1. Microbiota are essential for maturation and regulation of the immune system
  2. GI lymph tissue–microbiota interaction balance between inflammatory defense and tolerance
• Genetic polymorphisms in Crohn’s disease can result in relative immune deficiency
• Some joint disease in IBD genetically determined
• HLA-B27 interacts w/non–major histocompatibility complex genes
• Celiac disease common in adults (1% or more of the pop), 25% have joint manifestations
• Pts with Whipple’s disease often present with joint sxs
• Microscopic colitis also has extraenteric autoimmune manifestations

Question 37

What is enteropathic arthritis?

Answer 37

• Inflammatory arthritis associated with:
  1. Crohn’s disease
  2. Ulcerative colitis
  3. Whipple’s disease (rare IBD)
• Occurs in 2-20% of patients with IBD
• M = F
• Axial disease associated with HLA B27 (not peripheral arthritis -> can get this, but most likely B27-)
• Usually occurs after onset of GI disease

Question 38

What is the immune pathogenesis of enteropathic arthritis (image)?

Answer 38

Question 39

What are the two clinical presentations in the joints of enteropathic arthritis?

Answer 39

• Peripheral
  1. Oligoarticular, generally asymmetric
  2. Lower extremity joints
  3. Dactylitis and enthesitis
  4. GI inflammation often parallels arthritis
• Axial disease
  1. Clinically and radiographically identical to idiopathic AS
  2. Does NOT parallel GI disease

Question 40

What do you see here?

Answer 40

Spondylitis (in this case, a pt. w/enteropathic arthritis)

Question 41

How do you treat enteropathic arthritis?

Answer 41

• Symptomatic tx often adequate -> NSAIDS, although a potential problem causing flares of IBD, often well tolerated/effective for spine involvement or enthesitis
• Sulfasalazine and derivative 5-acetysalicyylic acid (5-ASA) INH NFkB -> shown efficacy in UC, but not CD
• Steroids effective in both UC/CD; local joint injection effective in oligoarthritis of IBD
• Azathioprine and MTX effective in both forms of IBD
• Infliximab and adalimumab are effective in CD and Infliximab is effective in UC

Question 42

What are the key points for the arthritis of celiac disease?

Answer 42

• Immune rxn to partly digested wheat gluten by T-cells in gut of genetically HLA-DQ2+ or 8+ people
• 2/3 of pts present w/diarrhea or irritated bowel sxs; fatigue, headache, and arthralgias are common
  1. 25% assoc w/devo of type I diabetes, anemia, osteoporosis, neuropathies, and joint symptoms
• Can be asymmetric oligoarthritis, polyarthritis, or axial involvement -> can be presenting sx of the disease
• Dx widely small bowel biopsy, presence of serum IgA anti-tissue transglutaninase and IgA antiedomysial Abs
  1. Can have celiac w/o these, however
• Tx is to eliminate gluten from the diet

Question 43

What is celiac disease?

Answer 43

• Aka, gluten enteropathy: inflam disorder of prox sm intestine triggered by ingestion of gluten, the alcohol-soluble fraction of wheat protein
• 1^o findings: mucosal inflammation, crypt hyperplasia, and villous atrophy -> marked ^o’s of mal-absorption
• Can cause weight loss, growth retardation in children, anemia, and vit deficiencies, esp. the B and D groups
  1. Osteomalacia can devo (vit def): affected pts may present w/diffuse achiness and bone pain; most prominent in lower spine, pelvis, and legs
• Arthritis: may be axial or peripheral; some pts have features of both (may only partially respond to diet tx)
• Assoc b/t selective lgA deficiency and celiac disease well established -> about 10% of these pts have celiac

Question 44

What is undifferentiated seronegative spondyloarthropathy?

Answer 44

Patients with features of more than one disease who do not fit in the defined categories of the four diseases discussed in this lecture

Question 45

What do you see here?

Answer 45

• Histo image from ileal biopsy of a 21-year-old patient taken at diagnosis of ankylosing spondylitis associated with ileitis (inflamed sm intestine) of spondylarthropathy
• Shows dense, chronic, inflammatory cell infiltrate, lymphoid follicles and a granuloma (b/t the arrows)
• NOTE: granulomas also a feature of Crohn’s disease

Question 46

What is this?

Answer 46

• Diffuse idiopathic skeletal hyperostosis
• Calcification and ossification is most common on the right side of the spine. NOT INFLAMMATORY
• Melted candle wax
• In people with dextrocardia and situs inversus, this calcification occurs on the left side, which confirms the role of the descending thoracic aorta in preventing the physical manifestations of DISH on one side of spine
• NOTE: Dr. Gupta mentioned this was just extra info

Question 47

What is the pathophysiologic quartet underlying systemic sclerosis?

Answer 47

• Patients with systemic sclerosis show evidence of:
  1. Inflammation
  2. Autoimmunity
  3. Vasculopathy, and
  4. Fibrosis: major defect/abormality; makes the disease unique (skin, lung, heart, endocrine)
• Autoimmunity and vasculopathy generally precede onset and contribute to progression of fibrosis
• Vascular obliteration + interstitial fibrosis continue and exacerbate chronic autoimmunity + inflam

Question 48

What is the epi of systemic sclerosis?

Answer 48

• 6.5 new pts/million pop per year in Memphis vs. 20 in PA (coal mining probs an envo trigger; maybe fracking too bc it involves sand blasting -> silica)
• Incidence in women INC more than men (3-4x)
• AA incidence > Caucasian, esp. in younger age groups (2x as frequent)
  1. Tends to be more severe in AA too

Question 49

What is the general pathogenesis of SSc?

Answer 49

• Fibrotic process (biopsy of skin)
• Microvascular alterations in pulmonary arterioles
• Autoantiboides detected by immunoflurosescence
• Mononuclear inflam cell infiltrates in affected skin
• Monocytes, when exposed to IFN-gamma, trans-differentiate into fibroblasts

Question 50

What does this woman have?

A 47-year-old woman is admitted to the hospi­tal following a seizure at home. Upon arrival, her blood pressure was 190/130 mmHg. She was confused, but w/o focal neurologic deficit. Fundoscopic exam revealed papilledema. There was thickening of the skin over the face, chest, forearms, thighs, calves, and feet. Raynaud’s is present with several healed digital pitting scars on finger tips noted.

Her serum creatinine was 2.4 mg/dL (212.1 mmol/L) (normal= 0.6 to 1.0 mg/dL [53to 88 mmol/L]). Urinalysis reveals 1+ proteinuria, but no cells or casts. The hemoglobin is 10.2 g/dL (6.3 mmol/L) (normal= 12 to 16 g/dL [74 to 9·9 mmol/L]) and schistocytes are noted on the smear.

Answer 50

Systemic sclerosis with diffuse scleroderma

Note: schistocytes are prominent in malignant HTN

CLICKER QUESTION: what is the most likely cause of this patient’s seizures, papilledema, proteinuria?

Scleroderma renal crisis

Question 51

What is the patho of SSc in the vasculature?

Answer 51

• Earliest patho changes that persist throughout the disease are changes in endothelial cell func: INC apoptosis, upregulation of MHC class II and ICAM-1 molecule expression on endothelial cells
• Platelet aggregates, micro-thrombi in microvasc
• Digital artery occlusion
• Intimal proliferation (thickening) w/narrowing of lumen, adventitial fibrosis, telangiectasias of vasa vasorum
• Thrombosis and attempted recanalization of occluded vessels

Question 52

What is Raynaud’s?

Answer 52

• Condition affecting blood vessels in extremities (fingers and toes)
• Characteristics: episodic vasospastic attacks -> blood vessels of digits constrict (narrow), usually in response to cold temps and/or emotional stress
• Types: A) 1^o raynaud’s phenomenon (no o/disease), B) 2^o raynaud’s phenomenon -> occurs w/SSc, RA, lupus, polymyositis, MCTD, etc.
• Attached image: blue = cyanosis and red = reactive hyperemia once hand is warmed

Question 53

What is going on here?

Answer 53

Active Raynaud’s phenomenon with well-demarcated pallor at the fingertips in a scleroderma patient.

Raynaud’s phenomenon is characterized by blood vessel spasms in the fingers, toes, ears or nose, usually brought on by exposure to cold. Raynaud’s phenomenon and Raynaud’s disease, a similar disorder, may occur on their own or they may be associated with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and scleroderma.

Question 54

What is going on here?

Answer 54

• Top image: normal nailfold capillary pattern
• Bottom: pt w/SSc, showing abnormal, widened capillary loops
  1. Marked dilatation and dropping out of blood vessels: can see this in Lupus or SSc (if pt with Raynaud’s has top pattern, probably just 1^o)

Question 55

What do you see here?

Answer 55

• Scleroderma and Raynaud’s phenomenon can be assoc w/digital ulcerations + severe digital ischemia

A: traumatic ulcers over prox interphalangeal joints

B and C: ischemic digital ulcerations secondary to small arterial disease

D: digital gangrene 2^o to macrovascular disease

Question 56

What happened here?

Answer 56

• Vascular disease progressed to necessitation of amputation of digits -> SSc
• Fingers will eventually just drop off due to marked decrease of blood supply in the distal hand

Question 57

What is up with this patient?

Answer 57

• Skin involvement in scleroderma is subdivided into “limited” and “diffuse” cutaneous forms

A: sclerodactyly in limited cutaneous disease

B: truncal changes in diffuse cutaneous disease

C: inflam signs in early active skin disease

D: finger contracture in chronic fibrotic phase of skin involvement in scleroderma

• Note: arthritis is usually not so severe

Question 58

What is going with each of these pts?

Answer 58

• Skin manifestations in scleroderma pts:

A: vitilligo-like (salt and pepper) discoloration of the forehead (highly assoc w/SSc, but can also exist as an isolated condition)

B: large facial telangiectasias

Question 59

What are the types of scleroderma (flow chart)?

Answer 59

• Localized: more common, and only affects the skin, w/o any internal organ involvement
  1. Morphea: waxy patches
  2. Linear: streaks on the skin
  3. Usually does NOT become systemic (skin manifestations look the same though)
• Systemic: always leads to some internal organ involvement
  1. Limited (CREST): skin tightening of fingers, hands, forearms distal to elbows, w/or w/o skin of feet and legs distal to knees tightening
  2. Pts w/diffuse are at greater risk for clinically significant major organ dysfunction (prox extremities & trunk also show skin tightening)
  3. Sine: rare disorder -> pts devo vascular and fibrotic damage to internal organs in absence of cutaneous sclerosis (<5% of total cases)

Question 60

How is the skin involvement different in SSc for limited vs. diffuse disease?

Answer 60

• Limited: skin tightening is confined to the fingers, hands, and forearms distal to the elbows, with or without tightening of skin of the feet and of the legs distal to the knees
  1. Better outcomes, but can get PAH
• Diffuse: skin of the proximal extremities and trunk is also involved
• Grey is the involved part of the body (white is NOT)

Question 61

How are the internal organs involved in SSc?

Answer 61

• Sjogren’s
• Esophageal dysmotility is a very early sign
• Pulm fibrosis, PAH, cor pulmonale
• Cardiac fibrosis, pericarditis, conduction defects, HTN
• GAVE: prominent, dilated arteries in the stomach
• Biliary cirrhosis
• Pancreatic insufficiency
• Osteopenia/osteoporosis
• Raynaud’s

Question 62

Which autoAb’s are associated with which phenotypes in SSc (table)?

Answer 62

• Sicca syndrome: dry eyes
• Acro-osteolysis: absorption of bones in distal portions of the fingers
• Anti-centromere: more common in limited disease
• Anti-U1 RNP: MCTD

Question 63

What is acro-osteolysis?

Answer 63

Terminal tuft bony erosions seen in SSc

Also can be seen w/psoriatic arthritis, dermatomyositis, and Raynaud’s

Question 64

What are the key points for renal involvement in SSc?

Answer 64

• Scleroderma renal crisis (SRC) is a life-threatening condition occuring in 5% to 10% of scleroderma pts
• Risk factors: early diffuse skin disease, chronic use of corticosteroids, and anti-RNA polymerase III Ab’s
• Early pharmaco intervention w/ACEI’s is crucial to control and possibly reverse the disease process
  1. Can put these people on dialysis, continue the ACEI, and keep them alive (important to keep the ACEI)

Question 65

What are some of the associations with SRC?

Answer 65

• New anemia
• New cardiac events (heart failure or pericardial effusion)
• Presence of anti-RNA polymerase I and III antibody (more so with III)
• Antecedent use of drugs, incl. high-dose steroids, NSAIDS, and cyclosporine
  1. Don’t use cyclosporine with this disease now

Question 66

What are the key points for GI involvement in SSc?

Answer 66

• Manifestations of gut dysmotility are universally present in scleroderma and can affect any segment of the gastrointestinal tract
• Involvement of the upper GI tract is more common and can present with severe symptoms
• Dysfunction and failure of the lower GI tract are associated with poor prognosis
• NOTE: raynaud’s and difficulty swallowing -> have to be on the lookout for SSc

Question 67

What is going on with these patients?

Answer 67

• GI manifestations in scleroderma

A: CT (sagittal view) w/severe esophageal dysmotility with dilation and (arrow) retention of gastric content

B: upper endoscopy -> gastric antral vascular ectasias presenting as “watermelon” stomach

C and D: plain abdominal x-ray and CT: small intestinal dysmotility with pseudo-obstruction, pneumatosis cystoides intestinalis

• Want to give pro-motility agents, and observe these people -> you won’t find an obstruction (bc it’s a pseudo-obstruction)

Question 68

What are some of the potential pulm problems in SSc?

Answer 68

• Pleurisy, pleural effusions, pleural scarring
• Aspiration pneumonia
• Malignancy-all cell types
• Interstitial Lung Disease (ILD)
• Pulmonary vascular disease (PAH)

Question 69

How is pulmonary fibrosis implicated in SSc?

Answer 69

• SSc-ILD and PAH are major causes of mortality and morbidity in SSc (combined: 60% of deaths)
• Symptoms of pulmonary fibrosis usually occur late, and include dyspnea, fatigue and dry cough
• Other causes of dyspnea like anemia, chest wall restriction, and concomitant conditions like reflux, infection, drug exposure (e.g., MTX) may contribute
  1. Chest skin can get so tight that they really can’t move their chest/ribs
• Used to lose patients from renal crisis, but now from ILD or PAH

Question 70

How is pulmonary HTN implicated in SSc?

Answer 70

• Prevalence of PAH in SSc 7 – 15% w/ a 5-yr survival of 10% compared with 80% in those w/o PAH
• Mean pulmonary arterial pressure (PAP) >25 mm Hg at rest or > 30 mm Hg w/exercise
• May occur in limited disease w/anticentromere Ab and diffuse SSc w/antifibrillarin antibodies (U3RNP)
• Early DX to optimize tx and improve prognosis -> 1-yr survival in late stage disease <50% despite tx
  1. Dx often delayed due to non-specific sxs and may be mistaken for lack of fitness like DOE, impaired exercise capacity, and fatigue
  2. Signs of RH failure and venous pressure elevation, edema and syncope may develop
• Dyspnea, loud P2 heart sounds on physical exam
• More likely in pts w/limited cutaneous SSc

Question 71

What are the key points for SSc?

