IE 1: Derm/Rheum (Elsaid)

Osteoarthritis

Chronic localized inflammatory joint disease causing irreversible loss of articular cartilage

Osteoarthritis Pathogenesis

Inflammatory trigger → INF-1 production → Signal chondrocytes to release proteinases to degrade cartilage

Rheumatoid Arthritis

Systemic, autoimmune disease

Characterized by activation of innate and adaptive immune response against joints

Rheumatoid Arthritis Pathophysiology

Tissue hyperplasia occurs → overload synovia (pannus) due to immune cells → destroys surrounding tissue

Rheumatoid Arthritis: Protein citrullination

Deamination of arginine → Citrulline (antigen) formation → B cell activation → Antibody release → Sustains inflammation via pro-inflammatory cytokines

What cytokines are involved in RA

IL-1, IL-6, TNF-a

What is rheumatoid factor?

• IgM directed against Fc region of IgG → immune complex formed -. macrophages recognizes it → inflammation

How can a patient be tested for rheumatoid arthritis? Which one can be used to see if treatment is working?

TNF-A, RF (used to see if treatment is working), ACPA

Factors in RA progression

Environment (smoking)

Epigenetic changes

Genetic markers (e.g HLA-DR4)

Age (happens in 3rd decade of life)

Gender (Females → greater risk)

What syndrome is common in RA? Explain it.

Sjorgen’s Syndrome

Extra-articular manifestation of RA

Destruction of salivary/lacrimal glands → dry eye/mouth

What syndrome is common in RA? Explain it.

Felty’s Syndrome

Extra-articular manifestation of RA

What is the Hypothalamus/Pituitary/Adrenal Cortex (HPA Axis)?

Pro-inflammatory cytokines → Hypothalamus release CRH → anterior pituitary release ACTH → acts on adrenal cortex → release cortisol → inhibit immune response

What immunosuppressant inhibits anterior pituitary and hypothalamus?

Cortisol

What is the effect of corticosteroids at a low dose vs. high dose?

Low dose: Anti-inflammatory

High dose: Immunosuppressant effect

What hormones does the adrenal cortex release? What are they derived from?

Cortisol, aldosterone, androgens (DHEA)

Derived from cholesterol

Glucorticoid MOA

Fast or slow onset?

Agonist on cystolic glucocorticoid receptor → translocation to nucleus → alters gene expression → anti-inflammatory, immunosuppressive, metabolic effects

Slow onsert

What happens when you use Prednisone for a long time for a patient that’s diabetic?

Counter therapeutic → causes hyperglycemia

What are the metabolic side effects of glucocorticoids?

Increased gluconeogenesis, increased protein breakdown, fat accumulation

Glucocorticoids use

Retain/mimic metabolic effects of cortisol (increase glucose)

What drug is identical to cortisol?

Hydrocortisone

Name 2 mineralocorticoids

• Aldosterone

• Fludrocortisone (Aldosterone supplement)

How do corticosteroids inhibit prostaglandin synthesis?

Inhibits phospholipase A2 → prevents arachidonic acid production → prevents COX → prevents prostaglandin synthesis

Mineralocorticoid MOA

Bind to MR in kidney → Promotes Na+/K+ exchange → sodium and water levels increase → increase in BP

For an effective anti-inflammatory drug, make sure it has the highest affinity to [ ] receptor

Glucocorticoid

What is the best way to use glucocorticoids? (Duration, dose, type of effect)

Shortest period of time

Lowest dose

Localized (minimize systemic exposure)

Explain cortisol’s diurnal rhythm

• Drops during day

• Picks up at night

TABLE QUESTION

What will happen if a patient is on systemic corticosteroids for a long time in relation to HPA Axis?

Body will produce less cortisol because body thinks there is enough (negative feedback loop)

• If prednisone is abruptly d/c → NO cortisol production → adrenal insufficiency → body gradually regains ability to produce cortisol

ADEs of Prednisone

• osteoporosis

• diabetes

• cataracts/glaucoma

• swelling/retention

• psych effects

Cortisol

• Affinity for GR and MR

• Effect on Na/K exchange

• Equal affinity

• No effect

Name an example of an intra-articular corticosteroid to treat osteoarthritis

Kenalog (Triamcinolone Hexacetonide)

Explain Kenalog (Triamcinolone Hexacetonide) DOA.

