Clinical Lectures

Question 1

Gout

Answer 1

– uric acid deposits (normally b/c under-excretion not overproduction); if conc of urate exceeds solubility (6.8) it forms crystals in joints/kidney/skin; crystals phagocytosed by myeloid cells à activation of NALP3 + adaptor + caspase 1 (INFLAMMASOME) à IL-1 overproduction à COX and prostaglandins, heat shock proteins, TNF, neutrophils, fever, acute phase reactants; associated w/ cardiac probs

• Yellow, parallel, needle-shaped crystals
• Acute Treat – NSAIDS, glucocorticoids, colchine blocks (block microtubules of intracellular inflammasome apparatus), IL-1 antagonist (Anakinra)
• Chronic Treat – porcein uricase to break it down (pegloticase- mainly for tophi), block reuptake by URAT1 and SLC2A9 in proximal tubule (Lesinurad specific to URAT 1, probenecid, benzbromarone), Xanthine oxidase inhibitors (allopurinol and febuxostat)

Question 2

CCPD

Answer 2

alcium pyrophosphate crystals; associated w/ osteoarthritis

• Blue, rhomboid shaped crystals
• Treat – NSAIDs, colchicine, treat underlying cause

Question 3

IBD (2 Types)

Answer 3

Chron’s

• discontinuous
• any portion of GI tract
• deeper; fistulas/strictures/abscesses
• ASCA antibdoes (anti saccharomyces cerevisiae)

UC

• continuous
• mainly colon
• superficial (mucosa and submucosa)
• atypical P-ANCA antibodies (atypical perinuclear anti-neutrophil cytoplasmic antibodies)

Overall…genetic susceptibility + aggravated by environmental factors à abberant innate immune response against intestinal flora (DCs in lumen and macrophages in lamina propria) à enhanced by adaptive immune response (esp Th1 and Th17 – may be helped by Th2 + predominantly switch to IgG instead of IgA in gut)

• Treat – infliximab (antibody against TNF-alpha) & vedolizumab (antibody against alpha4beta7 integrin which attracts mature GALT derived B cells back to gut)

Question 4

Celiac

Answer 4

immune response against gliadin (by intra-epithelial lymphocytes) DQ2 and DQ8 have high affinity for gliadin

inc permeability gliadin –> broken down by TTG in lamina propria –> glutamic acid (inc immunogenicity)

+ Anti-TTG antibodies

Tissue injury–> malabsorption

Question 5

Scleroderma Classification and Pathogenesis

Answer 5

• Diffuse - proximal to elbows or knees
  
  • Usually rapid progression; max skin involvement ~18 mo after first symptoms
  • Usually have internal organ involvement
  • scl-70 (chest/lungs-ILD, myopathy), RNA polymerase III (severe skin and renal)
• Limited- distal to elbows or knees; can also include face
  
  • Develops over many years; if organ involvement usually decades into the disease
• Overlap- have diffuse or limited cutaneous involvement BUT also features of other CTD
• -centromere (chest/lungs - ILD and pulmonary hypertension)
• Vascular/endothelial injury –> immune system activation –> fibroblasts (TGF-beta, PDGF and Th2 cells)
  
  • ET-1 inc when endothelial injury
  • EC activation –> leukocyte migration
  • Accompanied by defective vasculogenesis
• Intima hyperplasia and adventitia fibrosis

Question 6

Lupus

Answer 6

• WOMEN OF CHILD-BEARING YEARS
• Diagnosis-4-skin RASHNIA
  - Malar rash, photosensitivity, oral/nasal ulcers, discoid rash (think of butterfly face rash)
  - Renal, Arthritis, Serositis, Hematological cytopenias/hemolytic anemia, neuro, immunological, ANA (auto-antibodies)
  + new=Low complement levels, derm features (like hair loss w/o scar)
• Anti-nuclear antibodies (Esp dbl stranded DNA)
• MHC, deficiencies in complement system, genes off innate immunity/IFN production
• Defective clearing of damage (damage may be due to photo-sensitive skin damage) –> persistence –> antibody and immune complex formation
  - Both innate and adaptive immunity involved
• BLys and APRIL bind B cells to enhance memory B cell survival and differentiation into plasma cells + class switching
• Dendritic cells prod type I IFN when stimulated by debris –> bind TLR7 and TLR9
• Treatments
  
  • Corticosteroids
  • Oral agents (hydroxychloroquine affects TLR9 and antigen presentation)
  • Anti-BLys antibody (belimumab)
  • Anti-CD20 (rituximab) - targets B cells
  • Anti-IFNalpha

Question 7

3 Lupus Sub-sets

Answer 7

• Drug-induced more mild and associated w/ anti-histone antibodies; usually goes away if stop drug
• Co-morbidity of APS (anti-phospholipid antibody syndrome) –> thrombosis
• Neonatal lupus - if mom has anti-SSA or anti-Ro antibodies that cross placenta; SSA antibodies attack baby’s cardiomyocytes; usually goes away on own (~9 mo)

Question 8

GPA (Granulomatosis w/ polyangitis)

Answer 8

• Associated w/ ANCA (anti-neutrophil antibodies)
• Triad:
  
  • Vasculitis of upper and lower resp tract
  • Glomerulonephritis
  • Necrotizing, granulomatous inflammation (on biopsy)
• Clinical Manifestations
  
