Pharmacology
List the four pharmacologic treatment options for myositis.
Steroids
IVIg
MMF
Rituximab
This condition has principal cellular involvement with neutrophils and synovial macrophages. The driving cytokines are IL-1.
What is Gout?
Risk Factors: male, chronic renal failure, metabolic syndrome, aspiring, diuretics, high purring intake, alcohol consumpotion
Hyperuricemia results from increased production of uric acid or decreased renal excretion. Uric acid phagocytosed by neutrophils resulting in cell lysis releasing uric acid and lytic enzymes contributing to tissue damage. Uric acid phagocytosed by synovial macrophages (mediated by TLR2/4) and ferried to the NALP3 inflammasome where it triggers IL-1 production resulting in inflammation and tissue damage.
Identify this condition: patient presents following a recent infection with concern for asymmetric joint pain and a new rash that is mostly distributed over extensor surfaces.On physical exam, patient has nail pitting.The rash has silvery scales that bleed when scraped off.
Psoriatic Arthritis
Erythematous plaques with silvery scaling on extensor surfaces
Auspitz sign— pinpoint bleeding from exposure of dermal papillae when scales scraped off
Nail Pitting
Peripheral arthritis
Pencil in a cup on XR
Identify the condition:
ANA+
Anti-dsDNA, Anti-Sm+
Anti-Ro/La +
Low CH50
High ESR/CRP
SLE!!
List three conditions that may result in increased ESR.
Malignancy
GCA
Rheumatoid Arthritis
You build a break-through combination therapy drug that simultaneously inhibits IL-23, IL-17, and TNF-alpha.
What condition will this offer significant relief for?
Identify the T cell subtype(s) involved in the pathogenesis of this condition based on key cytokines.
Psoriatic Arthritis — proliferation of keratinocytes and skin-symptoms associated with high levels of IL-23, IL-17, IL-12 and TNF alpha.
The T cell subtype is CD4+. Specifically, Th 17 and Th1 cells.
The development of this condition is often related to the citrullination of protein antigens recognized by APCs (primarily Rf+ B cells) clearing antigen Ig complexes.
Identify the non-specific positive marker for this condition and the specific.
What is Rheumatoid Arthritis?
RF+ (non-specific), Anti-CCP (specific)
The development of this condition is often related to the citrullination of protein antigens recognized by APCs (primarily Rf+ B cells clearing antigen Ig complexes). T cell co-stimulation and activation occurs. T-cell interaction and activation of B cell. Autoantibody production . Resident fibroblast and macrophage activation. Inflammatory cytokine production and mediators of vascular growth factors (VEGF) + MMPs + upregulation of RANKL leads to osteoclast activation.
TNF, IL-1, IL-6 are drivers
Identify this: 60F presents with chief concern: ”my jaw has been killing me while I try to eat my oatmeal in the morning and I just feel like my head is throbbing on one side!!”
Bonus: what would you think if she was 30F w/ different pulses b/l?
LVV: GCA
Would think Takayasu.
Identify the condition:
Anti Jo1 +
Anti-Mi2+
Myositis— generally Jo1+
More specifically, dermatomyositis !!List three muscles that connect to the ischial tuberosity.
1. Biceps femoris
2. Semitendinosus
3. Semimembranosus
At low doses, this drug functions in two ways:
1. Anti-proliferative via decreased purine and pyrimidine synthesis in lymphocytes
2. Anti-inflammatory due to increased extracellular levels of adenosine
Identify the drug, a side effect/caution, and an indication for use
Methotrexate, RA/SLE/Psoriasis/Vasculitis
Side effects of low dose MTX:
Hepatotoxicity (no alcohol)
GI toxicity, mucositis
Bone marrow suppression
pneumonitis
Contraindicated in pregnancy
caution with renal insufficiency (80-90% renal cl)
This condition has two subtypes driven by different cells. Identify and match the cell driver to the subtype of the condition.
Bonus: describe the two types of immune responses that are elicited.