Answer 71

• Complex pathogenesis + various clinical features, reflecting underlying early immune dysregulation & microangiopathy + subsequent systemic fibrosis
• Marked pt-to-pt variability in clinical and laboratory manifestations, disease course, and molecular signatures, suggesting distinct disease subsets
• Vascular lesions in small blood vessels occur early and progress to obliterative vasculopathy, causing tissue hypoxia, oxidative stress, and vascular cxs
• Immune dysregulation -> autoAb’s, evidence of innate immune activation, “IFN signature,” but IFN role in pathogenesis has not been established
• Genetic association studies implicate the human leukocyte antigen (HLA) and o/immunoregulatory genes also associated with SLE
• Fibrosis assoc w/sustained mesenchymal cell activation by growth factors, cytokines, chemokines, hypoxia, ROS, & aberrant reactivation of devo paths

Question 72

What is this? What are its 5 types?

Answer 72

• Localized scleroderma (en coup de sabre): non- systemic skin disease seen primarily in children:
  1. Mixed forms: in about 15% of patients
  2. Plaque: most common form is an isolated circular patch of thickened skin
  3. Generalized: multiple lesions on extensive areas of skin; can occasionally coalesce, mimicking skin changes of SSc
  4. Keloid: nodular form resembling keloids
  5. Bullous: rare form with subepithelial bullae
  6. Linear scleroderma: linear streak crosses dermatomes -> assoc w/atrophy of muscle, bone, and rarely the brain, so you can have seizures (aka, en coup de sabre)

Question 73

What are the key points for MCTD?

Answer 73

• Prototypical overlap disease -> features of lupus, scleroderma, and inflam myositis
  1. Overlap features seldom occur concurrently, or at onset, but devo sequentially over mos/yrs
• U1-RNP Ab’s -> predicts lack of severe renal and CNS involvement
• Raynaud’s: nearly all pts -> if raynaud’s is absent, diagnosis should be reconsidered
• 25% devo renal disease -> usually membranous glomerulonephritis; proliferative GN uncommon
• Serious CNS biz rare: most comm findings trigeminal neuropathy, sensorineural hearing loss
• Pulmonary HTN most comm COD -> pts should be screened for on an ongoing basis (echo every year, and always listen for an accentuated P2)
  1. Isolated reduction in DLCO -> devo of PAH

Question 74

What is this?

Answer 74

Linear scleroderma (so says Google)

Question 75

What is going on here?

Answer 75

• Hand of a man with MCTD
• Fingers have a generally puffy appearance with a fusiform proximal interphalangeal swelling of the third finger from an inflammatory arthritis
• Periungual infarct at nail fold of the third finger
  1. Periungual: occurring around fingernail or toenail

Question 76

What pathological process do you see here?

Answer 76

• Histopath of skin lesions in scleroderma
• Characterized by:
  1. Excessive deposition of collagen
  2. Deep fibrosis
  3. Perivascular lymphohistiocytic infiltrates
• Tissue so firm that biopsy is almost a perfect rectangle shape (key to morphea)
• Hair follicle shown here, surrounded by inflam and DENSE COLLAGEN
• Localized (morphea) or systemic (skin of face, upper trunk, hands, arms, esophagus, heart, lungs)

Question 77

What is going on in these two images?

Answer 77

• Sclerosis/SSc: early (left), late (right) manifestations
• EARLY: not a whole lot of changes
  1. Orthokeratosis: normal appearing, basket-weave keratin
  2. Pigment at epidermal/dermal junction
  3. A little inflam, but nothing too abnormal
• LATE: papillae (rete pegs) disappeared, pushing up and flattening out the junction
  1. Hyperkeratosis, w/loss of the basket-weave (few, or no nuclei)
  2. Regression of the inflammatory features
  3. Secondary structures, like hair follicles and sebaceous and sweat glands reduced

Question 78

What is this?

Answer 78

• Calcareous lesion in scleroderma: related to tumoral calcinosis
  1. Large painful masses in the periarticular soft tissue composed of calcium hydroxyapatite

Question 79

What are the micro changes in the joints in scleroderma?

Answer 79

• Nonspecific
• Include changes like:
  1. Superficial fibrin deposition in synovial mem
  2. Mild mononuclear infiltrate
  3. Mild synovial hyperplasia
  4. Proliferation of collagen fibers
  5. Local obliteration of small vessels

Question 80

What is going on here?

Answer 80

• Scleroderma renal crisis histo
• Characteristic histologic findings include:

A: interstitial fibrosis

B: occlusion of intrarenal arteries w/neointima formation, fibrinoid necrosis of the vessel wall, and reduplication of the internal elastic lamina

C: glomeruli shrunken and lack inflammatory cells or proliferative changes

D: intravascular thrombosis resembling changes of thrombotic thrombocytopenic pupura may be present

• Brown in the bottom right is staining the epi cells; there are hardly any in the collapsed lumen

Question 81

What is this?

Answer 81

• Systemic sclerosis vasculopathy histo
• Pulmonary arteriole showing extensive medial hypertrophy and intimal thickening
• Leads to narrowing of the vascular lumen -> can tell it is occluded here

Question 82

What process is going on here?

Answer 82

• Raynaud’s: local asphyxia of the extremities
• Digital artery from a pt w/limited cutaneous SSc, showing intimal thickening
  1. Media also hypertrophied and thickened via same process happening in the vessels
• Lumen occluded with visible recanalisation (arrow)
• Structural abnormalities do NOT occur in 1^o Raynaud phenomenon
  1. Small proportion of patients (1–2% per year) w/what appears to be 1^o Raynaud phenom progress to SSc-spectrum disorder or other underlying disease

Question 83

What are the 4 major types of SLE?

Answer 83

• Systemic Lupus Erythematosus (SLE)
  1. Multisystem inflammatory disorder
  2. Autoantibodies to numerous self antigens
• Discoid Lupus Erythematosus (DLE)
  1. Confined to skin; no other systems involved
  2. Discoid lesions can be seen in SLE, and 5-10% of discoid patients morph into SLE
• Drug-Induced Lupus Erythematosus (DILE)
  1. Less severe than SLE, and resolves once offending drug removed
• Neonatal Lupus Erythematosus
  1. Newborns of mothers with SLE
  2. Skin rash (transient); heart block (permanent)

Question 84

What is this?

Answer 84

Discoid rash: can be seen in SLE and DLE

Question 85

What do you think this pt has?

• 23-y/o Hispanic female: 8-week history of joint pain and swelling in hands, knees, ankles, fever, myalgias, chest pain, weight loss, facial rash that worsened with sun exposure, proteinuria
• Diffuse LAD, malar rash, synovitis MCP, PIP joints
• • anti-ANA, anti-dsDNA, anti-Sm

Answer 85

Systemic lupus (SLE)

Question 86

What is the epi of SLE?

Answer 86

• Genetic
• Risk in gen pop: 0.05% (about ½ prevalence of RA)
• Risk of SLE among siblings of SLE patients: 5%
  1. SLE in twins: dizygotic (5% concordance) and monozygotic:( 25-50%) -> must be envo trigger
• Polygenic disease: multiple genes and gene interactions involved
• Susceptibility genes: HLA-DR2, HLA-DR-3 weakly associated, complement deficiency (e.g. C4A)
• Variation in race/ethnicity: more common in AA (3-6x), Hispanic and Native American (2-3x), and Asian (2x) populations than Caucasian Americans

Question 87

Briefly, what is the pathogenesis of SLE (image)?

Answer 87

• pDC: plasma dendritic cells

Question 88

How would you characterize the disease activity of SLE?

Answer 88

• Periods of flare (increased disease activity) and remission, or low-level disease activity
• Varying flare rates
• Predictors of flare (in some but not all cases):
  1. New evidence of complement consumption
  2. Rising anti-dsDNA titers
  3. Increased ESR
  4. New lymphopenia

Question 89

Describe the severity of SLE. What factors are associated with a more severe course?

Answer 89

• Characterized by:
  1. Abrupt onset of symptoms
  2. INC renal, neurologic, hematologic, serosal involvement
  3. Rapid accrual of damage (irreversible organ injury)
• Associated with a more severe course:
  1. Race/ethnicity: AA, Hispanic, Asian, and Native American populations
  2. Younger age of onset
  3. Male gender
  4. Lower socioeconomic status

Question 90

What does survival look like in SLE? Factors associated w/INC mortality?

Answer 90

• 5-year survival from 50% to >90% in last 60 yrs
• Leading causes of mortality are: heart disease, malignancy, and infection
  1. Used to die of renal failure, but now treatable
• Factors contributing to increased mortality*
  1. Disease duration; INC mortality early on
  2. High disease severity at diagnosis
  3. Younger age at diagnosis
  4. Ethnicity: AA, Hispanic, Asian, and Native American populations are at greater risk
  5. Male gender
  6. Low socioeconomic status
  7. Poor patient adherence*
  8. Inadequate patient support system*
  9. Limited patient education*
• These last 3 are very important: people run out of medicine, don’t know how important it is, etc.

Question 91

What are the clinical manifestations of SLE?

Answer 91

• Varied in number, location, and severity (see attached table of frequencies)
• Disease of a thousand faces
• Seldom are all manifestations present in a single patient, but include:
  1. Constitutional, cutaneous, muskuloskeletal, serous membranes, renal, neuropsychiatric, hematologic, GI, CV, pulm, and obstetrical
• SLE is a heterogeneous disease that can affect virtually any organ system in variable ways

Question 92

What are the CASPAR criteria for the classification of SLE?

Answer 92

• 4/11= 95% Specificity; 85% Sensitivity
  1. Malar rash
  2. Discoid rash
  3. Photosensitivity
  4. Oral ulcers
  5. Arthritis
  6. Serositis
  7. Glomerulonephritis
  8. Neurologic disorder: seizures and/or psychosis
  9. Hematologic disorder: immune-mediated hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia
  10. Antinuclear antibodies (ANA)
  11. Immunologic disorder: anti-DNA Ab, anti-Sm antibody, or antiphospholipid antibodies

Question 93

What do all lupus patients have in common?

Answer 93

• Anti-nuclear antibodies: ANA present in 95-98% of SLE pts (extremely uncommon for pt w/lupus to not be ANA+)
• Multiple methods for detection but IF most reliable
• Immunofluorescence ANA assay: serum sample applied to a glass slide covered w/fixed cells (to allow access to nuclear antigens)
• Ag-Ab rxn revealed by fluorochrome conjugated antihuman Ig antibodies
• Slide examined by fluorescence microscope

Question 94

What are ANA?

Answer 94

• Autoantibodies against various components of the cell nucleus -> present in many autoimmune disorders, and some healthy subjects
• Sensitive (but NOT specific for SLE)
  1. Low specificity: usefulness INC if the pretest probability for lupus is high; i.e., pt has sxs and signs that can be attributed to SLE
  2. High sensitivity: pt w/(-) ANA unlikely to have lupus even when her/his clinical presentation is suggestive of lupus
• Pts w/fibromyalgia may be “accidentally” dx with lupus if they have a +ANA

Question 95

What is the incidence of positive ANA in normal subjects and various other diseases?

Answer 95

• Normal subjects 3%−4%
• SLE 95%−99%
• Scleroderma 95%
• Hashimoto’s thyroiditis 50%
• Idiopathic pulmonary fibrosis 50%
• Incidence INC w/age, chronic infections, and other chronic conditions (like cirrhosis, TB, and pulmonary fibrosis)

Question 96

What autoantibodies are impicated in SLE (table of 7)? How specific are they for lupus, and what are their clinical associations?

Answer 96

• Anti-phospholipid can also be present outside of lupus

Question 97

What are 2 pathogenic autoantibodies in SLE?

Answer 97

• Anti-SSA and anti-SSB
• Implicated in subacute cutaneous lupus (image attached) and neonatal lupus

Question 98

What do you see here?

Answer 98

Subacute cutaneous lupus (think anti-SSA, SSB)

Question 99

What do you see?

Answer 99

Neonatal lupus (anti-SSA, SSB)

Question 100

Why might you get this in lupus?

Answer 100

• Complete heart block in utero in neonatal lupus
  1. Impulse generated in SA node in atrium of the heart does not propagate to the ventricles
• Anti-SSA, SSB

Question 101

How is complement implicated in SLE?

Answer 101

• Complement has a role in the pathogenesis of:
  1. Nephritis
  2. Arthritis
  3. Serositis
  4. Nervous system e.g. cerebritis, peripheral neuropathy
  5. Pulmonary – alveolitis, hemorrhage
  6. Congenital heart block
  7. Probably more

Question 102

Which complement component would you want to measure to assess whether classical complement pathway is being activated?

Answer 102

C4

Question 103

What are some of the MSK manifestations of SLE?

Answer 103

• Arthralgias
• Arthritis: symmetrical or asymmetrical
  1. Can be deforming, but non-erosive
  2. Peri-arteritis/synovitis outside joint capsule; ligaments around joint that are being loosened
  2. Reducible, while in RA, they become fixed
• Muscle: myalgias and weakness
  1. Inflammation -> myositis (measure CPK’s)

Question 104

What do you see here?

Answer 104

• Jaccoud’s-like arthropathy: hand deformities that resemble those in pts with a hx of rheumatic fever
  1. Caused by ligamentous and/or joint capsule laxity
• SLE: hand deformities, like ulnar drift at MP joints, swan neck and boutonnière deformities, and hyperextension at IP joint of thumb, closely resemble deformities seen in RA
  1. Absence of erosions on radiographs and their reducibility distinguish this condition from the deforming arthritis of rheumatoid arthritis

Question 105

How is serositis implicated in SLE?

Answer 105

• Pleura: pleuritic chest pain, pleural effusion
• Pericardium: chest pain, pericardial effusion, and cardiac tamponade
• Peritoneal cavity: abdominal pain
  1. Fluid accumulations usually subclinical
• Lateral decubitus position on the right
  1. Can see these in lupus and to some extent in systemic sclerosis, so these are NOT specific findings

Question 106

What do you see here? What autoimmune disease might this be associated with?

Answer 106

• Pleural effusions
• Lateral decubitus position on the right
  1. Can see these in lupus and to some extent in systemic sclerosis, so these are NOT specific findings

Question 107

What are some of the renal manifestations of SLE? Pathogenesis?

Answer 107

• Significant morbidity and mortality; affects up to 50% of SLE patients
• Correlated w/+ anti-dsDNA antibodies
• Any renal structure can be affected:
  1. Glomerulus
  2. Tubules and interstitium
  3. Vasculature
• Pathogenesis: immune complexes can form in the circulation and then deposit in the kidney, or can form in situ in the kidney
  1. Other needed factors: intact Ig antibody, deposition of aggregates of Ig, complement components, and membrane attack complex

Question 108

What are the hematologic manifestations of SLE?

Answer 108

• All cells lines may be affected -> heme symptoms extremely common in lupus
• RBC:
  1. Anemia of chronic inflammation
  2. Hemolytic anemia
• WBC: autoimmune lymphopenia
• Platelets: autoimmune thrombocytopenia
• Lymphadenopathy (LAD)

Question 109

What are the neuropsychiatric manifestations of lupus?

Answer 109

• Psychiatric abnormalities:
  1. Depression
  2. Psychosis
  3. Cognitive abnormalities: very common
• Neurologic disease:
  1. Brain: seizures, stroke, movement disorders
  2. Spinal cord: transverse myelitis, MS-like disease
  3. Peripheral nerves: neuropathy
  4. Difficult to diagnose: must exclude o/causes

Question 110

What are the GI manifestations of SLE?