  • Fever, chills, night sweats, weight loss, fatigue, ENT, pulmonary, renal, ocular, purpura/petichiae/ulcers/gangrene
• Diagnosis - tissue biopsy of lung, kidney or skin
• Inc ESR, CRP, rheumatoid factor, ANCA (specifically c-ANCA for PR-3) + urinalysis
  • TNF and IL-1 –> recruitment of leukocytes (ICAM/VCAM, selectins)
  • Adventitia - matrix deposition (scar)
  • Media - proteases digest elastic membrane
  • Intima - hyperplasia and NO cytotoxicity
  • End result = lumen diameter altered, dec vessel integrity, pro-coag/thrombosis, ischemia
• Disease onset may be related to bacterial infection (ex - S. aureus)
• Therapy
  
  • rituximab - to get to remission (targets CD20 of B cells)
  • methotrexate or other oral immunosuppressive once in remission
  • bactrim for underlying infection
  • IVIG
  • CYC, MMF, AZA 0 block DNA synthesis or enzymes of B or T cell proliferation
  • Abatacept - experimental; bind B7 of APCs to stop co-stimulation

Question 9

Spondyloarthritis

Answer 9

• Articular features - inflammation in discs, sacroiliac joints, ligaments b/n vertebrae, facet joints
• Extra-articular features - anterior uvelitis, psoriasis, IBD
• Pathogenesis - auto-inflammatory
  
  • Stress/infection/barrier dysfunction —> PAMPs and damage (which leads to DAMPs) —> innate response —> adaptive response
  • Esp Th17 cells (so involves IL-23 for differentiation and IL-22/IL-17 for effects)
• Associated w/ HLA-B27 (MHC class I) - in 90% of those w/ axial disease

Question 10

Mechanical v Inflammatory back pain

Answer 10

• Mechanical - acute onset, wide age range, no extra-articular involvement, exercise makes it worse while rest makes it better, sensory and motor symptoms, radiation to S1, L5
  
  • Inflammatory - family hx, >3 mo, sleep disturbances and several hours of morning stiffness, extra-articular symptoms, better w/ exercise while worse w/ rest, no sensory or motor problems; diffuse —> spine/butt

Question 11

IMM

Answer 11

• Clinical
  
  • Proximal musc weakness
  • Skin rashes -
    
    • Gottron papules - red and scaly rash
    • Heliotrope - looks like red eye shadow
    • Calcinosis and vasculitis in juvenile
  • Polymyositis (PM)- CD8+ invasion of myofiber BUT no necrotic tissue; within fasicle
  • Dermatomyositis (DM) - B cell and complement driven; attacks blood vessels around fasicle; see atrophy
  • Can have systemic involvement … fatigue, fever, arthritis, pulmonary disease, cardiac, GI
• Pathogenesis
  
  • Muscle cells themselves can act as APCs if surrounding inflammation provide 2nd signal
  • Anti-Jo 1 autoantibody: against RNA synthetase
    
    • Apoptosis —> TyrRS cleared —> cleaved into 2 cytokines that attract monocytes (including IL-8) —> adaptive immune response and autoantibodies
      
      • ANA (non-specific) anti JO 1 (very specific)
      • So TyrRS is an enzyme that in and of itself initiates inflammation

Question 12

Sjogren Clinical

Answer 12

• Clinical
  
  • Salivary and lacrimal glands affected (DRY)
  • Triad: dryness, fatigue, musculoskeletal
  • Others: Raynauds, purpura, mimicks RA in joints, nephritis, interstitial lung disease, CNS lesions, neuropathy, cirrhosis, leukopenia, thrombocytopenia, inflammatory myopathy
  • HIGH RISK OF LYMPHOMA (esp MALT lymphomas in glands)
• Diagnosis
  
  • Schrimer’s test for eye dryness
  • Harvest minor salivary glands - look for FOCI (lymph infiltrate of B cells)
• Treatment
  
  • Dryness- fluoride, artificial saliva, xylitol candies, secretagogues, topical cyclosporin, artificial tears
  • Immune suppression - methotrexate, hydroxychloroquine, rituximab

Question 13

Sjogren 2 Theories

Answer 13

• Pathophysiology (2 theories)
  
  • 1-Death of glandular cells (damaged epithelial cells act as APCs —> cytotoxic T cells —> epithelial apoptosis …this damage leads to chemicals that —> antibody production)
  • 2- Glandular function inhibited by autoantibodies that interrupt muscarinic receptors —> prevent intracellular signaling path
• *B cell hyperactivity
  - Autoantibodies (SSA, SSB, RF, ANA)
  - Immune complexes that affect vasculature
  - BLys overproduced in salivary glands + serum levels elevated (B cell proliferation and differentiation)

Question 14

Idiopathic Juvenile Arthritis (6 subtypes)

Answer 14

• Oligoarticular - 4 or less joints; ANA; NO Rh factor
• RF-Neg polyarticular - 5+ joints; also ANA+
• RF-Pos polyarticular - symmetric and in both small and large joints (very similar to adult RA), ANA-neg but ACCP and RF+, highly erosive (can be disfigured)
• Systemic- prominent extra-articular features; fever, macular rash, lymphadenopathy, elevated sed rate
• ERA (enthesitis related) - spondyloarthropathy + HLA-B27 associated
• Psoriatic Arthritis - ERA + ANA+ oligoarthritis of small joints

Question 15

Immune Problems in IJA

Answer 15

• Foci in joint (like lymph nodes)
  
  • Synovial hyperplasia
  • IL-6, IL-1 and TNFalpha upregulated
  • T cells - oligoclonal expansions; many IL-17 prod cells; dec Tregs; premature exhaustion; TCR-indep activation
  • Dendritic cells high and IFN-gamma prod
  • B cells - RF, ANA, ACCP
  • Synovial fibroblasts
  • MACROPHAGE ACTIVATION SYNDROME (IL-18 —> IFN gamma —> activation)