Polymyositis: CD8+, B cells
Dermamyositis: CD4+, B cells, complement
Direct attack leading to apoptosis vs. a humoral immune response
Associate the following dermatological findings with the underlying cellular processes and muscle biopsy findings:
Gottron papules
Heliotrope rash of eyelids
Shawl and face pruirtic rash
Mechanic’s Hands
Dermatomyositis (DM): CD4+ cells initiate humoral vasculopathy— autoantigens deposit on capillaries activating complement and damaging endothelial cells.
Leads to perivascular and perifascicular distribution.
This look lesssss destructive than polymyositis (CD8+)
Anti Ro/La +
Anti-dsDNA -
Anti-Sm -
and…complete heart block!
Neonatal lupus!
also associated with rash
This physical exam maneuver can be used to assess an anterior interosseous nerve injury.
The ”Ok” sign
This IgG subtype has the strongest ADCC due to high affinity for FcyR, exerts the second highest CDC.
This IgG subtype has the strongest CDC but the shortest half-life due to the weakest binding to FcRn, no clinical value.
This IgG subtype has the weakest ADCC, CDC, used when they are not desired.
IgG1
IgG3
IgG4
Sjogren’s Syndrome is triggered by predisposition via HLA-DR3 combined with environmental trigger leading to the activation of these T cell subtypes and creation of these autoantibodies.
What is Th1, Th17 and autoantibodies SSA/B (Ro/La)
Recognition of TLR and induction of IFN by pDC leads to inflammatory response and periductal deposition of CD4+ Th1 and Th17 cells. Stimulates BAFF with B cell activation. Apoptosis of affected cells with surface blebbing and generation of autoantibodies to apoptosis blebs. May result in early immune-mediated inhibition of acinar secretory function. More T cell and B cell activation in response to antibodies.
The initial presentation of Scleroderma may present with this autoimmune-associated but not indicative presentation. Identify and describe the underlying mechanism of this process.
Raynaud’s phenomenon.
Triggered by cold. Vasospasm leads to decreased blood flow and then restoration. White blue red.
Not ALWAYS indicative of autoimmunity, but associated with
Sensitive, not specific: RF+
Reed Sternberg cells are associated with the following group of conditions.
Hodgkins
Cytokine-release syndrome and specific for targeting tumor antigen are respectively one adverse effect and one advantage of this type of therapy.
CAR T Cell Therapy
Adoptive T cell transfer using CAR T cells to treat cancer.
Patients own T cells are collected and genetically modified to express chimeric antigen rcp (CAR) to specifically attack tumor cells. CARs combine all signals required for T cell activation into one leading to enhanced survivival.Grown in lab and infused back to Patient.
Cytokine released syndrome (CRS)— resulting fever, hypotension, tachycardia, tachypnea, rash due to increased IL-6, IFNy, and TNFa. Treat with tocilizumab and steroids
Two conditions we have learned are mediated by two classes of hypersensitivity.
Identify the conditions and describe the hypersensitivity reactions precipitating their pathogenesis.
SLE and Small Vessel Vasculitis are both mediated by Class II and III hypersensitivity.
SLE:
Ab targets cell surface such as WBC, RBC, platelets, and cardio lipins (II)
ICs adhere to endothelial cell initiating inflammatory response and complement system. Recognition of IC by pDC and release of Th1 IFN stimulates DC, neutrophils, and macrophages. Cytokine release and activation of adaptive immune system (requires autoreactive B and T cells). BAFF required for B cell activation leading to generation of plasma cells and secretion of autoantibodies.
SVV:
Ab-Ag recognition in small blood vessels and adherence of IC to endothelium. Complement activation and neutrophil recruitment. Inflammation and vascular damage with extravasation of RBC and inflammatory mediators. Attempt at vessel repair with fibrin deposition (fibrinoid necrosis)
Draw the presentation of Lupus. (Remember when we did this last time)
Arthritis: chronic, inflammatory, polyarticular
Ulnar deviation: reducible, unlike RA
Malar rash
Photosensitivity
Discoid rash
Oral/nasal ulcers
Raynaud’s
Alopecia
What is ankylosing spondylitis.
etc
Big picture B and T cell development.
Draw it.