Answer 110

• Less commonly affected
• Abdominal pain most common symptom:
  1. Serositis
  2. Vasculitis
  3. Bowel perforation
  4. Peritonitis
• Liver disease:
  1. Autoimmune hepatitis
  2. Liver enzyme elevation

Question 111

What are the obstetrical manifestations of SLE?

Answer 111

• Fertility usually not affected (but important to think about what drugs these patients are taking to prevent teratogenicity)
• Small for gestational age fetuses
• Recurrent fetal loss (anti-phospholipid antibody)
• Neonatal lupus (see attached image) via transplacental transfer of autoantibodies
  1. Rash, leukopenia
  2. Heart block

Question 112

What are the CV manifestations of lupus?

Answer 112

• Pericardium – pericarditis (very common)
• Myocardium – myocarditis (not as common)
• Valves – endocarditis (“Libman-Sacks”)
• Coronary artery disease:
  1. Lupus is strong risk factor for premature CAD
  2. Medications, esp. corticosteroids
  3. Inflammation may predispose to CAD
• Peripheral vasculature: see attached image
  1. Vasculitis
  2. Raynaud’s phenomenon

Question 113

What is this?

Answer 113

• SLE
• Verruchal endocharditis: can produce a murmur in some cases, but not clinically significant
• Aka, Libman Sacks: common board question
  1. Vegetations small, and formed from strands of fibrin, neutrophils, lymphocytes, histiocytes
  2. Mitral valve typically affected; vegetations on ventricular AND atrial surface of the valve
  3. Rarely produce significant valve dysfunction and the lesions only rarely embolize

Question 114

Young femal patient with polyarthritis, fever, and positive skin rash who is being treated for acne. What does she have?

Answer 114

• Minocycline-induced lupus: polyarthritis, fever, positive skin rash
• Nephritis would be LEAST characteristic of DILE, EXCEPT in the case of that induced by anti-TNF agents, i.e., in RA patients

Question 115

What drugs may cause DILE?

Answer 115

• Listed as most important: Hydralazine, Isoniazid, Procainamide, Minocycline (also used for RA pts sometimes -> always nervous about this), INF-alpha therapy
• Note: although each drug listed and many others can induce lupus-like sxs in predisposed individuals, little evidence they can induce true SLE or activate disease in pts with spontaneous, established SLE
  1. If clinical care of a pt w/SLE would benefit from use of one of these drugs, it should not be withheld

Question 116

Lupus Summary

Answer 116

• Clinical disease is characterized by:
  1. Symptom diversity
  2. Periods of flare and remission
• Pathogenesis is related to:

1. Genetic susceptibility + environmental and/or
   behavioral triggers
2. Immune dysregulation characterized by autoantibody production
   - Treatment is targeted to:
3. Clinical manifestations
4. Severity of organ system involvement

Question 117

What are some of the current therapies for SLE?

Answer 117

• Corticosteroids
• Cyclophosphamide
• Methotrexate
• Mycophenolate mofetil: expensive -> last resort
• Azathioprine
• Hydroxychloroquine: frequently used
• Belimumab

Question 118

What are some of the current limitations of lupus therapy?

Answer 118

• Immunosuppressive drugs confer INC risk for:
  1. Infection
  2. Cancer
  3. Infertility
• Common side effects of corticosteroids:
  1. Infections
  2. Cushingoid appearance
  3. Osteoporosis and osteonecrosis: tend to see a lot of vascular necrosis of femoral head
  4. Diabetes
  5. Mood disturbances
  6. HTN and lipid abnormalities

Question 119

What are the key points for antiphospholipid syndrome?

Answer 119

• Antiphospholipid antibodies (aPLs) are a family of autoantibodies against phospholipid-binding plasma proteins, most commonly β2-glycoprotein I
• Clinical manifest: asymptomatic to catastrophic (rare form w/multiple thromboses of med, sm aa over days that clot everything -> need lots of Rx)
• Stroke most common presentation of arterial thrombosis; DVT most comm venous manifestation
• Pregnancy losses typically occur after 10 weeks’ gestation (fetal loss), but earlier losses also occur
• Dx should be made via clinical manifestations and persistently positive aPLs (measured 12 weeks apart -> can put pt. on anti-coagulants during this time)
  1. Single aPL test NOT sufficient to make the dx -> need to come back in 12 weeks, check again
• Don’t give them birth control bc you don’t want to cause clotting, but still want to prevent pregnancy with many of the drugs these people are on
• aPL was originally discovered in Lupus patients, which is why it is called lupus anti-coagulant test, but then we found out that there are a number of people who have this (who do not have Lupus)

Question 120

What facts should we know about APS?

Answer 120

• Dx requires pt to have a clinical event (thrombosis or pregnancy morbidity) and persistent presence of aPL Ab, documented by solid phase serum assay (anticardiolipin or anti-β-glycoprotein (Anti-β2GPI) IgG or IgM), coagulation assay (INH of phospholipid-dependent clotting-lupus anticoag test), or both
• Low titer, usually transient, anticardiolipin in up to 10% and mod to high-titer anti-cardiolipin or (+) lupus anticoag test in less than 1% of normal blood donors
  1. Prevalence of (+) aPL test INC w/age; 10-40% SLE pts and 20% of RA pts have a (+) aPL test
  2. 10% first-stroke pts have aPLs, esp. those who are young (up to 29%) and up to 20% of F who have suffered 3 or more consecutive fetal losses; 14% of pts w/recent, known thrombo-embolic disease have aPLs

Question 121

What are some clinical and lab features that suggest the presence of antiphospholipid?

Answer 121

• Livedo reticularis: rash from small vessel vasculitis

Question 122

What is this?

Answer 122

• Livedo reticularis: rash from small vessel vasculitis
• Clinical feature suggesting the presence of anti-phospholipid antibody

Question 123

What do you see here?

Answer 123

• Joints not a typical pathology specimen for SLE patients -> skin and renal biopsies more frequent
• Skin shows superficial AND deep perivascular inflammation and mucin in the reticular dermis
• Normal skin reminder: epidermis, dermis, sebaceous glands (surrounded by lymphos in this image due to SLE)
• Bluish haze is the mucin (it should look pink)

Question 124

What do you see here?

Answer 124

• Dermis has variable edema + perivascular inflam
• Vasculitis w/fibrinoid necrosis may be prominent
• IF microscopy (have to use fresh, not fixed, tissue) shows depo of IgG and complement along dermo-epidermal junction (+), which may also be present in uninvolved skin -> granular
  1. NOT DIAGNOSTIC of SLE and is sometimes seen in scleroderma or dermatomyositis
• Anytime you have any kind of injury to the skin, you can get melanin deposition -> sun-exposed skin tends to give you more likelihood of a false positive
• Degeneration in the top image

Question 125

How do we classify lupus nephritis (6)?

Answer 125

• Class I: normal histology (but there are ARE immune complexes there that you can’t see yet)
• Class II: mesangial proliferation
• Class III: focal proliferative GN (<50% of glomeruli)
• Class IV: diffuse proliferative GN (>50% of glomeruli); see this a lot
• Class V: membranous pattern (start to see thickened vessel walls, and can have crescent formation, but this is uncommon)
• Class VI: advanced sclerosing glomerulopathy

Question 126

What do you see here?

Answer 126

• Class III lupus nephritis
• Focal proliferative glomerulonephritis (FPGN) with two focal necrotizing lesions at the 11 o’clock and 2 o’clock positions
• Extracapillary proliferation is not prominent in this case

Question 127

What is the difference b/t these 2 glomeruli?

Answer 127

• Diffuse proliferative glomerulonephritis (class IV – most common) on the left
  1. Note marked INC in cellularity throughout the glomerulus (H&E stain)
• Normal glomerulus on the right

Question 128

What do you see in these two images?

Answer 128

• Lupus nephritis (class IV) glomerulus with several “wire loop” lesions -> extensive subendothelial deposits of immune complexes (PAS stain).
• Electron micrograph of a renal glomerular capillary loop from a patient with SLE nephritis
  1. Subendothelial dense deposits (arrowheads) correspond to “wire loops” seen by light micro

Question 129

What is this?

Answer 129

• Deposition of IgG antibody in a granular pattern, detected by immunofluorescence -> SLE glomerulonephritis
• This is an IMPORTANT IMAGE

Question 130

What do you see here?

Answer 130

• Renal thrombotic microangiopathy in antiphospholipid syndrome (APS)
  1. 1/3rd of pts w/lupus have vascular lesions consistent with APL nephropathy
• Left: kidney biopsy from 35-y/o woman w/primary APS, microhematuria, non-nephrotic proteinuria
  1. Glomerulus w/microthrombi and occluding cap lumina, and endothelial swelling is evident
• Right: same pt’s sm renal artery contains organized thrombus, with recanalization and arteriosclerosis
• In general, these are not specific changes to lupus

Question 131

What is this?

Answer 131

Normal skin histo

Question 132

What are the key points for Sjogren’s syndrome?

Answer 132

• Divided into 1^o and 2^o forms -> 1^o form in about 0.1-0.6% of the general population
• Clinical hallmarks: keratoconjunctivitis sicca (dry eyes), xerostomia, parotid gland swelling
• Extra-glandular features of 1^o: fatigue, Raynaud’s, polyarthralgia/arthritis, interstitial lung disease, neuropathy, purpura
• Chronic mononuclear cell infiltration of lacrimal and salivary glands is characteristic histopatho
• Dx of 1^o by subjective and objective assessment of dry eyes, dry mouth, testing for serum antinuclear antibodies (anti-Ro/SS-A, anti-La/SS-B), and labial salivary gland biopsy
• Tx: aims to provide symptomatic improvement in symptoms of dry eyes and dry mouth, as well as control of extraglandular manifestations of disease

Question 133

What is the epi of Sjogren’s?

Answer 133

• Affects all races and all ages, but onset is greatest in middle age
• 90% of patients are female
• Increased incidence of autoimmune disease in family members, especially SLE
• Prevalence may be as high as 0.4%-0.8%

Question 134

What other exocrine glands are involved in Sjogren’s?

Answer 134

• Nose, pharynx, larynx, and tracheobronchial tree-hoarseness, pneumonia
• Skin and vaginal dryness
• Biliary tree inflammation-cirrhosis
• Chronic atrophic gastritis
• Non-Hodgkin’s lymphoma: 44-fold increased risk
  1. Always check for lymph node or spleen enlargement & weight loss in these pts (NHL)

Question 135

What other organs are involved in Sjogren’s?

Answer 135

• Pulmonary
• Kidneys
• GI
• Small and medium-sized vessel vasculitis
• Nervous system and peripheral nervous system
• Non-Hodgkin’s lymphoma

Question 136

How are the kidneys and GI involved in Sjogren’s?

Answer 136

• Renal disease: infrequently of clinical significance in 1^o SS; due to tubular interstitial nephritis, type I renal tubular acidosis (RTA), glomerulonephritis, and nephrogenic diabetic insipidus
• GI symptoms: INC in SS; 1/3 have varying degrees of esophageal dysfunction; some have chronic atrophic gastritis; liver involvement can be due to primary biliary cirrhosis, nonspecific hepatitis or autoimmune hepatitis

Question 137

How are the nervous system and peripheral NS involved in Sjogren’s?

Answer 137

• Nervous system: can be due to focal CNS deficits incl. optic neuropathy, hemiparesis, mvmt disorders, cerebellar syndromes, spinal cord syndromes resembling MS like transverse myelitis, and progressive myelopathy; neuromyelitis optica occurs in pts w/serum anti-aquaporin-4 antibodies
• Peripheral nervous system: infrequently involved, producing sensory neuropathy, motor neuropathy, sensorimotor neuropathy, cranial neuropathies, autonomic neuropathies, and multiple mono-neuropathies

Question 138

How are vasculitis, Non-Hodgkin’s lymphoma, and pulm involvement implicated in Sjogren’s?

Answer 138

• Sm/med-sized vessel vasculitis: rarely, w/features from multiple mononeuropathies to ischemic bowel
• NHL: prevalence of 4.3% in 1^o SS, w/median time to devo from dx being 7.5 yrs.; mucosa-associated lymphoid tissue (MALT) lymphoma occurs mostly in chronic autoimmune disease such as SS
• Pulm: 11% of patients w/SS; may take several forms incl xertrachea, xerobronchitis, nonspecific interstitial pneumonitis (NSIP), lymphocytic interstitial pneumonitis (LIP); usual interstitial pneumonitis (UIP), bronchiolitis and lymphoma

Question 139

What are the lab findings with Sjogren’s?

Answer 139

• Most pts test (+) for serum ANAs (85%)
• About 1/3-1/2 have anti-Ro/SS-A, anti-La/SS-B Ab’s
• 5-10% have low blood levels of C3 and C4
• 5-10% have type II or III cryoglobulinemia, or a monoclonal gammopathy
• 5-15% have leukopenia or thrombocytopenia
• 75-95% have (+) rheumatoid factor
• Some overlapping findings with Lupus and RA

Question 140

What are the ocular manifestations of Sjogren’s?

Answer 140

• Keratoconjunctivitis sicca: keratitis caused by decreased lacrimal secretions
  1. Symptoms: dryness of the eyes, foreign body sensation, burning, photosensitivity
  2. Best detected by exam of the eyes after instilling rose Bengal dye to highlight epithelial lesions
• Schirmer’s test using filter paper is used to document decreased tear flow -> attached image

Question 141

What do you see here?

Answer 141

Keratoconjunctivitis sicca: keratitis caused by decreased lacrimal secretions

Characteristic of Sjogren’s

Question 142

What are the oral manifestations of Sjogren’s?

Answer 142

• Severe mouth dryness (xerostomia)
• Multiple dental caries
• Fissuring and ulceration of the lips, tongue, and buccal membranes (see image)
• Difficulty chewing and swallowing
• Parotid and/or submandibular salivary gland enlargement occurs in 50% of patients and is most often unilateral and episodic (see image)
• Histology: infiltration of tissues by lymphos, plasma cells w/loss of secretory epi in exocrine glands

Question 143

What are the 2 types of Sjogren’s?

Answer 143

• Primary: chronic autoimmune inflam disorder
  1. Lymphocytic infiltration and proliferation
  2. Destroys exocrine glands (esp. salivary and lacrimal glands)
  3. Infiltrates in other organs to a variable extent
  4. Malignant transformation possible
• Secondary:
  1. Complication of another autoimmune connective tissue disease
  2. Commonly seen in RA and SLE

Question 144

How would you treat a patient’s recent onset of parotid gland swelling?

Answer 144

Obtain a biopsy of the salivary gland

Question 145

What is the difference between these 2 images?

Answer 145

• Normal salivary gland on L & Sjogren’s gland on R
• Sjogrens – a chronic lymphocytic saladentis
  1. Gross – the salivary gland is enlarged, white (due to fibrosis) & sometimes admixed w/cysts
  2. Micro – Mononuclear inflam infiltrates, interstitial fibrosis, and acinar atrophy of a minor salivary gland in a biopsy of lip is typical for long-standing Sjögren syndrome
• Note: non-specific, and usually LYMPHOCYTES -> biopsy-dependent (you may have one cluster of lymphocytes, or many)

Question 146

What do you see here?