Long-acting (lipophilic, suspension)

21 days (3 weeks)

Which COX enzyme does not alter the GI?

COX 2 because prostaglandins come from COX-2!

How do non-selective NSAIDs cause gastric ulcers?

• COX non-selective inhibitors affect COX1 → inhibit Inhibit postaglanin in stomach  → gastric ulcers

Where does APAP inhibit COX? What effect does this cause?

In CNS → No inflammatory effect, just analgesic and antipyretic

Prostaglandin synthesis pathway

Inflammatory stimulus → phospholipase A2 → Arachidonic Acid → COX enzymes → prostaglandins

What is the effect of NSAIDs on renal function?

NSAIDs → block prostaglandins → blood vessels in kidney blocked → vasoconstriction → blood flow and filtration decreases → urine output decreases

Celecoxib (Celebrex)

Selective COX-2 Inhibitor

How can you supplement viscosity in joint?

Synvisc

Hyalagan

OrthoVisc

Sodium Hyaluronate

What type of testing is required before rheumatoid arthritis therapy?

TB test

Infliximab (Remicade)

• Given IV

• Chimeric

• Neutralizes TNF-A, can induce apoptosis of immune cells w/ TNF-A on them

Adalimuab/Humira

• Preferred

• Given SQ

• Fully human mAb

• Neutralize TNF-A, cannot induce apoptosis of immune cells w/ TNF-A on them

Cetrolizumab Pegol (Cimzia)

• Pegylated Fab fragment (no Fc portion) → Not fully mAb, but smaller mouse % than Infliximab

• Neutralize TNF-A, cannot induce apoptosis of immune cells w/ TNF-A on them

Etanercept

• Soluble decoy TNF-a receptor

• Less immunosuppressive → less significant effect 

• Neutralize TNF-A, cannot induce apoptosis of immune cells w/ TNF-A on them

Rilonacept

• IL-1 decoy receptor → Neutralizes IL-1

Canakinumab

• IL-1 Blocker

Tocilizumab

• Anti IL-6 receptor

• Blocks IL-6 signaling

What are the two different ways IL-6 can signal?

• Can bind to IL-6 receptor on surface of immune cells → prevent IL-6 binding → activates inflammation → immunosuppressive effect

• Can bind to soluble IL-6 receptors in solid form → prevents IL-6 binding → translocates to membrane → immunosuppressive effect

What are three different ways Rituximab targets B cells?

1. Apoptosis

   1. Antibody bound to CD20 → B cell senses dangerous signal → dies

2. Antibody-dependent cell-mediated cytotoxicity (ADCC)

   1. Antibody recruits macrophages & monocytes/NKC to destroy plasma cells

3. Complement-dependent cytotoxicity

   1. Activate complement system → lysis of cells

Abatacept

• Decoy CTLA-4 receptor

• Binds to B7 on APCs → prevents from binding to CD28 on T cells → inhibits T-cell co-stimulation and activation

T cell requires what two cells?

• MHC on APC and T cell receptor

• CD28 (T cell) with B7 on APC

T/F: Rituximab is first line

F → use when IL-X inhibitors don’t work

CTLA-4 has greater binding affinity to [] than CD28.

B7

Methotrexate

• Oral DMARD

• Inhibits DNA replication of immune cells by antagonizing folic acid → immunosupressive effect

• 1x week dosing

What is folic acid essential for?

dUMP → dTMP for DNA synthesis

Tofacitinib (Xelijanz)

• JAK Inhibitor

• Oral DMARD

• Blocks IL-6 signaling by inhibiting JAK-STAT pathway

Upadactitinib (Rinvoq)

• JAK Inhibitor

• Oral DMARD

• Blocks IL-6 signaling by inhibiting JAK-STAT pathway

Definitive diagnosis of gout

MSU Crystals

[ ] acid levels increase in gout

Uric

Leflunomide

• Prodrug

• Immunosuppressive drug

• Antimalarial

• Treats rheumatoid arthritis

Hydroxychloroquine (Plaquenil)

• Antimalarial

• Used for SLE

Pathogenesis of acute gout flares

Significant inflammation

Sharp, pain episodes

What is used for the management of acute gout flares?

Colcichine

NSAIDs (not ideal for pts w/ HTN)

Corticosteroids (not ideal for pts w/ diabetes)

IL-1 Antagonists

What drugs reduce uric acid synthesis? What’s their MOA?

