Pathophysiology of rheumatoid arthritis

Pathophysiology of rheumatoid arthritis

1. Pathophysiology of Rheumatoid arthritis
Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammatory disorder that may affect many tissues and
organs, but principally attacks flexible (synovial) joints. It can be a disabling and painful condition, which can lead to substantial loss of
functioning and mobility if not adequately treated.
Etiology:
Rheumatoid arthritis is a chronic systematic disease of unknown cause. An external trigger like cigrattes smoking, infections, or trauma can trigger the auto
immune disorder, leading to synovial hypertrophy and chronic joint inflammation alone with the potential for extra- articular manifestations, is theorized to
occur in genetically susceptible individuals.
Check for symptoms:
 Systemic symptoms include early morning stiffness of affected joints,
 generalized afternoon fatigue and malaise
 anorexia (loss of appetite for food)
 weakness
 occasionally, low-grade fever.
 Joint symptoms include pain, swelling, and stiffness.
 Involved joints become tender, with erythematic (superficial reddening of the skin), warmth, swelling, and limitation of motion.
 With the progression of disease, the inflammatory activity leads to erosion and destructions of joints surface with the impaired movements and leads
to deformity.

2. Diagnosis:
 Clinical criteria (RA should be suspected in patients with polyarticular, symmetric arthritis, particularly if the wrists and 2nd and 3rd
metacarpophalangeal joints are involved.)
 Serum rheumatoid factor (RF), anti-CCP(anti-cyclic citrullinated peptide antibodies), and ESR or C-reactive protein (CRP)
 X-rays
Nonselective Dosage
Maximum Recommended
Daily Dose
Diclofenac



75 mg twice daily or 50
mg thrice daily
100 mg once/day
sustained-release
150 mg
Etodolac


300–500 mg twice daily 1200 mg
Fenoprofen


300–600 mg four times a
day
3200 mg
Flurbiprofen


100 mg twice or thrice
daily
300 mg

3. Ibuprofen




400–800 mg 4 times in a
day
3200 mg
Indomethacin


25 mg thrice or four times
a day
75 mg twice a day
sustained-release
200 mg
Ketoprofen



50–75 mg four times a
day
200 mg once/day
sustained-release
300 mg
Meclofenamate


50 mg thrice or four times
a day
400 mg
Nabumetone


1000–2000 mg/day in 1
dose or in divided doses
2000 mg
Naproxen


250–500 mg twice daily 1500 mg

4. Oxaprozin


1200 mg once/day 1800 mg
Piroxicam


20 mg once/day

Prescription contains:
Disease-modifying antirheumatic drugs (DMARDs) (The most commonly used agent is methotrexate with other frequently used agents including
sulfasalazine and leflunomide. Sodium aurothiomalate (Gold) and cyclosporine are less commonly used due to more common adverse effects.
Agents may be used in combinations.
Anti-inflammatory agents
NSAIDS (Diclofenac, etodolac.fenoprofen etc)
COX-2 inhibitors, such as celecoxib
Glucocorticoids (Cortisol)
Counselling on side effects:
NSAIDs:
 Aspirin is no longer used for RA, as effective doses are often toxic

5.  NSAIDs other than coxibs should be avoided in patients with previous peptic ulcer disease or dyspepsia. Other possible adverse effects of all
NSAIDs include headache, confusion and other CNS symptoms, increased BP, worsening of hypertension, edema, and decreased platelet function.
 NSAIDs increase cardiovascular risk . Creatinine levels can rise reversibly because of inhibited renal prostaglandins; less frequently, interstitial
nephritis can occur.
 Patients with urticaria, rhinitis, or asthma caused by aspirin can have the same problems with these other NSAIDs.
 Hydroxychloroquine-Usually mild dermatitis, Myopathy,Corneal opacity (generally reversible),Occasionally irreversible retinal degeneration.
 Leflunomide-Skin reactions,Hepatic dysfunction,Diarrhea
 Methotrexate – Liver fibrosis (dose-related, often reversible),Nausea,Possibly bone marrow, suppression,Stomatitis,Rarely pneumonitis (potentially
fatal)
 Sulfasalazine-Bone marrow suppression,Gastric symptoms,Neutropenia,Hemolysis,Hepatitis
COX-2 inhibitors: They have a similar gastrointestinal risk as an NSAIDs plus a proton pump inhibitor. In the elderly there is less gastrointestinal
intolerance to celecoxib than to NSAIDs alone.There however is an increased risk of myocardial infarction with COX-2 inhibitors. Anti-ulcer
medications are not recommended routinely but only in those high risk of gastrointestinal problems.
Glucocorticoids : While long-term use reduces joint damage it also results in osteoporosis (a medical condition in which the bones become brittle
and fragile from loss of tissue, typically as a result of hormonal changes, or deficiency of calcium or vitamin D) and susceptibility to infections,
and thus is not recommended.

6. Anti-­­TNFα
INFLIXMAB (i.v.)
Used successfully in the treatment of Crohn’s Disease
Some evidence of effectiveness in Ulcerative Colitis
Potentially curative, rather than just simply palliative
Successful in some patients with refractory disease
and fistulae
Mechanism of Action of Infliximab (Anti-­‐TNFα)
 Indicates that TNFα plays an important role in the
pathogenesis of IBD
 Anti-­‐TNFα reduces activation of TNDα receptors in the
gut.
 Production of other cytokines, infiltration and
activation of leukocytes is also reduced.