Answer 146

• Labial salivary gland biopsy from pt w/Sjogren’s
  1. C: Anti-CD3 staining of T cells and D: Anti-CD21 staining of B cells -> can become a monoclonal MALT lymphoma
  2. Mononuclear cells aggregate in foci throughout gland in a periductal distribution (A and B)
  3. In this biopsy, most of the mononuclear cells are T cells (C) and the minority are B cells (D)
• INFLAMMATION

Question 147

What do you see here (hint: neoplastic risk of Sjogren’s)?

Answer 147

• In some cases, lympho infiltrate polytypic, like reactive process should be -> can form small clonal populations and develop into full blown lymphomas
• Malt lymphoma (parotid gland): note multiple lymphoid clusters around ducts, glands in parotid parenchyma -> lymphocytic sialadenitis may be seen in pts w/SS and have almost identical histo
  1. Distinction can be difficult on morphologic grounds; dx of lymphomas favored in presence of obvious monoclonality, abundant mono-cytoid B-cells with pale cyto, and abundance of B-cells in sheets (AMINO STAINS)

Question 148

What is RA?

Answer 148

• Chronic multisystem disease of unknown etiology w/variety of systemic features
• Hallmark is persistent inflammatory synovitis usually involving peripheral joints in symmetrical distribution -> propensity to erode cartilage and bone and reduce joint integrity
• Variable course and likely influenced by genetics and envo factors (i.e., smoking) w/some pts experiencing only mild oligoarticular disease with minimal joint damage whereas o/pts have chronic relentless and progressive arthritis -> can lead to marked functional impairment if not tx properly

Question 149

What is the epi of RA?

Answer 149

• Worldwide distribution across all ethnic groups
• Peak incidence ranges from mid-30s to 50s
• Prevalence in North America approximately 1%
• Prevalence INC w/age, and 3x more common in F
• Genetic predisposition, familial aggregation confirmed
• Associated with increased mortality; mortality rates increased about 2x over gen pop – RA is NOT a “non-fatal” disease
  1. Knocks about 10 years off of your life (comparable to non-Hodgkin’s lymphoma)

Question 150

What genetic risk loci are associated with RA?

Answer 150

• MHC Class II (HLA-DR4, aka HLA-DRB1; left on the attached image) imparts a 30% genetic risk
• Other inflammatory markers (on the right in the attached image) with about a 5% risk

Question 151

Genetic risk for RA is most strongly associated with shared epitope alleles for…?

Answer 151

HLA-DRB1

Question 152

How is HLA-DR4 involved in the pathogenesis of RA?

Answer 152

• HLA-DR4 selectively binds, presents Ag to T-cells
  1. APC has DR4 on it -> binds and presents arthritogenic peptide antigen(s) to T-cells with CD4 as co-receptor
  a. Collagen T2 is one of the antigens (sequence in alpha 1, CD 11 that most pts. w/shared epitope of RA can interact with)
  2. Molecular mimics of arthritogenic peptide also thought to exist
  3. Direct interactions between DR4 shared epitope and the T cell receptor
  4. Selection of autoreactive T cells in thymus (problem with selection and tolerance, so no elimination of all of these T-cells)

Question 153

How do genes and the envo influence RA?

Answer 153

• Gene-environment interactions may be additive or multiplicative in RA risk
• Heritability of RA has been estimated to be about 60%, based on twin studies
• Genetic factors account for a large proportion of the population’s liability to the disease

Question 154

What is rheumatoid factor? In what diseases has it been identified?

Answer 154

• Antibodies directed against the Fc portion of IgG
  1. Usually IgM, but IgG and IgA described
  2. 1st auto-Ab described in medicine
  3. Not a specific marker, but it is useful
• Rheumatic diseases:
  1. RA: 26 to 90%
  2. SS: 75 to 95%
  3. MCTD: 50 to 60%
  4. Mixed cryoglobulinemia (types II and III): 40 to 100% (i.e., after hepatitis infection)
  5. SLE: 15 to 35%
  6. Polymyositis or dermatomyositis: 5 to 10%
• Others:
  1. Healthy ppl: young (3-4%) and older (3-25%)
  2. Indolent or chronic infection, as with subacute bac endocarditis (SBE) or hep B or C virus infection
  3. Inflammatory or fibrosing pulm disorders, like sarcoidosis
  4. Malignancy, particularly B-cell neoplasms
  5. Primary biliary cirrhosis: most likely an auto-immune disease of the scleroderma spectrum

Question 155

What Ab’s (other than RF) are implicated in RA?

Answer 155

• Anti-CCP antibodies
  1. Cyclic citrullinated peptide
  2. More specific marker of RA than RF
• Antinuclear antibodies
  1. Seen in 20% of RA patients
  2. Does not necessarily mean lupus
• Can be a Lupus, RA overlap, aka Rupus

Question 156

What are ACPA’s?

Answer 156

• Anti-cyclic citrullinated peptide antibodies: nearly 20% of unaffected, 1st^o relatives, and > 10% of more distant relatives have these
• Also produced by synovial tissue B-cells and can be detected in synovial fluid
• Predictors of more aggressive disease marked by bone and cartilage destruction (and INC risk of atherosclerosis, heart attacks, and strokes)
• Accelerated atherosclerosis in RA, independent risk factor for ischemic heart disease
• In pts wwith early undifferentiated inflam arthritis, predictive for individuals who will progress to RA
• Pathogenic potential: can activate complement
• IgE ACPAs from patients with RA can sensitize basophils and mast cells leading to degranulation

Question 157

Briefly describe the autoimmunity of RA.

Answer 157

• Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis
• Autoantibodies such as RFs and anti-citrullinated protein antibodies commonly associated with RA
• Autoantibodies in RA can either recognize joint antigens such as type II collagen, or systemic antigens such as glucose phosphate isomerase
• Autoantibodies can contribute to synovial inflam via several mechs, incl local complement activation
• Variety of auto-antigens -> common in many auto-immune diseases, so treatments for specific auto-antigens may not be particularly helpful
• C3 and C4 will be reduced; C3a, C5a contribute to inflammation

Question 158

What is the role of T-cell cytokines in RA?

Answer 158

• Several subsets of T-cells implicated in RA pathogenesis (i.e., TH1 and TH17)
• Relatively low levels of T-cell cytokines are present in RA synovium -> those that are present, like IFN-γ & IL-17, can be produced by Th1 cells or Th17 cells
• Regulatory T cell function (suppressing activation of o/T cells) might be low in RA synovium or might not function as well as they normally do
• Contribution of T cells to synovial inflammation can be through antigen-independent mechanisms such as direct cell-cell contact with macrophages (IFN-gamma is a macrophage activator)

Question 159

What are the key macro and fibro cytokines involved in RA?

Answer 159

• Abundant in RA synovium
• Proinflammatory cytokines like IL-1, TNFα, IL-6, IL-15, IL-18, GM-CSF, and IL-33 -> help perpetuate synovial inflammation
• Chemokines that recruit inflam cells into joint are commonly produced by macros and fibroblasts
• Anti-inflammatory cytokines like IL-1Ra and IL-10 are produced in rheumatoid synovium, but in amts insufficient to suppress pro-inflam cytokine func
• Mab’s for: IL-1, IL-6, and TNF-alpha
• Monoclonal for IL-17 developed, but it wasn’t very effective at controlling disease

Question 160

Are osteoclasts involved in RA?

Answer 160

• YES -> osteoclasts also activated, and there is production MMP’s
• Most of the erosions that we see in RA are on the outside of the peripheral joints
  1. Psoriatic arthritis most destructive arthritis (RA doesn’t go quite that far, but worse than OA)

Question 161

How is the synovial fluid affected in RA?

Answer 161

• RA synovial effusions: neutrophils + mononuclear cells
• Immune complexes that contain autoAB’s like RF or anti-CCP Ab’s can fix complement, leading to gen of chemo-attractants -> neutrophils and monocytes
• Small molecule mediators of inflam like PG’s and LT’s present in RA synovial fluid, and cause vasodilation and pain (this is why NSAID’s are effective in controlling some of the symptoms)

Question 162

What are some of the systemic features of RA?

Answer 162

• Fatigue, anorexia, weight loss, weakness, generalized aching and stiffness, low grade fever
  1. None of these are present in OA patient
• Often appear as a prodrome (early symptom indicative of disease onset) to disease onset and are commonly worse with increases in disease activity (flares)

Question 163

What does this woman have?

• 58-y/o woman with 2-month history of hand, feet, and knee pain
• Joints stiff for 90 minutes in the AM
• Tenderness and mild swelling of MCP and PIP joints of the hand and metatarsal heads of both feet
• Moderate effusion of knee
• Elevated C-reactive protein

Answer 163

RA

Question 164

What are the articular features of RA at its onset?

Answer 164

• Often insidious, occurs over weeks to months
• Joint involvement:
  1. Can be intermittent at onset

2, Not usually migratory (doesn’t bounce around)

3. Develops into a persistent polyarthritis

Question 165

What are the signs and symptoms of active RA?

Answer 165

• Morning stiffness is prolonged
  1. Lasts at least 30 minutes, and may persist for several hours
  2. In non-inflammatory joint diseases such as osteoarthritis, morning joint stiffness is brief, lasting 5-15 minutes
• Swelling, warmth, erythema around joint
• Synovial fluid analysis:
  1. Exudative, yellow fluid
  2. Elevated number of white blood cells
  3. Reduced viscosity (because hyaluronic acid is destroyed)

Question 166

What is the pattern of joint involvement in RA at the onset of disease?

Answer 166

• May begin as a _mono- or oligo_arthritis (one or a few scattered joints)
• Often involves large peripheral joints such as the knee

Question 167

What is the pattern of joint involvement in established RA disease?

Answer 167

• Evolves into typical pattern useful in distinguishing RA from other forms of arthritis
  1. Tends to be symmetrical
  2. Most characteristic pattern is wrist and prox hand joint involvement, i.e. MCP and PIP
  3. Other joints that frequently become involved include knees, hips, ankles, elbows, shoulders
• NOT the DIP’s in the feet or hands
• Sparing of the spine, but TMJ can be involved, and the first 3 vertebrae (which have synovial joints)

Question 168

How is the cervical spine involved in RA?

Answer 168

• Cervical spine:
  1. Damage usually occurs after several years of disease
  2. May manifest as neck pain only
  3. Risk of spinal cord compression – symptoms from sensory loss to catastrophic neurologic compromise and sudden death
• Very serious complication, in which you can have a slippage of C1 forward onto C2
• Can get electrical sensations down the arms and into the lower extremities

Question 169

What structural damage and deformities can you see in RA joints?

Answer 169

• Chronic inflammation:
  1. May weaken tissues & supporting structures e.g. ligaments, joint capsules
  2. May lead to fibrosis and tightening of tissues e.g. lumbical muscles of the hand
• Muscle atrophy from inflammation and disuse
• Deformities occur under normal forces of muscular traction:
  1. Wrist: volar subluxation with radial-ward rotation (see attached image)
  2. MCP joints: ulnar deviation
  3. PIP and DIP joints: Swan-neck and Boutonniere deformities

Question 170

What’s up with these hands?

Answer 170

RA

Question 171

What is going on with this hand?

Answer 171

RA

Question 172

What are some of the structural damage and deformities of the lower extremities seen in RA?

Answer 172

• Flexion contractures (“bent,” or “stuck” joint) frequently occur at larger peripheral joints such as the knee, hip, and elbow
• Weakening of supporting structures in the foot often leads to pain and altered functional anatomy and mechanics of walking

Question 173

What are these x-rays characteristic of?

Answer 173

RA: note that the ankle and elbow are shown here, which usually are NOT involved in OA

Question 174

What are some of the skin manifestations of RA?

Answer 174

• Rheumatoid nodules: about 30% of patients
  1. Most often on extensor surfaces such as the olecranon process and proximal ulna. They can also occur in the pleura, meninges, or ears (can occur anywhere)
• Vasculitis: inflammation of small (or medium) blood vessels in the skin manifested by palpable purpura or skin ulceration

Question 175

What is going on here?

Answer 175

• Vasculitis in RA: inflammation of small (or medium) blood vessels in the skin manifested by palpable purpura or skin ulceration

Question 176

What do you see here?

Answer 176

• Rheumatoid nodules in RA
• Gross image: in olecranon bursa and along proximal ulna
• Histo image: granulomatous transformation -> prominent central fibrinoid necrosis, with surrounding palisading histiocytes and an outer layer of chronic fibrosing connective tissue with inflammatory cells including lymphocytes and fibroblast

Question 177

What are some of the ocular manifestations of RA?

Answer 177

• Keratoconjuctivitis sicca (“dry eyes”): resulting from lympho cell infiltration of lacrimal glands and gland dysfunction
• Xerostomia (“dry mouth”): lympho infiltration of salivary glands can diminish saliva production
• Episcleritis and scleritis: irritation, inflammation of sclera or episclera (thin tissue layer covering sclera)
  1. Similar etiology as rheumatoid nodules
  2. Erosion of sclerae in most severe form

Question 178

What is this?

Answer 178

Episcleritis: seen in RA

Question 179

What is this?

Answer 179

Scleromalacia: seen in RA

Question 180

What do you see here?

Answer 180

Central keratolysis and corneal perforation in RA

Question 181

What is this?

Answer 181

Marginal corneal melt (ulcer) with inflammation in RA

Question 182

What are the cardiorespiratory manifestations of RA?

Answer 182

• Respiratory:
  1. Interstitial fibrosis
  2. Pulmonary nodules
  3. Pleuritis with pleural effusion
• Cardiac:
  1. Pericarditis – common, but largely asymptomatic (tamponade is rare)
  2. Nodule formation on valves

Question 183

What are some of the neurological manifestations of RA?

Answer 183

• Cervical myelopathy
• Compressive peripheral neuropathy:
  1. Carpal tunnel syndrome (median nerve)
  2. Ulnar tunnel syndrome (ulnar nerve compressed at Guyon’s canal)

Question 184

What are some of the RA treatments?

Answer 184

Question 185

Briefly describe the pathology of RA.

Answer 185

• Immune complexes manifest as chronic poly-articular arthritis
• Lysosomes and interleukins are mediators of the inflammatory reaction
• Basic fibroblastic growth factor (FGF) plays a role in synovial hyperplasia and join destruction
• Except for acute stage of disease, polymorpho-nuclear leukocytes rare in proportion to mononuclear cells infiltrating the synovial mem
  1. In general, NO neutrophils -> mostly plasma cells and lymphocytes

Question 186

What are these cells? When might you see them in the synovium?

Answer 186

• Plasma cells and lymphos in RA
• Earliest changes incl hyperemia of the synovium with proliferation of the synovial lining cells with infiltration by plasma cells and lymphocytes
• Plasma cells have clock-face chromatin and peri-nuclear hof (see attached image)

Question 187

What do you see here?

Answer 187

• Rheumatoid arthritis w/hyperplastic synovial villi eroding and replacing cartilage at the joint margin
• Villous

Question 188

What do you see here? Hint: there are 2 different types of predominating cells here.

Answer 188

• Rheumatoid synovitis with multiple layers of proliferated (hyperplastic) synoviocytes underlain by lymphocytic infiltration (H&E)
  1. Blue arrow (top): hyperplastic synovium
  2. Yellow arrow (bottom): lymphocytes
• Multinucleated giant cells of uncertain, possibly synoviocyte, derivation are occasionally formed near the synovial surface

Question 189

What is going on here?

