• Rlieve symptoms 
• Delay joint damage 

• NSAIDs:  These are taken chronically. Make sure patient does not end up with a GI bleed. Use Cox-2 selective in patients prone to bleeding. These do NOT modify the disease progression
• Corticosteroids:  Reduce pain and swelling and also SLOW disease progression. But to slow progression, need really high doses, so start these super high, then taper off to reduce side-effects. 
• Disease modifying Anti-Rheumatic Drugs (DMARDs): These drugs are poorly tolerated except for methotrexate.  These are going to ALL alter the rate at which the joints are lost to RA. 

Methotrexate

MOA

Use

• Dihydrofolate reductase inhibitor and blocks the synthesis of purines needed for DNA/RNA synthesis.  

 Use:

• Very potent immunosupressive activity so useful in cancer chemotherapy 
• Treatment of immune disease 
• Low dose = treatment of RA 

Methotrexate 

Side effects

Low dose: (so when treating RA)

• Nausea
• Mucosal ulcers

High dose:

• Severe WBC depression 
• Cirrhosis of the liver 
• Pneumonia-like symptoms (pneumonitis) (might not go away when you remove the drug) 

Infliximab

MOA

Use

MOA:

• Monocolonal Ab that binds to TNF-alpha 
• Chimeric Ab of human/mouse 

Use:

• Used in combination with methotrexate 

Infliximab

Adverse effect

• Upper respiratory infections is the most common effect
• Concern of immunologic reaction b/c this is a chimeric compound

Etanercept

MOA

• Recombinant protein that have two soluble portions of TNF-alpha receptor molecule and the Fc portion of human IgG
• Binds to two molecules of TNF-alpha 

Adalimumab

MOA

MOA:

• This is like infliximab but uses entirely human monoclonal Ab 

• Approved for Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis 

• Used for RA and Crohn's disease
• Reserved for patients that fail on other DMRAs 

Leflunomide

MOA

Use

Side-effects

MOA:

• Inhibition of tyrosine kinase activity 
• Inhibits pyrimidine biosynthesis in de novo

Use:

• Alternative to methotrexate 

Side effects:

• Elevated liver enzymes 
• Other toxicities b/c of suppression of fast-tunover cells 

Abatacept

USE

MOA

Use:

• Treating moderate-severe RA when patients have inadequate response to TNF-alpha inhibitors 
• These are costimulation modulators

MOA:

• Renders T-cells inactive by not allowing them to become activated → thereby decreasing T-cell-mediated inflammation + joint damage from RA 
• Abatacept binds to CD80 and CD86 and blocks T-cell activation 

• T cells are activated by first binding to an antigen-presenting cell (APC) → then having CD28 interact with CD80 or CD86 on the APC → causes activation 

When do you use abatcept?

Contraindications

• Patients w/moderate-severe RA that do not benefit from methotrexate or TNF-alpha inhibitors are candidates 
• Can reverse some of the sings of joint damage (disease modification)
• Can be given with methotrexate but do NOT use in combination with TNF-alpha inhibitors b/c increases incidence of infection 
• Contraindications: TNF-alpha treatment or someone w/COPD b/c can worsen COPD

Rituximab

MOA

Use

Rituximab 

Side effects

• Flu-like symptoms 
• Can also cause breathing problems
• Cardiac rhythm problems 
• Cardiogenic shock (this is the most severe reaction that can occur and happens after the first-dose) 

Sulfasalazine

MOA

Side-effects

Use

MOA:

• Mmeber of sulfa drugs class 
• Poorly absorbed in GI tract → bacteria change it to sulfapyridine (sulfa-antibiotic) and 5-amino-salicylate (anti-inflammatory) 

Side effects:

• Hypersensitivity reaction due to sulfa allergy 

Sulfasalazine

Use

Side-effects

• Inflammatory bowel diseases 
• Ulcerative colitis 
• Crohn's disease
• 2nd line for autoimmune diseases (RA, ankylosing spondylitis, seronegative spondyloarthropathy)
• Good for alternative to methotrexate for patients with liver disease

Causes GI problems

Hydroxychloroquine

General info

Toxicity

General:

• Anti-malaterial drugs (hydroxhloroquine and chloroquine) are rapidly absorbed and safe/well-tolerated 
• Effective for treatment of RA especially if mild 

