Postlethwaite Flashcards

Question

What is this?

Answer 1

Plaque psoriasis (psoriasis vulgaris)

Answer 2

- 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

Answer 3

- 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_

Answer 4

- 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

Answer 5

- 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_

Answer 6

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

Answer 7

_Arthritis mutilans_: characteristic of psoriatic arthritis

Answer 8

- X-ray of hand of _psoriatic arthritis_ patient - DIP involvement - "Pencil in a cup" appearance

Answer 9

- 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

Answer 10

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

Answer 11

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

Answer 12

- 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

Answer 13

- 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

Answer 14

- **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

Answer 15

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

Answer 16

- 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

Answer 17

- 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

Answer 18

- 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

Answer 19

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

Answer 20

- 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

Answer 21

- _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

Answer 22

- 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

Answer 23

- 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

Answer 24

- 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_

Answer 25

**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_

Answer 26

- 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

Answer 27

- 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^oraynaud’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

Answer 28

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.

Answer 29

- 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)

Answer 30

- 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

Answer 31

- 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_

Answer 32

- 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

Answer 33

- 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

Answer 34

- **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)

Answer 35

- _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)

Answer 36

- 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_

Answer 37

- _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

Answer 38

Terminal tuft bony erosions seen in SSc Also can be seen w/psoriatic arthritis, dermatomyositis, and Raynaud's

Answer 39

- **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)

Answer 40

- 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

Answer 41

- 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

Answer 42

- **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)

Answer 43

- Pleurisy, _pleural effusions_, pleural scarring - Aspiration pneumonia - Malignancy-all cell types - Interstitial Lung Disease (_ILD_) - Pulmonary vascular disease (_PAH_)

Answer 44

- 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

Answer 45

- 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

Answer 46

- 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

Answer 47

- **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)

Answer 48

- 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

Answer 49

Linear scleroderma (so says Google)

Answer 50

- 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

Answer 51

- Histopath of **skin lesions in scleroderma** - Characterized by: 1. Excessive deposition of _collagen_ 2. Deep _fibrosis_ 3. Perivascular **_lympho_**histiocytic 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)

Answer 52

- **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

Answer 53

- _Calcareous lesion in scleroderma_: related to tumoral calcinosis 1. Large painful masses in the periarticular soft tissue composed of calcium hydroxyapatite

Answer 54

- **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_

Answer 55

- **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

Answer 56

- **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

Answer 57

- **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

Answer 58

- _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)

Answer 59

Discoid rash: can be seen in SLE and DLE

Answer 60

Systemic lupus (SLE)

Answer 61

- **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

Answer 62

- pDC: plasma dendritic cells

Answer 63

- 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

Answer 64

- _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

Answer 65

- 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.

Answer 66

- **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

Answer 67

- 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

Answer 68

- **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

Answer 69

- **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

Answer 70

- 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)

Answer 71

- Anti-phospholipid can also be present outside of lupus

Answer 72

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

Answer 73

Subacute cutaneous lupus (think anti-SSA, SSB)

Answer 74

Neonatal lupus (anti-SSA, SSB)

Answer 75

- 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

Answer 76

- 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

Answer 77

- 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)

Answer 78

- **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

Answer 79

- _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

Answer 80

- **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

Answer 81

- 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

Answer 82

- _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)

Answer 83

- _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

Answer 84

- 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

Answer 85

- _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

Answer 86

- 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

Answer 87

- **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_

Answer 88

- _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

Answer 89

- 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

Answer 90

- _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: 1. Clinical manifestations 2. Severity of organ system involvement

Answer 91

- Corticosteroids - Cyclophosphamide - Methotrexate - Mycophenolate mofetil: expensive -\> last resort - Azathioprine - _Hydroxychloroquine_: frequently used - Belimumab

Answer 92

- _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

Answer 93

- _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)

Answer 94

- 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

Answer 95

- Livedo reticularis: rash from small vessel vasculitis

Answer 96

- _Livedo reticularis_: rash from small vessel vasculitis - Clinical feature suggesting the presence of anti-phospholipid antibody

Answer 97

- 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)