Answer 189

• Multinucleated giant cells underlying proliferated synovial lining cells in rheumatoid synovitis (H&E)
• Synovial membrane becomes focally and diffusely infiltrated with chronic inflam cells - lymphocytes, macrophages, and plasma cells, along with a scattering of polys which are more numerous in the acute stages of the disease

Question 190

What are these?

Answer 190

• Low power view of lymphoid nodules, some with pale germinal centers, in rheumatoid synovitis (H&E)
• Germinal centers: almost like you would see in a lymph node (B and T cells start to organize)
• These are the villi we see in the attached gross image

Question 191

What do you see here?

Answer 191

• Fibrin deposition and fibrinoid change in rheumatoid synovitis (H&E)
• Fibrin deposition and foci of fibrinoid change and necrosis are present in, or on, the inflamed synovial membrane in some cases
• Almost a cap on top of the joint

Question 192

What are these images of?

Answer 192

• Chronic proliferative (hyperplastic) and exudative synovitis in long standing rheumatoid arthritis (H&E)
• Left: low power view of lymphoid nodules, some with pale germinal centers, in rheumatoid synovitis
• Right: inflammatory process may continue for mos or years -> exudate eventually undergoes organization by granulation tissue composed of newly formed capillaries, macrophages, and fibroblasts

Question 193

What is this?

Answer 193

• Rheumatoid synovitis with pannus formation
• Synovial inflam and granulation tissue adjacent to margin of the joint covers and adheres to cartilage as a membrane or pannus (from Latin: a cloth)
• Hyperplastic and chronically inflamed synovial villus extends over surface of the articular cartilage as a fibrous inflammatory membrane (pannus) that erodes and replaces the underlying cartilage (H&E)

Question 194

What do you see here (hint: what does pannus do)?

Answer 194

​- Destruction of articular cartilage (of metacarpal joint) by rheumatoid pannus (H&E)

• Articular cartilage under the pannus undergoes degradation and disappears, beginning at the joint margin and extending centrally

Question 195

What is this? How does it happen?

Answer 195

• Fibrous ankylosis (fixation) of interphalangeal joint in rheumatoid arthritis (H&E)
• Cartilage matrix destroyed from above and below, mainly by lytic enzymes (collagenass & proteases) released from synoviocytes and inflam cells in the pannus and the synovial effusion
• Synovial inflammatory tissue may extend into the subchondral bone by penetrating the bone cortex, resulting in cortical erosion
• As cartilage disappears and pannus is organized, fibrous adhesions formed and the bone ends are bound together by fibrous tissue (fibrous ankylosis) or subsequently, with osseous metaplasia, by solid bone (bony ankylosis)
• Pannus, leading to ankylosis, eventually fixing the joint
• Fibrous tissue in the joint space shown above (no cartilage; just residual bone and bone marrow)

Question 196

How is the skin involved in RA?

Answer 196

• Extra-articular manifestations of RA occur more often in seropositive patients with severe disease and circulating complexes of rheumatoid factor
• Subcutaneous rheumatoid nodules in about 20-25% of pts -> measure up to 2 cm in diameter, are firm, non-tender, and palpable in subcutaneous tissue usually over a bony prominence, like elbow
• Histo: granulomatous lesion w/central zone of collagen necrosis and fibrinoid change, a middle zone of epithelioid cells, macrophages, and an outer zone of granulation tissue infiltrated by lymphocytes, plasma cells, and macrophages
• Usually on weight-bearing surfaces that touch things a lot (e.g., elbows)

Question 197

What is this? Arrows?

Answer 197

• Rheumatoid nodule
• Arrows: central zone of necrosis surrounded by epithelioid histiocytes (i.e., macrophages)
• Weight-bearing surfaces that touch things a lot (e.g., elbows)
• Similar rheumatoid nodules are sometimes formed in other organs, such as lungs, heart, and tendons

Question 198

What are some of the extra-articular manifestations of RA?

Answer 198

• Rheumatoid vasculitis: may involve venules, caps, arterioles, and arteries of skin or other organs and, rarely, may appear as a systemic necrotizing vasculitis of small and medium sized arteries resembling polyarteritis nodosa
• Nonspecific inflam changes or rheumatoid nodules may be present in heart (pericarditis is most frequent), lungs (pleuritis, also nodular “coin” lesions), and eyes (keratoconjunctivitis)
• Peripheral neuropathy may result from nerve entrapment (as in the “carpal tunnel syndrome”)
• Enlargement (hyperplasia) of regional lymph nodes is common, and palpable splenomegaly occurs in ~10% of patients with RA
• Can get cystic changes in bone, and even bone marrow proceeding into the joint with severe disease (pannus penetrating into the bone) -> still not same degree of bone destruction you get with more severe arthritic disease (i.e., psoriatic arthritis)
• Extra-articular changes before articular changes is possible

Question 199

What is Felty’s syndrome?

Answer 199

• Clinical triad: hypersplenism + leukopenia + RA
  1. DEC platelets due to hypersplenism

Question 200

Why should you ask about occupation if you are concerned about RA?

Answer 200

• Because exposure to toxins and damage to joints is important to know about
• Sometimes these can cause arthritis in abnormal joints

Question 201

Will the joint be enlarged in RA?

Answer 201

• It can be -> actual structure around the joint is going to be enlarged in due to pannus
  1. Synovial enlargement vs. bone enlargement in OA

Question 202

How do TNF-alpha and IL-1 affect the bone in RA?

Answer 202

• TNF-alpha and IL-1 will cause osteoporotic changes (via inactivation of osteoblasts) in RA

Question 203

What is OA? What are the risk factors and common morphological changes?

Answer 203

• Degenerative joint disease, primarily in older ppl, characterized by erosion of articular cartilage, hypertrophy of bone at margins (i.e., osteophytes)
• Risk factors: age, joint location, obesity, genetic predisposition, joint malalignment, trauma, gender
• Morphologic changes:
  1. Early: articular cartilage surface irregularity, superficial clefts in the tissue, and altered proteoglycan distribution
  2. Late: deepened clefts, INC in surface irregularities, and eventual articular cartilage ulceration, exposing the underlying bone -> chondrocytes can form clusters or clones in attempt to self-repair (marginal osteophytes can also form)

Question 204

What are some of the mediators involved in the pathogenesis of OA?

Answer 204

• MMP’s degrade proteoglycans (aggrecanases) and collagen (collagenases)
• Suboptimal repair response of normal articular cartilage to injury typically results in 2^o osteoarthritis
• Mediators clinically assoc w/inflam in OA are: IL-IB and TNF (more limited damage than in RA)
• NO, produced by iNOS, is a major catabolic factor produced by chondrocytes in response to pro-inflam cytokines
• Expression of COX-2 INC in OA chondrocytes
• Low-grade inflam in OA synovial tissues

Question 205

What is the primary focus of OA treatment?

Answer 205

Improving signs and symptoms

Question 206

Is joint location important in OA?

Answer 206

• YES
• Location of the joint is very important -> some joints are very resistant, i.e., the ankle
• Knee is the most common

Question 207

How should you exam the temp of joints? How will they feel in OA?

Answer 207

• Best way to feel temperature is to rub back of hand over unaffected joint, then over affected joint
  1. Shouldn’t see much of a difference in temp b/t affected and unaffected joints in OA

Question 208

What is one of the earliest pathological changes in OA?

Answer 208

• Washout of proteoglycans
  1. This also occurs in animal models, and is a very early morphologic change

Question 209

What does crepitation mean?

Answer 209

• If you feel crepitation, there are going to be some changes in the articular cartilage (or loss of it)

Question 210

What kind of cartilage is in the joints?

Answer 210

• Most of the collagen in articular cartilage is T2 (although there are also some others, like T10)

Question 211

What are the key clinical features of OA?

Answer 211

• Most common form of arthritis, typically affecting the hands, hips, knees, spine, and feet
• Can be defined radiographically, clinically, or symptomatically
• As more sensitive measures of damage become available, such as improved imaging and molecular biomarkers, definitions may change
  1. No good biomarkers at this point
• Pain and functional limitations contribute substantially to disability
• Mortality is increased among individuals with OA compared with the general population (decreased mobility, INC BMI and diabetes).

Question 212

What are joint mice?

Answer 212

• Fragments of cartilage that have broken off into the joint space (occurs in more advanced cases)

Question 213

What is the pathogenesis of OA?

Answer 213

• Mechanical stress initiates altered metabolism characterized by release of MMP’s (converted to active form by PAF), proinflammatory cytokines, and mediators like NO and PGE2
• Cartilage breakdown products stimulate release of cytokines from synovial lining cells and induce MMP production by chondrocytes
• Perpetuation of cartilage damage amplified by the autocrine and paracrine actions of IL-1β and TNF
• Self-perpetuating process
• TGF-beta: important for maintaining cartilage; also may be important for osteophyte formation

Question 214

How is OA multifactorial?

Answer 214

• Multiple factors predispose you to, initiate and perpetuate OA

Question 215

What is the problem with biologic agents targeting things like IL-1?

Answer 215

• Potential problem is that you can’t give these systemically bc you need these biologic agents in other parts of the body to maintain homeostasis

Question 216

What does this image show?

Answer 216

• Natural history of OA: progressive cartilage loss, subchondral thickening, marginal osteophytes

Question 217

What is going on with this guy?

• 65-y/o man with left knee pain that began insidiously about 1 year ago -> no lab abnormalities
• Recalls having serious injury to left knee while playing football many years ago, stretching the ACL (pain and swelling for several weeks) à this is a serious injury
• Abnormally functioning knee over many years
• Image on the far right is getting close to needing a joint replacement

Answer 217

OA

Question 218

What are the radiologic features of OA?

Answer 218

• Joint space narrowing: medial aspect looks like bone on bone in attached image
• Marginal osteophytes
• Subchondral cysts
• Bony sclerosis: on the right in the attached image
• Malalignment

Question 219

What would the synovial fluid features be like in OA?

Answer 219

• Leukocyte count 200-2,000/mm3, 25% PMN’s (a little more leukocytes than normal, which would be around 60-180)
• Normal viscosity of synovial fluid -> hyaluronic acid content pretty well maintained (HA makes this fluid a little more viscous than your normal serum)

Question 220

What are the signs and symptoms of OA?

Answer 220

• Pain is related to use, and gets worse during the day (different than RA, where joints feel better when you move them around a bit)
  1. Bone rubbing on bone
• Minimal morning stiffness (<20 min) and after inactivity (gelling time) -> helps differentiate b/t OA and RA
• Range of motion decreases (restricted mvmt)
• Variable joint instability and swelling: not specific (also see this in RA)
• Bony enlargement due to sclerosis: very characteristic, and do NOT see this in RA or gout
• Crepitus: grinding like sandpaper

Question 221

What are the risk factors for OA?

Answer 221

• Age: 75% of persons over age 70 have OA
• Female sex
• Obesity
• Hereditary
• Trauma
• Neuromuscular dysfunction, i.e., diabetes: proprioception, loss of pain perception -> excessive forces generated in the joint
• Metabolic disorders

Question 222

What are the lab tests for OA?

Answer 222

• No specific tests or associated lab abnormalities
  1. ESR/C-reactive protein normal in OA pt, unless they have some other metabolic condition elevating these
• Investigational: cartilage degradation products in serum and joint fluid
  1. Joint sampling important to obtain if you suspect gout or another crystalline arthritis

Question 223

What is the distribution of primary OA?

Answer 223

• Primary OA typically involves variable number of joints in characteristic locations (shown in attached image)
• Exceptions may occur, but should trigger consideration of secondary causes of OA

Question 224

What is going on with this woman?

• 75-y/o woman with pain and stiffness in both knees, restricted ROM of both hips, and occasional back pain
• Heberden’s and Bouchard’s nodes
• Family history reveals mom had similar problems
• Lumbosacral is really involved

Answer 224

OA

Remember: don’t get back pain in RA, except in cervical spine -> first three vertebrae

Question 225

What disease are these images characteristic of?

Answer 225

OA: DIP and PIP involvement

Question 226

What do you see here?

Answer 226

• Radiograph showing severe changes in the carpometacarpal joint in OA
• Most common location in hand
• May cause significant loss of function

Question 227

What do you see here?

Answer 227

• X-ray showing osteophytes, subchondral sclerosis, and complete loss of joint space in the hip in OA
• Patients often present with deep groin pain that radiates into the medial thigh
• Very common, and these have to be replaced

Question 228

How can diabetic neuropathy complicate OA?

Answer 228

• Destructive changes on x-ray far in excess of those seen in primary OA
• MTPs 2 to 5 involved in addition to 1st bilaterally
• Midfoot involvement also common

Question 229

What are some of the underlying disease associations of OA and CPPD (pseudo-gout)?

Answer 229

• Hemochromatosis
• Hyperparathyroidism
• Hypothyroidism
• Hypophosphatasia
• Hypomagnesaemia
• Neuropathic joints
• Trauma
• Aging, hereditary
• Think about these when you have arthritis in the “wrong place”

Question 230

What are the keys to the management of OA?

Answer 230

• Establish the diagnosis of OA on the basis of history and physical and x-ray examinations
• Decrease pain to increase function
• Prescribe progressive exercise to INC endurance and strength
  1. Reduce fall risk by strengthening muscles
• Patient education: self-help course
• Weight loss
• Heat/cold modalities
• Acetaminophen

Question 231

What are the keys to pharmacologic mgmt of OA?

Answer 231

• Non-opioid analgesics
  1. Acetaminophen is first-line: pain relief comparable to NSAIDs, less toxicity (beware of toxicity from use of multiple acetaminophen-containing products)
  a. Max safe dose 4 g/d if no liver disease
• Topical agents
• Intra-articular agents, i.e., corticosteroids
• Opioid analgesics
• NSAIDs: like to try to stay away from these
• Unconventional therapies

Question 232

What are the possible intra-articular therapies in OA?

Answer 232

• Intra-articular steroids: good pain relief
  1. Most often used in knees, up to every 3 mo
  2. Frequent injections: risk of infection, worse diabetes, or CHF
• Hyaluronate injections: symptomatic relief
  1. Improved function, but no evidence of long-term benefit
  2. Expensive and require series of injections
  3. Limited to knees

Question 233

What are some possible sx therapies for OA?

Answer 233

• Arthroscopy: joint tx or exam (minimally invasive)
  1. May reveal unsuspected focal abnormalities
  2. Results in tidal lavage
  3. Expensive, complications possible
• Osteotomy: bone is cut to shorten, lengthen, or change its alignment
  1. May delay need for TKR for 2-3 years
• Total joint replacement: when pain severe and function significantly limited

Question 234

Management summary for OA: 1st, 2nd, and 3rd-line treatments?

Answer 234

• First: be sure pain is joint related (not a tendonitis or bursitis adjacent to joint)
• Initial treatment: muscle strengthening exercises and reconditioning walking program to reestablish muscle tone and prevent falls
  1. Weight loss
  2. Acetaminophen first
  3. Local heat/cold and topical agents
• Second-line approach: intra-articular agents (i.e., steroids or hyaluronic acid) or lavage
  1. NSAIDs, if acetaminophen fails
  2. Opioids
• Third-line:
  1. Arthroscopy
  2. Osteotomy
  3. Total joint replacement

Question 235

What are the pathologic features of OA?