Toxicity:

• Ocular is the most dangerous (corneal deposits, extraocular muscle weakness, loss of accommodation, and reinopathy → irreversible loss of vision) 

Gold Salts

Examples

• Gold sodium thiomalate 
• Aurothioglucose 
• Auranofin 

Gold salts

Use

MOA

Use:

• Gold salts supress but do NOT cure RA 
• Have a minimal effect on inflammation in other circumstances 
• Cause gradual reduction of signs/symptoms of RA induced inflammation 
• Used in early, active arthritis, esp. for diseases that progresses despitre adequate NSAIDs 

MOA:

• Inhibit the maturation and fucntion of mononuclear phagocytes and T-cells → suppressing immune response 

Gold Salt 

Side effects

• Most common are the ones associated with lesions of the skin and mucousal membranes (usually of the mouth) 
• Can have simple erythema → severe exfoliative dermatits 
• Other effects are kidney damage + blood dyscrasias 

D-penicillamine

Used for?

Side-effects?

• Analog of cysteine 
• Slows bone destruction in RA via unknown MOA 
• Only used if other treatments have failed

Side effects

• Dermatological problems 
• Nephritis 
• Aplastic anemia 

• IL-1ra
• Anakinra

• IL-1 found in synovial tissue of joints 
• IL-1 stimulates its own increased production (positive feedback) → causes increased PG-E2, NO, and metalloproteases → which causes increased joint degradation 
• Macrophages also release IL-1 but ALSO release a compound that binds to the IL-1 receptor that serves as an antagonist called interleukin-1 reeptor antagonist (IL-1ra) 

Anakinra and IL-1ra

What are they?

What are they used for?

Contraindications?

• Anakinra is a recombinant form of the human IL-1ra 
• Efficacy as a DMARD is good 
• Well tolerated 

Contraindications:

• Do not give with TNF-alpha inhibitor → severe infection 

• Tocilizumab 
• Actemra

IL-6 receptor Ab 

MOA

Benefit

Tocilizumab + Actemra

MOA:

• Bind to and inactivate IL-6 receptors 
• IL-6 is secreted by macroaphages and T-cells → stimulates immune reponse (esp. in area of injury) 
• IL-6 also stimulates osteoclast formation → enhanced bone reabsorption 

Dosing benefit:

• One benefit is once monthly administration 

IL-6 Ab 

Adverse events

Adverse events:

• Upper respiratory tract infection 
• Elevated BP + headache
• Elevated liver enzymes 
• Elevated LDL 
• Decreased neutrophil + platelet counts 
• Serious AE = infection, GI perfration, and HS reaction (anaphylaxis)
• Increased risk for cancer 

Because of all the side-effects, only use with patients that have failed on TNF-alpha therapy

Cyclosporine 

Azathioprine

Cyclosporine

General

Use

General:

• Complex cyclic peptide isolated from fungus 

Use:

• Immunosuppressive agent in organ transplants
• Reserved for patients that fail to respond to other therapies 

MOA:

• Inhibits T-lymphocytes very selectively 

Cyclosporine 

Adverse effects

• Expensive
• Renal toxicity

Azathioprine

MOA

Toxicity

B/c of side effects, use is limited to:

• Treatment of transplant rejection 
• Cancer 
• Severe refractory RA 
• Systemic lupus erythematosus 

Cyclophosphamide

MOA

Use

MOA:

• Nitrogen mustard 
• Alkylating agent that alkylates DNA and interferes w/synthesis and function → leads to B-cell and T-cell suppression b/c they require DNA formation to activate and also inhibits all rapidly proliferating tissues 

Use:

• Anti-cancer agent 
• Severe autoimmune diseases especially systemic complications such as vasculitis 

Capsaicin

MOA

MOA:

• Causes local depletion of substance-P (a neuropeptide that is involved in transmission of pain impulses) 
• It is applied topically to relieve pain associated with rheumatoid arthritis and osteoarthritis 

• Exercise 
• Weight control 
• Healthy diet 
• Smoking cessation
• Alcohol cessation
• Hydration 