Answer 98

- 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

Answer 99

- _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

Answer 100

- _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

Answer 101

- _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

Answer 102

- 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

Answer 103

- _Deposition of IgG_ antibody in a **granular pattern**, detected by immunofluorescence -\> **SLE glomerulonephritis** - This is an IMPORTANT IMAGE

Answer 104

- **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

Answer 105

Normal skin histo

Answer 106

- Divided into 1^o and 2^o forms -\> 1^oform 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^oby 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

Answer 107

- 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%

Answer 108

- 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)

Answer 109

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

Answer 110

- **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

Answer 111

- **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

Answer 112

- **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

Answer 113

- 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

Answer 114

- **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

Answer 115

**Keratoconjunctivitis sicca**: keratitis caused by decreased lacrimal secretions Characteristic of Sjogren's

Answer 116

- 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

Answer 117

- _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

Answer 118

Obtain a biopsy of the salivary gland

Answer 119

- 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)

Answer 120

- **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

Answer 121

- 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)

Answer 122

- 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

Answer 123

- 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)

Answer 124

- 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

Answer 125

- **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)

Answer 126

- 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**

Answer 127

- **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

Answer 128

- **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

Answer 129

- **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

Answer 130

- **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

Answer 131

- 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)

Answer 132

- 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

Answer 133

- 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)

Answer 134

- 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)

Answer 135

- 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)

Answer 136

- 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

Answer 137

- **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_)

Answer 138

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

Answer 139

- _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)

Answer 140

- 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

Answer 141

- 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

Answer 142

- _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

Answer 143

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

Answer 144

- **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_

Answer 145

- **Vasculitis in RA**: inflammation of small (or medium) blood vessels in the skin manifested by _palpable purpura or skin ulceration_

Answer 146

- **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

Answer 147

- _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

Answer 148

Episcleritis: seen in RA

Answer 149

Scleromalacia: seen in RA

Answer 150

Central keratolysis and corneal perforation in RA

Answer 151

Marginal corneal melt (ulcer) with inflammation in RA

Answer 152

- _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

Answer 153

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

Answer 154

- 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_

Answer 155

- _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)

Answer 156

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

Answer 157

- **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

Answer 158

- _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_

Answer 159

- 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

Answer 160

- **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_

Answer 161

- 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

Answer 162

- **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)

Answer 163

- 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

Answer 164

- **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_)

Answer 165

- 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)

Answer 166

- 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

Answer 167

- **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**

Answer 168

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

Answer 169

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

Answer 170

- 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

Answer 171

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

Answer 172

- 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)

Answer 173

- **MMP's** degrade proteoglycans (aggrecanases) and collagen (collagenases) - Suboptimal repair response of normal articular cartilage to injury typically results in 2^oosteoarthritis - 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

Answer 174

Improving signs and symptoms

Answer 175

- YES - Location of the joint is very important -\> some joints are very _resistant, i.e., the ankle_ - **Knee is the most common**

Answer 176

- 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

Answer 177

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

Answer 178

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

Answer 179

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

Answer 180

- 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).

Answer 181

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

Answer 182

- _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

Answer 183

- Multiple factors predispose you to, initiate and perpetuate OA

Answer 184

- 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

Answer 185

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

Answer 186

- 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

Answer 187

- 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)

Answer 188

- **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

Answer 189

- 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

Answer 190

- 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

Answer 191

- 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

Answer 192

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

Answer 193

OA: DIP and PIP involvement

Answer 194

- Radiograph showing severe changes in the _carpometacarpal joint in OA_ - **Most common location in hand** - May cause significant loss of function

Answer 195

- 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

Answer 196

- 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

Answer 197

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

Answer 198

- 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

Answer 199

- 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

Answer 200

- **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

Answer 201

- _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

Answer 202

- _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

Answer 203

- 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

Answer 204

- 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

Answer 205

- 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

Answer 206

- Fibrous-lined **"cysts"** under exposed _subchondral bone_ in advanced osteoarthritis (of hip) - Cartilage is basically gone here -\> this is _really advanced_

Answer 207

- _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_

Answer 208

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

Answer 209

- 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

Answer 210

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

Answer 211

- 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)