Answer 235

• NO inflammation -> DEGENERATIVE (path report will say “degenerative changes,” not OA)
• Cytokine mediated: IL-1
• FIRST is disruption of the cartilage that lines the articular surface
• Then, eburnation or progressive thickening (of the bone trabeculae) at the areas of cartilage loss
• INC activity at perichondrium -> Heberden nodes
• Synovial membrane stays normal or thickens, with papillary metaplasia (cartilage, bone or fat)
  1. Detachment of these leads to -> fragments of cartilage can float in joint space: loose bodies
• Secondary changes can include cyst formation
• Not something that is typically biopsied for diagnosis, but people do have surgeries for this
• Has to do with CHONDROCYTES -> fissuring and clusters to try and “fix” the problem; doesn’t work

Question 236

What is the difference b/t these 2 images?

Answer 236

• Normal bone/cartilage on the left
• Early osteoarthritis (of hip) on the right, showing fibrillation of articular cartilage and colonies (“clones”) of regenerating cartilage cells
• This is one of the first signs you will see with degenerative changes

Question 237

What types of bone changes might you see with OA?

Answer 237

• Highly polished (“eburnated”) appearance of exposed subchondral bone in advanced osteoarthritis of knee (see attached images)
• Normal bone is rough-feeling, but the bone in OA looks freshly “polished” due to eburnation

Question 238

What do you see here?

Answer 238

• Fibrous-lined “cysts” under exposed subchondral bone in advanced osteoarthritis (of hip)
• Cartilage is basically gone here -> this is really advanced

Question 239

What is this?

Answer 239

• Osteophyte (“spur”) formation in osteoarthritis (of interphalangeal joint)
• Joint surface on top, and marrow space beneath it
• Growth still looks kind of degenerative (atypical growth pattern) -> cysts and fissures
• These are going to occur in the later stages

Question 240

Know this.

Answer 240

Good job!

Question 241

What are some things you might see in the histo of advanced OA?

Answer 241

• See attached image
• Subchondral bone exposed, and becoming much thicker than normal
• Residual cartilage with thickening; fissuring, pitting, flaking
• Cyst formation
• Really advanced

Question 242

How are DM and PM systemic diseases? Describe the key organ systems involved.

Answer 242

• Symmetric upper and lower extremity prox muscle weakening can include neck and abdominal mm and upper 1/3 of esophagus and diaphragm and thoracic muscles; striated muscles can be involved, like lower esophagus (reflux) or sphincter ani (incontinence)
• DM: skin involved with different patterns
• Arthritis common, esp. pts w/anti-Jo-1 Ab’s (against histidyl-tRNA synthetase) & o/antisynthetase autoAb’s
• Heart can be involved: conduction abnormalities and arrhythmias, myocarditis and CAD, and involvement of small vessels of the myocardium
• Lungs frequently involved in PM and DM and pose a major risk factor for morbidity and mortality; ILD may be present in up to 70% to varying degrees
• GI tract involvement incl weakness of the tongue, pharyngeal mm and sometimes lower esophagus, and constipation, diarrhea, and stomach pain secondary to disturbed motility; vasculitis in blood vessels of GI is rare but may be complicated by intestinal bleeding

Question 243

What are 4 types of inflammatory myopathies (not incl. DM and PM)?

Answer 243

• Antisynthetase syndrome
• Amyopathic dermatomyositis
• Juvenile dermatomyositis
• Inclusion body myositis

Question 244

What is antisynthetase syndrome?

Answer 244

• 20% of pts w/PM or DM have Jo-1 (antihistidyl tRNA sythetase antibody)
• Clinical features include:
  1. Myositis
  2. Non-erosive symmetric polyarthritis of small joints
  3. “Mechanic’s hands:” roughening and cracking of the skin of the tips and sides of the fingers, resulting in irregular, dirty-appearing lines that resemble those of a manual laborer (see attached image)

Question 245

What is amyopathic dermatomyositis?

Answer 245

• Patients have DM-type rash confirmed by skin biopsy
• No myositis, but may develop myositis late
• At risk for severe ILD and can be associated with misdiagnosis

Question 246

What is juvenile dermatomyositis?

Answer 246

• Incidence of 1.7 to 3 per 1 million children
• Peak onset at age 6 and 11 years with features commonly seen in adult DM
• 30% to 70% have calcinosis, cutaneous ulceration and lipodystrophy

Question 247

What is inclusion body myositis?

Answer 247

• Sporadic and familial hereditary forms
• Characteristic histo features incl: sarcoplasmic and nuclear inclusions and rimmed vacuoles
• Insidious onset of proximal muscle weakness over months to years localized predominantly to the thigh muscle (lower extremities) and finger flexors (distal muscle supplying upper extremities)
• Poor response to glucocorticoid treatment (resistance)
• Mostly in men over 50 yrs (older men)

Question 248

What do you see in these images?

Answer 248

• Dermatomyositis
• A: Gottron’s papules
• B: Heliotrope rash
• C and D: Gottron’s sign on knees and elbows

Question 249

What 2 conditions are shown here?

Answer 249

• Erythematous hand rashes -> dermatomyositis v. SLE:

A: note the changes on the knuckles and dorsum of the hand in dermatomyositis (Gottron’s sign)

B: rash is absent on the knuckles but present on the phalanges in lupus

C: capillary nail-fold changes in dermatomyositis

Question 250

What do you see here?

Answer 250

• Characteristic dermatomyositis skin changes:

A: linear erythema

B: scalp rash

C: V-like sign

D: shawl sign

Question 251

What are some characteristic skin changes in dermatomyositis?

Answer 251

• Gottron’s papules on knuckles (sign on knees, elbows)
• Heliotrope rash on pt eyelids
• Linear erythema
• Scalp rash
• V-like sign
• Shawl sign (see attached image for last 4)

Question 252

What is going on with these manos?

Answer 252

• Mechanic’s hands in a white (A) and a black (B) patient
• Note the characteristic skin changes on the lateral side of the fingers
• Seen in antisynthetase syndrome: myositis, non-erosive symmetric polyarthritis of sm joints, and mechanic’s hands

Question 253

What is the epi of inflammatory myopathies?

Answer 253

• Annual incidence of DM + PM + IBM est. at 10 per million individuals -> varies w/ethnicity, age, gender
  1. PM/DM more common in F, > 2:1 ratio
• Disease onset:
  1. PM: usually late teens or older (mean, 50-60)
  2. DM: peaks-5 to 15 years and 45-65 years
  3. IBM: > 50 years, and rare in younger adults
• 11-40% can occur w/other autoimmune CT disease like SSc, SLE, RA, SS, polyarteritis nodosa, sarcoidosis.
• 12% assoc w/malignancy (breast, adenocarcinoma) and detected in the first year of diagnosis of myositis; majority DM (81%), PM is 19%

Question 254

How is the humoral immune response involved in inflammatory myopathies (hint: think auto-Ab’s)?

Answer 254

• >50% have uniquely defined auto-Ab’s against Ag’s of protein syn pathway (aminoacyl-tRNA synthases & signal recognition particles) and nuclear components (nuclear helicase [Mi2] )
• Often associated with distinct clinical disease groups and subgroups:
  1. tRNA synthetases with interstitial lung disease
  2. Mi-2 with DM with Gottron’s papules, V sign, heliotrope rash, and the shawl sign

Question 255

What HLA’s are associated with the myositis-specific antibodies?

Answer 255

• Some of the myositis specific antibodies show strong immunogenetic association:
  1. Aminoacyl-tRNA synthetases:HLA-DQA1*0501
  2. Anti-PM-Scl: DR3
  3. Anti-SRP: DR5
  4. Anti-Mi-2: DR7

Question 256

Which myositic associated Ab is frequently associated w/a characteristic overlap syndrome?

Answer 256

• PM-Scl is frequently associated with a characteristic overlap syndrome that includes features of scleroderma:
  1. Mild muscle disease, prominent arthritis and limited skin sclerosis that frequently responds to therapy

Question 257

How is the cell-mediated immune response involved in the different inflammatory myopathies?

Answer 257

• Distinct features in different myositis types:
  1. DM: predominantly perivascular infiltrates, often in perimysium -> CD+4 T cells, macros, and dendritic cells with associated B cells
  2. PM or IBM: mostly CD8+ T cells and macros surround predominantly endomysium w/mono-nuclear inflammatory cells often surrounding, and sometimes invading non-necrotic muscle fibers
  a. CD8+ recognize MHC class I mm fibers and may mediate muscle fiber damage
  b. Evidence of clonal proliferation of CD8+ T cells in muscle and peripheral circulation
  c. See attached image

Question 258

What are the key points for the inflammatory myopathies?

Answer 258

• Heterogeneous gp of mm diseases characterized by symmetric proximal muscle weakness and frequent involvement of other organs
• Often accompanied by elevated levels of serum muscle enzymes and abnormal electromyograms
• Histology shows varying degrees of inflammation and muscle fiber degeneration and regeneration
• Some pts have autoantibodies that bind molecules involved in protein synthesis, and these antibodies are often associated with distinct clinical phenotypes
• Corticosteroids and cytotoxic drugs are common therapies

Question 259

What is the yield of temporal artery biopsy in patients with pure PMR?

Answer 259

• LOW: positive in only 4% of patients in one study
• Patients who are under age 70, have no headache or jaw claudification, and have clinically normal temporal arteries have a very low risk of vasculitis

Question 260

Describe the relationship between PMR and GCA.

Answer 260

• Polymyalgia rheumatica occurs in about 50 percent of patients with GCA
• Approximately 15 percent of patients with PMR as the primary diagnosis develop GCA

Question 261

What is PMR?

Answer 261

• Polymyalgia rheumatica: clinical syndrome (not a vasculitis) in pts > 50, characterized by AM stiffness and pain in shoulder and hip musculature
  1. Limited active motion, NOT passive
• Often profound difuse atrophy of mm and weakness, leading to suspicion of polymyositis; ESR often elevated
• Inflammation of extra-articular synovial structures, like the tendon sheaths in the hands and feet
  1. Shoulder: subacromial bursitis
• Tenosynovitis (tendon inflam/swelling) may cause carpal tunnel syndrome in 10-14% of these patients
  1. Subset of pts get swelling, pitting edema of hands, wrists, ankles, and top of the feet -> can be presenting symptom; appears to represent tenosynovitis and synovitis in regional structures
• May occur in association with temporal arteritis, and portion of patient with PMR develop temporal arteritis
• Typically, does NOT evolve into RA

Question 262

What is giant cell (temporal) arteritis?

Answer 262

• Necrotizing inflam of lg-sized arteries originating from arch of the aorta:
  1. Associated with granulomas
  2. NOT associated with a glomerulonephritis

Question 263

What is the proposed model for the pathogenesis of giant cell arteritis (image)?

Answer 263

• Key points:
  1. Antigen recognition in adventitia -> IFN-gamma
  2. Giant cell formation
  a. Arterial wall destruction
  b. Occlusive intimal hyperplasia

Question 264

What are the clinical manifestations of temporal arteritis?

Answer 264

• Systemic symptoms: fever, weight loss, fatigue
• Temporal headaches
• Visual disturbances (amaurosis): can progress to double vision and even sudden blindness
• Jaw or tongue claudication
• Arthralgias
• Physical examination may reveal tender, swollen, temporal artery

Question 265

What are some of the potential complications in giant cell arteritis?

Answer 265

• 10% of pts have upper respiratory symptoms, incl. cough (usually nonproductive) and sore throat (may be very severe)
  1. Repeatedly (-) throat cultures and absence of parenchymal infiltrate on chest radiograph are consistent with this diagnosis
• Development of thoracic aortic aneurysms (TAA) is a potentially serious complication that warrants ongoing monitoring; can be caused by:
  1. Chronic or late recrudescent aortitis causing elastin and collagen disruption
  2. Mechanical stress on aortic wall weakened in early active phase of the disease
  3. Yearly CXR recommended for up to 10 years by some bc can be detected as mediastinal widening (prior to rupture)
• INC hepatic enzymes (AST, alkaline phosphatase) in 25-35% of pts -> revert to normal w/glucocorticoid tx; liver biopsy shows nonspecific changes

Question 266

What is the ESR?

Answer 266

• Simple and inexpensive test that measures rate at which RBC fall through plasma (in 1 hr)
• Distance between the top of the plasma level and the top of the sedimented RBC is the ESR
• Indirect measure of fibrinogen levels
• Influenced by RBC properties

Question 267

What is the CRP?

Answer 267

• A direct measure of the amount of CRP in the blood
• More sensitive than the ESR
• Wider range

Question 268

Is CRP or ESR more sensitive?

Answer 268

CRP

Question 269

What are the labs and pathology in temporal arteritis?

Answer 269

• Labs: anemia, thrombocytosis, markedly INC ESR
  1. Diagnosis is by temporal artery biopsy
• Pathology: lymphocytes early in disease in region of internal or external elastic membrane or adventitia
  1. Later there is necrosis of portions of arterial wall, granuloma formation w/multinucleated giant cells, histocytes, plasma cells and fibroblasts
  2. Thrombosis may occur
  3. Inflammation most marked near elastic mem, which is typically destroyed or interrupted

Question 270

What is the algorithm for treating PMR w/o GCA (image)?

Answer 270

Question 271

What is the treatment for temporal arteritis?

Answer 271

• Corticosteroids in high doses (1mg/kg/day of prednisone or equivalent)
  1. Critical to begin treatment with steroids as soon as diagnosis is suspected, or pt may go blind permanently
  2. Treat and make arrangements for the temporal artery biopsy, but do not wait for biopsy to be done or results returned before starting tx
• Prognosis is good with treatment, but blindness is irreversible

Question 272

What do you see here?

Answer 272

• Inclusion body myositis
• Trichrome stain: red-rimmed inclusions and marked variation in muscle fiber size
• H and E: marked variation in muscle fiber size

Question 273

What do you see here (hint: what is the arrow pointing at)?

Answer 273

• Micro appearance of dermatomyositis
• Muscles show myositis with myofiber necrosis, fragmentation and phagocytosis
• Late: myofiber atrophy, fibrosis and fatty change
• Left image: perifascicular atrophy and perimysial inflammation
• Right image: perivascular mononuclear cells -> vasculitis

Question 274

What is going on here?

Answer 274

• Lymphocytes invadin a myofiber in polymyositis
• Biopsy findings can be variable, but chronic inflam and muscle degeneration, regeneration are typical
• Definite diagnosis made by m. biopsy recommended before treatment to exclude other muscle disorders

Question 275

What is the difference b/t these 2 images? What is the arrow pointing at?

Answer 275

• Normal muscle vs. muscle in x-linked muscular dystrophy
  1. Arrow is pointing at adipose tissue
• Degenerative disorder characterized by muscle wasting and replacement of skeletal muscle by fat
• Defect in Dystrophin gene: longest human gene, so subject to mutation
  1. Duchenne MD is a deletion of dystrophin
  2. Becker MD dystrophin is just mutated, so milder disease

Question 276

What are 3 key features of PMR?

Answer 276

• Half of patients with temporal (giant cell) arteritis also have polymyalgia rheumatica = syndrome of:
  1. Proximal muscle aches and stiffness
  2. Elevated ESR
  3. Rapid resolution of symptoms with low-dose corticosteroid therapy

Question 277

What pathologic process is going on here?