• Organ meats (liver)
• High-fructose corn syrup 
• Ecessive alcohol use 

• Large protions/concentrations of meat + seafood 

• Low-fat/non-fat dairy 
• Low-fat/non-fat vegetables 

• NSAIDs 
• Colchicine 
• Allopurinol
• Febuxostat 
• Uricosuric agents (probenecid + sulfinpyrazone) 

• Indomethacin (also used for PG-E2 inhibitor and helps to close the ductus arteriosus) 

Why do we use them:

• Besides inhibiting PG-synthesis, NSAIDs inhibit phagocytosis of urate cyrstals but you MUST USE HIGH DOSES!!! Low doses of NSAIDs and aspirin MUST NOT BE USED because this will inhibit renal secretion
• Higher doses inhibit both secretion + reabsorption which results in greatly enhanced elimiation in the urine 

Colchicine

Use in gout?

MOA

Why do we use it:

• This is almost diagnostic of gout pain b/c it ONLY treats pain associated with gout

MOA:

• Binds tubulin + mitotic spindles + other micro-tubular structures → cuases arrest of cell division + cell mobility and decreases the secretion of granules (need microtubules for this) 

Colchicine 

Side-effects

• Diarrhea, nausea, vomiting, and abdominal pain (causes this b/c cells are unable to devide in the gut and causes malabsorption and alter GI lining) 
• Long term use leads to myopathy, agranulocytosis, aplastic anemia, and alopecia 

• Allopurinol 
• Febuxostat 

Allopurinol 

MOA

Use

MOA:

• Purine analog that competitively inhibits the last two steps in urice acid biosytnehsis that is catalyzed by xanthine oxidase

Use:

• Treatment of primary hyperuricemia of gout 
• Hyperuriciemia secondary to other causes such as malignancy or renal disease 

Allopurinol 

Side effects

• Most common SE is hypersensitivity
• Upon initial administration, may cause an acute attack of gout → so to alleviate this issue, start with lower doses of allopurinol and also give colchicine.  Once allopurinol has caused a decreased concentration of uric acid in the blood, colchincine can be withdrawn 

Febuxostat

MOA

Use

MOA:

• Xanthine oxidase inhibitor 
• Decreases urate levels more than allopurinol but NO benefit in terms of reduced number or severity of attacks of gout have been found

Uricosuric 

Drug examples 

Basic MOA

Drug examples:

• Probenecid 
• Sulfinpyrazone 
• Aspirin (NSAIDs)

Basic MOA:

• "Pardoxical effect"
• Low dose = increase serum uric acid b/c decrease excretion 
• High dose = decrease serum uric acid b/c increase excretion by blocking both secretion and reabsorption, but reabsorption inhibition has more of an impact 

Prebenecid

Use

MOA

Use:

• Low dose use was originally to decrease secretion of antibiotics when antibiotic supply was low 

MOA:

• Blocks tubular secretion (at low dose) and reabsorption (at high dose) of organic acids (such as uric acid) 
• The uricouric action of probenecid is BLUNTED by salicylates and to make things worse, the excretion of these drugs is decreased in the presence of probenecid, so DO NOT give them together 

Probenecid 

Side effects

Contraindications

• Well tolerated in most 
• Low incidence of GI irritation 
• Use with caution in patients with a history of peptic ulcers 
• Hypersensitivity reactions 

Contraindications

• Patients prone to urate stone formation
• Decrease renal function 

Sulfinpyrazone

Use

MOA

Drug interactions/side effects

Uricosuric action is additive to that of probenecid

MOA:

• Inhibitor of renal acid reabsorption 
• Also inhibits renal tubular secretion 

Side effects/drug interactions:

• Hypoglycemia by inhibiting metabolism of oral hypoglycemic agents
• Warfarin metabolism is also impaired
• GI-irritation 

Estrogen (maybe)

Bisphosphonates

Biphophate ("dronate" drugs)

MOA

Side effects

MOA:

• Bind to bone → taken up by osteoclasts → cause apoptosis of osteoclasts and also prevent resorption by directly binding to the calcium/phosphate mineralizations

Side effects:

• Esophagitis:  Less frequent administration reduces this. Decrease incidence by taking on empty stomach and standing up after taking it. 
• Osteonecrosis of the jaw:  Dose related 
• GI irritation:  Poorly absorbed