Allopurinol and Febuxostat

Xanthine Oxidase Inhibitors

What drugs inhibit Uric Acid Reabsorption Transporter (URAT)? What’s the effect?

• Probenecid

• Lesinurad

Enhances uric acid elimination

What drugs are a recombinant urate oxidase? What’s the MOA?

Rasburicase

Pegloticase

MOA: IV biologic converts uric acid → water-soluble product

Colchicine MOA?

• Inhibits IL-1 B production following macrophage activation

Main S.E of Colchicine

Diarrhea

What drug that treats gout may trigger hypersensitivity reactions?

Allopurinol

What drug is preferred for tophaceous gout? Why?

Pegloticase b/c of longer half-life

Gout medications can also be used to treat []?

Tumor Lysis Syndrome

• Cancer cells dying → DNA degradation → body makes uric acid → uric crystals ppt INSIDE nephron → acute renal failure

Can you take anti-inflammatory medications with uric-acid lowering therapy?

Yes!

• Pt. on uric acid-lowering therapy can trigger acute flares → that is why we need anti-inflammatory meds too!  

  • Ex.) Allopurinol + Colchicine PRN 

Pathogenesis of Psoriasis

1. Th1 and Th17 via dendritic cells releasing IL-12/IL-23 cytokines in lymph nodes

2. T cells migrate to skin

3. T cell expansion and release of inflammatory factors in skin

4. Angiogenesis, keratinocyte proliferation

IL-23 is composed of two subunits: [] + []

P19 + P40

IL-12 is composed of two subunits [] + []

P35 + P40

[ ] releases IL-17 which causes kerationcyte proliferation

Th17

Adalumab/Humira

• Anti-TNF-A drugs for treatment of psoriasis

Ustekinumab (Stelara)

• p-40 inhibitor

Secukinumab (Cosentex)

• IL-17 inhibitor

Risankizumab (Skyrizi)

• P-19 Inhibitor

Guselkumab (Tremfya)

• P19 Inhibitor

Ixekizumab/Talz

• IL-17 Inhibitor

Apremilast (Otezia)

• Oral PDE-4 Inhibitor

Roflumilast (Daliresp)

• Oral PDE-4 Inhibitor

Roflumilast (Zoryve)

• PDE-4 Inhibitor

Why are PDE-4 inhibitors important for psoriasis?

Inhibits PDE-4 → increases intracellular cAMP → decreases inflammatory signaling → prevent keratinocyte

What happens when IKK-B gets phosphorylated?

TNF-a causes pro-inflammatory cytokine → NF-kappaB which is bound to IKK-B

IKK-B gets phosphorylated → NF-kappa-B can translocate to nucleus → keratinocyte production

What do Rasburicase and Pegloticase convert uric acid to?

Allantoin

Tretinoin (Class, MOA)

• Retinoic Acid Agonist

  • Tretinoin (Ligand - Vitamin A) binds to retinoic acid receptor → overactivation of receptors → resolution of acne and psoriasis

What can happen with overactivation of retinoic acid receptors?

• Hypervitaminosis (high leves of Vitamin A) → skin dryness, lipid abnormalities (increase in triglycerides & LDL)

T/F: Tretinoin is teratogenic

T

Transcription factors bind to [ ] proteins whereas ligands bind to [ ] proteins

Co-repressors

Co-activators

Tazarotene

• Retinoic Acid Agonist

• Topical treatment for mild psoriasis

Acitretin (Soriante)

• Retinoic Acid Agonist

• For severe psoriasis

• Metabolite of Etretinate

What conditions is Aciterin (Soriatane) contraindicated in?

• C/I: Pregnancy, alcohol (risk of accelerating treatment)

Acitretin (Soriatane) vs. Etretinate

Acitretin = Metabolite of Etretinate

• Etretinate → highly lipophillic (even if d/c for 2 months, the drug is still in the body → can’t get pregnant)

• Acitretin → less lipophillic (within 2 months of d/c majority of drug is eliminated → pt. can become pregnant)

Tapinarof

• Aryl Hydrocarbon Receptor Agonist

• Skin Protectant

• Coal tar

Psoriatic Arthritis

• Chronic inflammatory arthritis w/ skin psoriasis

Dysfunction of [ ] causes psoriatic arthritis?

Th17 axis

Psoriatic Arthritis responds well to what type of drugs?

• Anti-TNF-a drugs and Th17 inhibitors