Answer 277

• Micro appearance of temporal arteritis:
  1. Inflammation of vessel wall
  2. Disruption of internal elastic lamina
  3. Intimal fibrosis
• Granulomatous vasculitis that involves branches of the carotid
• Older (>50), white females
• Headache, visual changes, jaw claudication and ESR often elevated
• Suggestion that this is T-cell mediated
• Treatment: steroids (want to avoid the dreaded complication of blindness)

Question 278

How can moonshine give you gout?

Answer 278

• INC risk of getting saturnine gout via chronic lead nephropathy
• Kidney atrophy, ischemic changes of glomeruli, fibrosis of the adventitia of small renal arteries
• Can lead to hyperuricemia
• Radiators with lead soder used to make the moonshine sometimes

Question 279

What is gout?

Answer 279

• Arthritis via monosodium urate (MSU) crystals after many yrs of hyperuricemia (plasma level >7.0.g/dL)
• INC total body urate: INC production or DEC excretion, or combo of the two
• Begins as acute monoarticular arthritis, most often 1st MTP distal lower extremity (severe pain 5-7 days)
  1. Podagra
• Can get tophi (lg deposits of MSU) over extensor surface of upper/lower extremity joints
• Can also deposit in interstitium of kidney and cause renal func impairment or urolithiasis
• May also become polyarticular in later stages and be confused with rheumatoid arthritis

Question 280

Excretion vs. clearance in gout

Answer 280

• Underexcreters actually have a normal rate of UA excretion bc this is required to maintain steady state in which production and clearance are about equal
• Reduced efficiency of urate excretion (decreased clearance) obligates a higher serum urate concentration to achieve the necessary rate of UA excretion

Question 281

Why is the lower extremity more predisposed to attacks in gout?

Answer 281

• Less blood supply to lower extremity at night
• Pt gets a little acidotic, making it more possible for urate crystals to solidify in the low pH environment
• Cooler, making urate less soluble
• Many exacerbations are early in the AM -> patients wakened from sleep by this

Question 282

How may gout look like RA? Different?

Answer 282

• Tend to get tophi over the elbows, which look like rheumatoid nodules, in some cases, so this can be confused for RA by some clinicians
• May have (+) RF due to age, and because it occurs in normal people
• Not going to be completely symmetrical, unlike RA (on x-ray)

Question 283

What are the 2 primary mechanisms of gout?

Answer 283

• DEC efficiency of UA excretion: 85-90% of 1^o or 2^o hyperuricemia
• Overproduction of UA: 10-15%
  1. Typically due to inherited defects in regulation of purine nucleotide synthesis, disordered ATP metabolism, or disorders resulting in INC rates of cell turnover
  2. 4 known inborn errors of purine metabolism with overproduction of urate account for less than 1% of cases of 2^o hyperuricemia and gout

Question 284

How does total body urate vary by sex?

Answer 284

• Normal adult male has a pool of approx 1200 mg, 2x that of the adult female
• May be explained by enhancement of renal urate excretion due to effects of estrogenic compounds in premenopausal women

Question 285

How is the intestine involved in UA degradation?

Answer 285

• Entry of urate into intestine a passive process that varies w/serum urate concentration
• GI tract bacteria able to degrade uric acid (intestinal uricolysis) -> 1/3rd of total urate metabolism (and nearly all urate disposed of extra-renally)
• Under normal conditions, UA almost completely degraded by colonic bacteria, with little being found in the stool

Question 286

How is uric acid generated in humans?

Answer 286

• Purine catabolism, esp. inosine monophosphate and guanosine monophosphate results in urate synthesis via the common substrate xanthine
• Xanthine oxidase is necessary for urate synthesis from any purine and is the target for agents that inhibit uric acid synthesis (Allopurinol, Febuxostat)
• Purine salvage via hypoxanthine guanine phosphoribosyl transferase (HGPRT) returns hypoxanthine and guanine to IMP and GMP
  1. HGPRT deficiencies INC hypoxanthine and guanine and subsequent uric acid synthesis but also deplete nucleotides that provide feedback inhibition on purine biosynthesis
• NOTE: most mammals have uricase -> converts uric acid to allantoic acid (Pegloticase)

Question 287

How is UA handled by the kidney?

Answer 287

• Freely filtered (100%) at the glomerulus into prox tubules, and completely reabsorbed (98-100%)
• 50% of reabsorbed urate is secreted back into prox tubules, where it is largely reabsorbed
  1. In the end, 8-12% of urate originally filtered by glomeruli excreted into the urine as UA
• Multiple transporters involved (URAT, OAT)
• Small amount of urate is protein-bound

Question 288

Answer 288

A: primary hyperuricemia in men usually begins at puberty

Question 289

What is a “normal” serum urate level? What happens if you exceed this?

Answer 289

• Balance b/t UA production/excretion determines serum urate level -> most ppl b/t 4 and 6.8 mg/dL
• Ppl w/high serum levels may deposit urate occultly or as tophi, so total body urate pool may be much higher than in non-hyperuremics
• Occult deposition of UA (total body urate burden) may have implications for treatment because they may form a “buffering reservoir” of urate that that resists initial treatment with urate-lowering agents

Question 290

Describe the sex differences in hyperuricemia. How do these affect incidence?

Answer 290

• 1^o hyper-U in M at puberty bc change from child to adult levels
• M values exceed F of reproductive age due to enhancing effect of estrogenic compounds on renal urate clearance
• Hyper-U in F delayed until after menopause, when their levels approx those of M of same age (lesser rise if treated w/estrogen replacement therapy)
• Highest incidence of gout b/t 30-45 for M and 55-70 for F -> clinical manifestations about 2 decades later than initial physiologic INC in serum urate
  1. Lengthy period of asymptomatic hyper-U preceding gout in both M and F

Question 291

Why does gout have a latency period?

Answer 291

• Takes a long time for high serum urate in EC space outside vessels to get into synovium, cartilage, and subcutaneous tissues
• Take 2-3 decades for it to get deposited there
• Example: won’t see gout in acute renal failure even though UA levels will be really high (not enough time to surpass the asymptomatic, latency period)

Question 292

How does a gout attack develop?

Answer 292

• “Fresh” urate crystals from either spontaneous precipitation or liberation from established pools activates complement and resident synovial inflam cells (macros, fibros, masts)
• IL-1β + o/cytokines/mediators activate bloodstream polys and endo cells -> permits neutros to adhere to and traverse the endo, influxing and propagating inflammation (direct activation by urate crystals)
• Colchicine is only going to work in the first few days of the attack because it prevents migration of polys from the blood into the tissue/synovium

Question 293

How is the gout attack propagated?

Answer 293

• Neutrophils that enter joint migrate toward and phago crystals
• Crystals coated with Ig’s/complement activate syn and release of inflam mediators like IL-1B, IL-8, TNF, proteases, and ROS
• Crystals can lyse membrane of phagolysosome, spilling toxic contents and leading to cell lysis
• Result of both of these is LOCAL TISSUE DAMAGE and recruitment of ADD’L POLYS from bloodstream

Question 294

How is gout diagnosed?

Answer 294

• Presence of urate crystals in the joint, or a tophus
• Or 6 of the following:
  1. >1 attack of arthritis
  2. Max inflam w/in 1 day
  3. Attack of monoarticular arthritis
  4. Joint redness
  5. First MTP painful or swollen
  6. Unilateral attack of first MTP joint
  7. Unilateral attack of tarsal joint
  8. Suspected tophus
  9. Hyperuricemia
  10. Asymmetric swelling of joint (radiograph)
  11. Subcortical cysts w/o erosions (radiograph)
  12. (-) culture of joint for microorgs during attack of joint inflammation

Question 295

What is this?

Answer 295

• Tophus of the fifth digit, with a smaller tophus over the fourth proximal interphalangeal joint

Question 296

What is this?

Answer 296

• Tophus of the helix of the ear adjacent to the auricular tubercle

Question 297

What do you see here?

Answer 297

• Tophi of Achilles tendons and their insertions in a patient with gout

Question 298

What is this?

Answer 298

• Saccular tophaceous enlargements of oclecranon bursae, with small cutaneous deposits of urate
• Tophi may drain a white, chalky material

Question 299

What do you see here?

Answer 299

• Radiographs demonstrating severe, destructive, cystic changes in tophaceous gout

Question 300

What is this?

Answer 300

• Radiographs showing changes typical of bony tophi, incl soft tissue distortion, erosions w/sclerotic margins, and overhanging edges
• Joint space narrowing is minimal, despite the large erosions
• Over-hanging, hooked edges very characteristic of gout -> only kind of arthritis that really causes this

Question 301

What is this?

Answer 301

• Right foot radiograph of tophaceous gout
• Note the soft tissue distortion, erosions, and over-hanging bone

Question 302

What is Lesch-Nyhan?

Answer 302

• Inherited deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), produced by mutations on the X chromosomere
• Over-production of UA, INC purine biosynthesis
• Disposition for self-mutilation (bite themselves); usually don’t live long enough to actually get gout
• X-linked, recessive inheritance
• Note: also G6PD and fructose-1-phosphate aldolase def (overproduce + underexcrete; auto rec)

Question 303

What are some conditions that can predispose you to hyperuricemia?

Answer 303

• Overproduction: hemolytic anemia, sickle cell, PV, thalassemia, leukemia/lymphoma, MM, solid tumors, psoriasis, sarcoidosis, tumor lysis syndrome, mito or metabolic myopathies
• Underexcretion: renal insufficiency, dehydration, lactic acidoses, ketoacidosis
• Overprod/underexc: MI, CHF, sepsis
• Metabolic states: hyper or hypothyroid, hyper or hypoPTH, obesity

Question 304

What drugs promote hyperuricemia?

Answer 304

• Diuretics: thiazides, loops
• Organic acids: salicylates (low-dose), nicotinic acid, pyrazinamide
• Other: cyclosporine, ethambutol, ethanol, colony-stimulating factors

Question 305

How common are UA stones in gout pts? What are the 3 primary risk factors?

Answer 305

• Morbidity! 5-10% of all urinary tract stones in US; 40% or more of stones in areas w/hot, arid climates (with tendency for low urine vol and acidic urine pH)
• >80% of calculi in pts w/gout all UA, w/remainder containing calcium oxalate or calcium phosphate surrounding a central nidus of uric acid
• There are three major risk factors:
  1. INC UA excretion
  2. Reduced urine volume
  3. Low urine pH (most of UA exists as the intact insoluble acid, and not the soluble urate anion)

Question 306

Prior to effective anti-hyperuricemic tx, what % of gout patients had stones?

Answer 306

About 20% (several hundred-fold more than those in the non-gouty population)

Question 307

What are the tx options for gout (flow chart)?

Answer 307

• Some inflammation inhibitors may also be used for prophylaxis when initiating urate lowering therapy

Question 308

What are the indications for an XO inhibitor?

Answer 308

• XO INH: Allopurinol, Febuxostat
• Indications:
  1. Hyper-U w/INC UA production
  a. HPRT def or PRPP synthetase muts
  b. UA nephropathy or nephrolithiasis
  c. Prophylaxis before cytolitic therapy
  d. Urinary UA excretion >1000mg in 24 hr
  2. Intolerance or DEC efficacy of uricosurics
  a. Gout w/renal insufficiency (GFR<60)
  b. Allergy to uricosurics (e.g., Probenecid)

Question 309

What are some common drugs that are uricosuric in humans?

Answer 309

• Probenecid
• Estrogen
• Calcium ipodate
• Glycopyrrolate
• Iopanoic acid
• Lasartan
• Salicylates

Question 310

How can you treat acute gout?

Answer 310

• NSAIDs
• Colchicine
• Corticosteroids
• Adrenocorticotropic hormone
• The effectiveness of tx depends more on how quickly the therapy is initiated than which agent is used

Question 311

What should you give a pt before starting a specific urate-lowering agent?

Answer 311

• Before starting a specific urate-lowering agent, the patient should be treated with low-dose colchicine or an NSAID
• This is an attempt to prevent further attacks

Question 312

What should be the goal serum urate level? Dosing?

Answer 312

• Regardless of whether a xanthine oxidase inhibitor, a uricosuric agent, or a uricase is used to treat hyperuricemia, the patient should receive the lowest dose that maintains the serum urate level below 6.8 mg/dL—preferably below 6 mg/dL
• In addition to allopurinol, febuxostat and pegloticase are now available as urate-lowering agents for the treatment of gout

Question 313

What should hyperuricemic people be screened for?

Answer 313

• Hypertension
• Coronary artery disease
• Diabetes
• Obesity
• Alcoholism

Question 314

Should you give a urate-lowering agent to an asymptomatic hyper-U patient?

Answer 314

• NO -> using a specific urate-lowering agent to manage asymptomatic hyperuricemia is not recommended
  1. Usually wait until you get the first attack
• However, assoc conditions like HTN, CAD, diabetes, obesity, and alcoholism should be managed in these patients, as well as in those with symptomatic gout

Question 315

At what plasma level do you start getting saturated UA?

Answer 315

6.4 is where you start getting saturated levels of UA in plasma

Question 316

How does diet impact gout?

Answer 316

• Alcohol consumption, particularly beer
• Diet -> certain foods promote hyperuricemia and gout including alcohol, seafood, and red meat
• Consumption of some foods may be protective, especially milk and yogurt
  1. Red wine supposed to help too

Question 317

How is genetics implicated in gout?

Answer 317

• Rare forms of early hyperuricemia and gout have a clear genetic and metabolic basis (e.g., HGPRT)
• Gout often runs in families, probs due to inherited factors affecting serum urate levels via renal urate clearance
• Recent genome-wide assoc studies have ID’d polymorphisms in several candidate genes encoding urate transporters in renal prox tubules as determinants of serum urate levels and risk of gout
• Can get interstitial nephritis with long-standing gout, especially if there are tophi

Question 318

What are some conditions associated with gout?

Answer 318

• Obesity, hyper-TG, glucose intolerance/metabolic syndrome, HTN, atherosclerosis, hypothyroidism
• Renal insufficiency
• Alcohol use, lead intoxication, cyclosporine tx
• Hyper-U is a common caus of nephrolithiasis, and rarely, chronic hyper-U causes urate nephropathy
• Acute hyperuricemia may lead to uric acid nephropathy in the tumor lysis syndrome
• A diagnosis of gout should prompt a search for the coexistence of these associated conditions

Question 319

What should be in your differential for gout?

Answer 319

• Acute gouty arthritis (look for CRYSTALS):
  1. CPPD, basic calcium phosphate
  2. Septic or reactive arthritis
  3. Trauma
  4. Cellulitis
  5. Lyme arthritis
  6. Psoriatic arthritis
  7. Sarcoidosis
• Chronic gouty arthritis
  1. RA, or other chronic arthritides
  2. Lyme disease
  3. Indolent infections, like mycobacterial

Question 320

Will a gouty joint be warm?

Answer 320

• YES, can actually be very warm because very inflammatory

Question 321

What is the next step when you encounter asymptomatic hyperuricemia in a pt?

Answer 321

• Asymptomatic hyperuricemia is generally not treated
• But, its identification should lead to a search for the cause and/or associated conditions (like HTN or coronary artery disease)

Question 322

How can you treat episodes of acute gouty arthritis? Prophylaxis?