Answer 212

- 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

Answer 213

- 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

Answer 214

- 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)

Answer 215

- **Dermatomyositis** - A: Gottron's papules - B: Heliotrope rash - C and D: Gottron's sign on knees and elbows

Answer 216

- 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_

Answer 217

- Characteristic dermatomyositis skin changes: A: linear erythema B: scalp rash C: V-like sign D: shawl sign

Answer 218

- 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)

Answer 219

- **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

Answer 220

- 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%

Answer 221

- \>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

Answer 222

- 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

Answer 223

- **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

Answer 224

- 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

Answer 225

- _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

Answer 226

- **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_

Answer 227

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

Answer 228

- **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

Answer 229

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

Answer 230

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

Answer 231

- **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

Answer 232

- 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

Answer 233

- 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

Answer 234

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

Answer 235

- **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

Answer 236

- **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

Answer 237

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

Answer 238

- 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

Answer 239

- 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

Answer 240

- 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

Answer 241

- 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

Answer 242

- 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)

Answer 243

- 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

Answer 244

- 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

Answer 245

- 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

Answer 246

- _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

Answer 247

- 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)

Answer 248

- _DEC efficiency of UA excretion_: 85-90% of 1^o or 2^ohyperuricemia - _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

Answer 249

- 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

Answer 250

- 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

Answer 251

- 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)

Answer 252

- _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

Answer 253

A: primary hyperuricemia in men usually begins at puberty

Answer 254

- 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_

Answer 255

- 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

Answer 256

- 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)

Answer 257

- _"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

Answer 258

- 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

Answer 259

- 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

Answer 260

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

Answer 261

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

Answer 262

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

Answer 263

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

Answer 264

- Radiographs demonstrating severe, destructive, cystic changes in _tophaceous gout_

Answer 265

- 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

Answer 266

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

Answer 267

- 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)

Answer 268

- _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

Answer 269

- _Diuretics_: thiazides, loops - _Organic acids_: salicylates (low-dose), nicotinic acid, pyrazinamide - _Other_: cyclosporine, _ethambutol_, ethanol, colony-stimulating factors

Answer 270

- 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)

Answer 271

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

Answer 272

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

Answer 273

- 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)

Answer 274

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

Answer 275

- NSAIDs - Colchicine - Corticosteroids - Adrenocorticotropic hormone - The effectiveness of tx depends more on _how quickly the therapy is initiated_ than which agent is used

Answer 276

- 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

Answer 277

- 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

Answer 278

- Hypertension - Coronary artery disease - Diabetes - Obesity - Alcoholism

Answer 279

- 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

Answer 280

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

Answer 281

- 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

Answer 282

- 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

Answer 283

- 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

Answer 284

- 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

Answer 285

- YES, can actually be very warm because very inflammatory

Answer 286

- 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)

Answer 287

- 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

Answer 288

- 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

Answer 289

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

Answer 290

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

Answer 291

- 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

Answer 292

- 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 **u****nknown 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)

Answer 293

- 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

Answer 294

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

Answer 295

- 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

Answer 296

- _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

Answer 297

- _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)

Answer 298

- **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

Answer 299

- 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

Answer 300

- _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

Answer 301

- 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

Answer 302

- 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)

Answer 303

- HA is 1^omineral 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_

Answer 304

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

Answer 305

- Urate on the left - CPPD on the right

Answer 306

- 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

Answer 307

- 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)

Answer 308

- _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

Answer 309

- _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

Answer 310

- _Gouty bursitis_: urate deposits (brownish areas) preserved by alcohol fixation (sliver stain) - Brown to black staining material is all of the crystals

Answer 311

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

Answer 312

- _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)

Answer 313

- 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

Answer 314

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

Answer 315

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

Answer 316

- 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

Answer 317

- NLRP3 (cryopyrin) _inflammasome activation_ - Consequent _caspase-1_ activation - Interleukin _(IL)-1β_ processing and secretion

Answer 318

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

Answer 319

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

Answer 320

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

Answer 321

- 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

Answer 322

- 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

Answer 323

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

Answer 324

- **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^ohyperPTH - 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

Answer 325

- **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)

Answer 326

- **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)