Answer 322

• Episodes of acute gouty arthritis can be treated with:
  1. Colchicine
  2. NSAIDs
  3. Adrenocorticotropic hormone, and
  4. Systemic or intra-articular steroids
• Prophylaxis against acute attacks with colchicine or NSAIDs can be effective, but does not change the underlying process w/o concomitant urate-lowering therapy

Question 323

When should you start a patient on urate-lowering therapy? Name some tx options.

Answer 323

• Starting urate-lowering therapy after a single attack of gout remains debatable, but accepted indications include:
  1. Recurrent attacks of gout
  2. Urate nephrolithiasis
  3. Tophaceous gout, and/or
  4. Evidence of gout-induced joint damage
• XO INH (Allopuroinol, Febuxostat) and uricosurics (Probencid) are effective at lowering serum urate levels in most patients
  1. Uricases such as pegloticase should be reserved for refractory tophaceous gout
• Serum urate of < 6 mg/dL should be targeted

Question 324

After starting urate-lowering therapy, should you continue prophylaxis?

Answer 324

• Prophylaxis with colchicine, NSAIDs, or less preferably, systemic steroids should be continued for at least 6 months after initiation of urate-lowering therapy

Question 325

How is long-term compliance in gout?

Answer 325

• Long-term compliance with the treatment regimen remains a major issue in gout
• Forming a therapeutic alliance with the patient is critical

Question 326

Can lifestyle modifications affect gout?

Answer 326

• Lifestyle modifications may help somewhat in the control of gout, especially reduced alcohol consumption
• These are more important for the management of associated conditions like obesity and hyperlipidemia

Question 327

What is CPPD crystal deposition disease?

Answer 327

• Calcium pyrophosphate dihydrate (CPPD) crystals can cause a spectrum of conditions: asympomatic deposits in cartilage (chondrocalcinosis), synovium, periarticular ligaments, tendons (mostly elderly) to clinical arthritis that can mimic other arthritides
• CPPD deposition has unknown cause
• Aka, pseudogout; low-grade inflam sometimes confused w/OA
• Metabolic abnormalities or hereditary disease in a minority of pts, incl: hyperPTH, hemochromatosis, gout, hypophosphatasia, hypo-Mg, or ochronosis (syndrome caused by accumulation of homogentisic acid in CT -> degradative pathway of tyrosine)

Question 328

What is the epi of pseudogout?

Answer 328

• INC prevalence w/each decade of life, even into age groups over 50
• Average age of pts usually 70-75 y/o
• Radiographic chondrocalcinosis shows an INC prevalence related to age, w/prevalence of approx 50% in pts over 85 y/o

Question 329

What factor is most likely to be associated with devo of CPPD arthritis?

Answer 329

Age

Question 330

What do CPPD crystals look like?

Answer 330

• Weakly positive birefringent: blue when parallel, and yellow when perpendicular
• Rhomboid-shaped

Question 331

What conditions are associated with CPPD?

Answer 331

• Well-defined associations:
  1. Hyperparathyroidism
  2. Hemochromatosis
  3. Chronic hypomagnesemia
  4. Hypophosphatasia
• Some association with a history of trauma, or in familial aggregates
• Associations w/gout, hypothyroidism, diabetes have not been substantiated
• No known assoc w/renal disease or diuretic use

Question 332

What are some of the “causes” of CPPD?

Answer 332

• High prev: IDIOPATHIC (assoc w/aging), cx of 1^o OA, long-term consequence of mech joint trauma
• Mod prev: familial, assoc w/systemic metabolic disease (the H’s)
• Low prev (case reports): ochronosis, gout, articular amyloidosis, x-linked hypophosphatemic ricket’s

Question 333

What things can CPPD mimic?

Answer 333

• Asymptomatic, incidental finding (asymptomatic knee fibrocartilage chondrocalcinosis in the elderly)
• Recurrent acute inflam monoarticular arthritis (e.g., wrist, knee, incl provocation by trauma, concurrent med or surgical illness, or intra-articular hyaluronan)
• Pseudoseptic arthritis
• Recurrent acute hemarthrosis
• Chronic degenerative arthritis (pseudo-osteoarthritis or pseudo-neuropathic arthritis)
• Chronic symmetric inflammatory polyarthritis (pseudorheumatoid arthritis)
• Systemic illness (pseudo-polymyalgia rheumatica, fever of unknown origin)
• Destructive arthritis in dialysis-dependent renal failure
• Carpal tunnel syndrome
• Tumoral and pseudotophaceous CPPD crystal deposits
• CNS disease complicating ligamentum flavum or transverse ligament of atlas involvement (cervical canal stenosis, cervical myelopathy, meningismus, foramen magnum syndrome, odontoid fracture)

Question 334

84-y/o F w/hx of past R carpal tunnel syndrome and chronic symmetric proliferative synovitis of both wrists and 2nd, 3rd MCP joints, w/physical findings of synovial and dorsal extensor tenosynovial swelling of the wrists and synovial swelling at the second to third MCP joints. See attached image.

What does she have?

Answer 334

• Idiopathic symmetric pseudorheumatoid CPPD deposition arthropathy in an elderly female
• Changes on hand, wrist plain radiographs consistent with diagnosis of CPPD
  1. Cystic changes in multiple carpal bones, incl the scaphoid and lunate
  2. Linear calcification on ulnar side of carpus (arrow) typical for chondrocalcinosis of CPPD
  3. Mild narrowing of radiocarpal joint indicative of cartilage loss
  5. Ulnar styloid also intact, but would probably be eroded in RA

Question 335

What do you see here?

Answer 335

• CPPD
• Chondrocalcinosis most commonly affected joints:

A: linear calcifications in knee menisci and fibrocartilage

B: calcification of articular cartilage as a line parallel to the femoral condyles (lateral view)

C: calcification of intercarpal joints and triangular ligament

D: symphysis pubis fibrocartilage calcification associated with subchondral bone erosions and subchondral increased bone density

Question 336

How is genetics implicated in CPPD?

Answer 336

• Vast majority of CPPD crystal deposition disease is idiopathic/sporadic, but early-onset familial disease also occurs
• Linkage of familial CPPD crystal deposition disease to the gene ANKH on chromosome 5p (which encodes a transmembrane protein with functions including PPi transport) is well established

Question 337

What is the pathogenesis of CPPD?

Answer 337

• Loose avascular CT matrices of articular hyaline cartilage, fibrocartilaginous menisci, and of certain ligaments and tendons are particularly susceptible to pathologic calcification
• Joint cartilage pathologic calcification reflects complex interplay between organic and inorganic biochemistry of Pi and PPi metabolism, aging, dysregulated chondrocyte growth factor responsiveness and differentiation, and other factors

Question 338

What are the clinical features of CPPD?

Answer 338

• In elderly, CPPD deposition can mimic gout, infectious arthritis, 1^o OA, RA, or PMR -> can also present as fever of unknown origin
• Major cause of acute mono- or oligoarticular arthritis in the elderly; attacks typically involve large joint, most often knee, and less often wrist or ankle; unlike gout, rarely the first MTP joint
• Chronic degenerative arthropathy in CPPD deposition disease commonly affects certain joints that are typically spared in primary OA (e.g., MCP joints, wrists, elbows, glenohumeral joints)

Question 339

What is calcium hydroxyapatite deposition disease?

Answer 339

• HA is 1^o mineral of bone and teeth; abnormal accumulations can occur in areas of tissue damage (dystrophic calcification) and other conditions
• Chronic renal failure: hypophosphatemia enhances HA deposition both in and around joints
• HA may be released from exposed bone and cause acute synovitis occasionally seen in chronic stable OA -> this is an extremely destructive chronic arthropathy of the elderly that occurs most often in knees and shoulders (Milwaukee shoulder)
• Joint destruction is associated with attenuation or rupture of supporting structures, leading to instability and deformity -> progression is usually indolent, with low WBC counts (<1000 cells/μl) in synovium fluid and symptoms can range from minimal to severe pain and disability with need for joint replacement surgery

Question 340

What are these?

Answer 340

• Cholesterol crystals in a synovial fluid sample: may be seen in RA

Question 341

What are these 2 types of crystals?

Answer 341

• Urate on the left
• CPPD on the right

Question 342

What disease process do these images how? Describe each one.

Answer 342

• CPPD crystal deposition arthropathy of knee joint
• A: femoral condyle with extensive foci of chalky, white particulate deposits in the articular cartilage
• B: hypertrophic chondrocytes adjacent to crystal aggregates in in enlarged chondrons -> can’t really see the crystals, but see the amorphous areas where they were
• C: polarized light microscopy of CPPD crystal aggregates in hyaline articular cartilage -> crystals have rod and rhomboid shapes, and are positively birefringent

Question 343

What are these?

Answer 343

• Calcium pyrophosphate crystals: aspiration reveals positively birefringent, rhomboid-shaped crystals
  1. Positive birefringence: crystals yellow when perpendicular and blue when parallel to the plane of light (opposite of gout)
  2. Positive for Pyrophosphate in Pseudogout
• Presentation identical to gout, but caused by deposition of calcium pyrophosphate dihydrate crystals (CPPD)

Question 344

What do you see in these images?

Answer 344

• Urate deposits in the medulla of the kidneys as:
  1. Alcohol-fixed section stained w/H&E
  2. Stained with methenamine silver
  3. Seen with polarized light
• Stellate, star-looking space where the crystals were

Question 345

What do you see here?

Answer 345

• Gouty arthritis with urate deposits in subchondral bone; alcohol fixation and silver stain
• Chondrocytes on the surface, sub-chondral bone, then bony matrix and marrow below with black crystals being deposited
• Tophaceous deposits around joints erode into cartilage and subchondral bone and may cause marginal erosions of bone as seen in clinical x-rays

Question 346

What are these?

Answer 346

• Gouty bursitis: urate deposits (brownish areas) preserved by alcohol fixation (sliver stain)
• Brown to black staining material is all of the crystals

Question 347

What is this?

Answer 347

• Gouty tophus: urate deposits (amorphous pink areas) dissolved by formalin fixation; H&E
• Really light areas are where the crystals once were

Question 348

What do you see here?

Answer 348

• Typical granuloma in gout: central part formed by urate crystals (not easily ID’d here bc tissue was fixed in formalin)
• Inflammatory cells surrounding area of crystals typically include macros, lymphos, plasma cells, and giant cells (chronic) -> typical morphology in tophi
• Can’t just throw these specimens in formalin because crystals dissolve, and lab won’t be able to polarize and look at them (end up w/amorphous space where the crystals once were)

Question 349

What do you see here?

Answer 349

• Gout: devo of tophi (white, chalky aggregates of monosodium urate crystals)
  1. Body initially attacks gout like it would an infection (with a neutrophilic infiltrate), making the joint red and warm
• Negative (needle-shaped) birefringence: blue when perpendicular and yellow when parallel
• Can cause renal failure: urate crystals deposit in kidney tubules

Question 350

What is this?

Answer 350

• Intracellular urate crystal
• Can be IC or in the fluid

Question 351

What are two central features in the pathogenesis of CPPD?

Answer 351

• Dysregulated chondrocyte differentiation to hypertrophy
• Inorganic pyrophosphate (PPi) metabolism

Question 352

What mutation is linked to auto dom familial CPPD?

Answer 352

• Mutations in ANKH, a gene encoding a PPi transporter
• Remember: dx of CPPD before age 55, esp. if it is polyarticular, should prompt differential diagnostic consideration of a 1^o metabolic or familial disorder
  1. Hyperparathyroidism should always be considered in CPPD presenting in patients older than the age of 55

Question 353

What immune processes drive cell responses to CPPD crystals and inflammation?

Answer 353

• NLRP3 (cryopyrin) inflammasome activation
• Consequent caspase-1 activation
• Interleukin (IL)-1β processing and secretion

Question 354

How might you distinguish CPPD from OA?

Answer 354

• Degenerative arthropathy caused by CPPD crystal deposition disease often involves joints not commonly affected by primary OA like MCP, wrist, and elbow joints

Question 355

What imaging test is particularly helpful in dx of CPPD?

Answer 355

• High-resolution ultrasound
• Partly because radiographic chondrocalcinosis is not detectable in all joints affected by the disease

Question 356

What other form of arthritis is HA linked with?

Answer 356

• HA crystal deposition in articular cartilage is intimately LINKED WITH OSTEOARTHRITIS, particularly with osteoarthritis of increased severity

Question 357

Do HA crystals show birefringence?

Answer 357

• HA crystals (unlike urate and CPPD crystals) do NOT demonstrate birefringence
• Specialized methods are required to conclusively identify HA crystals in specimens from the joint

Question 358

What are the key points for HA?

Answer 358

• Unlike urate and CPPD, acute synovitis due to HA is unusual
• Acute inflammatory syndromes, incl subacromial bursitis and form of pseudopodagra in young F may occur in assoc w/periarticular HA crystal depo in bursae, tendons, ligaments, and soft tissues
• Pts w/advanced chronic renal failure, esp. on dialysis may devo symptomatic (peri)articular HA crystal depo that may be destructive and involve axial skeleton -> these may resemble or be assoc w/CPPD

Question 359

What txs are there for (peri)articular HA crystal depo?

Answer 359

• NSAIDs or selective COX-2 inhibitors
• Local corticosteriod injection
• Local irrigation
• High-frequency therapeutic ultrasound to degrade BCP (basic calcium phosphate) crystal deposits

Question 360

What do you see in these images?

Answer 360

• HA crystal-assoc calcific bursitis in shoulder of pt w/chronic renal failure (on hemodialysis) and 2^o hyperPTH
• A: chronic soft tissue swelling involving R shoulder due to calcific R shoulder subacromial bursitis; note the convex contour of R compared to L
• B: radiograph showing extensive calcification both w/in rotator cuff and expanded subacromial bursa surrounding R shoulder joint
  1. Resorption of distal end of clavicle consistent w/2^o hyperPTH
• C: subacromial bursa fluid from R shoulder; note the milk-white appearance w/chalky sediment of particulate material in fluid after centrifugation consistent w/crystal depo disease

Question 361

What do you see in these 2 images?

Answer 361

• HA crystals: from calcific bursitis in shoulder of pt w/chronic renal failure (on hemodialysis) and 2^o hyperPTH
• A: Micro appearance of bursa fluid aggregates of basic calcium phosphate (BCP) crystals in absence of special stains -> particles are irregular, but have approximately spherical profiles
• B: Appearance of bursa fluid under polarized light microscopy -> aggregated particles of BCP crystals demonstrate edge birefringence but do not display intrusive birefringence, as seen in the figure
• Sort of amorphous little globs (rather than long and thin or rhomboid)

Question 362

What is going on in these two images?

Answer 362

• HA crystal: from calcific bursitis in shoulder of pt w/chronic renal failure (on hemodialysis) and 2o hyperPTH
• A: EM of mononuclear phagocyte from bursa fluid that contained phagocytosed e- dense (dark black) spherical aggregates of crystals of BCP HA in 3 phagolysosomes oriented vertically to right of the nucleus -> 100’s of tiny, needle-shaped HA crystals are clumped in each of these dense aggregates
  1. Size of the mononuclear phagocyte approx 20 microns, and an individual (nonaggregated) hydroxyapatite crystal is approximately 0.04 × 0.01 × 0.01 microns in size (i.e., very small)
• B: Electron diffraction pattern of HA crystal aggregates -> diffraction rings indicative of a powder pattern (i.e., small crystals); position of the bright rings with d-spacings = 3.44 and 2.81 are characteristic of hydroxyapatite (calcium apatite)