 Anti-­‐TNFα also binds to membrane associated TNFα
 Mediates complement activation and induces
cytolysis of cells expressing TNFα
 This promotes apoptosis of activated T-­­Cells

Pharmacokinetics of Infliximab (Anti-­‐TNFα)
 Given intravenously
 Very long half-­­life (9.5 days)
 Benefits can last for 30 weeks after a single infusion
 Most patients relapse after 8-­‐12 weeks
 Therefore, it is important to repeat infusion every 8
weeks.

Adverse Effects of Infliximab (Anti-­‐TNFα)
 4x to 5x increase in incidence of Tuberculosis and
other infections
 Also risk of reactivating dormant TB
 Increased risk of SEPTICAEMIA – therefore,
contraindications if abscesses are present
 Worsening of heart failure
 Increased risk of demyelinating disease
 Increased risk of malignancy

7. home rheumatoid arthritis (ra) medications article
Privacy & Trust Info
 Rheumatoid arthritis overview
 Rheumatoid arthritis medications list
 What are the new classes of rheumatoid arthritis medications?
 What are effective over-the-counter medications for rheumatoid arthritis?
 What are effective natural medications for rheumatoid arthritis?
 What are the potential risks and benefits of injectable medications for rheumatoid arthritis?
 What are the best rheumatoid arthritis medications for pain?
 What are the side effects of rheumatoid arthritis medications?
 Rheumatoid arthritis medications special considerations: weight gain and pregnancy
 What are rheumatoid arthritis medications in development?
 What are the treatment options if rheumatoid arthritis medications are not working?
 Can be immunogenic (monoclonal antibody) – therefore given with azathioprine
 Should only be used by specialists where adequate resuscitation facilities are available – due
to a RISK OF ANAPHYLAXIS
 2-­‐4% risk of serious side-­‐effect

Infliximab Summary
 In steroid-­‐dependent patients infliximab + AZA doubles the number of patients in steroid-­­free
remission after 1 year of treatment, but still only by 40%.
 This combination delays relapse
 It is most beneficial in patients who:
o Have not taken thiopurines before
o Are young (~26 years)
o Have colonic CD

Adalimumab
(sc.)
TNF Inhibitor Binds to TNFα and prevents activation
Natalizumab Antibody against
alpha-­­4-­­integrin
 Antibody against alpha-­­4-­­integrin
 Cell adhesion molecule
 Evidence that it induces remission in some patients with Crohn’s Disease
 Generally well tolerated
 Rarely (1:1000) encephalopathy if taken in combination with other drugs.

8. RHEUMATOID ARTHRITIS OVERVIEW
Rheumatoid arthritis (RA) is a disease in which the body's immune system attacks its own joints.
This results in pain, swelling and potentially permanent damage. About 1.5 million people in the
United States have RA and it affects women far more than men. RA should not be confused
with osteoarthritis (OA) which is joint pain resulting from wearing down of cartilage – most
commonly in the knees and hips. By contrast, RA commonly affects smaller joints, such as in the
fingers and toes.

SLIDESHOW
Rheumatoid Arthritis (RA) Symptoms & TreatmentSee Slideshow
RHEUMATOID ARTHRITIS MEDICATIONS LIST
Analgesics
Analgesics, or painkillers, are a staple of RA treatment. Mild-to-moderate RA pain can usually
be treated with non-opioid analgesics. But for severe pain, opioids and opioid combinations are
more effective. That increased effectiveness does come with the potential for side effects,
including drowsiness and constipation.

9. Non-Opioid Medications
 Acetaminophen (Tylenol)
 Tramadol (Ultram)
Combination Products: Opioids plus Other Analgesics
 Acetaminophen with codeine (Tylenol #3, Tylenol #4)
 Acetaminophen with hydrocodone (Hycet, Lortab, Norco, Vicodin, Vicodin ES, Vicodin HP,
Xodol, Zamicet)
 Aspirin with dihydrocodeine and caffeine (Synalgos-DC)
 Ibuprofen with hydrocodone (Ibudone, Reprexain, Vicoprofen)
 Acetaminophen with oxycodone (Percocet, Roxicet, Xartemis XR)
 Aspirin with oxycodone (Percodan)
Opoids (single ingredients)
 Fentanyl (Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis, Subsys)
 Hydrocodone bitartrate (Hyslinga ER, Zohydro ER)
 Hydromorphone (Dilaudid, Dilaudid HP, Exalgo)
 Meperidine (Demerol)
 Methadone (Dolophine)
 Morphine sulfate (MS Contin, Kadian, Avinza)
 Oxycodone (Oxycontin, Oxecta)
 Oxymorphone (Opana, Opana ER)
 Tapentadol (Nucynta, Nucynta ER)
Opioid Agonists/Antagonists
 Buprenorphine (Butrans, Buprenex)
 Butorphanol (Butorphanol NS, Stadol)
 Nalbuphine
 Pentazocine (Talwin)
Anti-Inflammatory Medications
This class of drugs is also known as non-steroidal anti-inflammatory drugs (NSAIDs). They
work by inhibiting and/or interfering with chemicals in the body which cause inflammation. The
most common drawback to NSAID use is their propensity to
cause stomach and gastrointestinal bleeding.
 Aspirin
 Celecoxib (Celebrex)
 Diclofenac
 Diclofenac/Misoprostol (Arthrotect)
 Diflunisal
 Etodolac

10.  Ibuprofen (Motrin, Advil)
 Indomethacin (Indocin)
 Ketoprofen
 Nabumetone
 Naproxen (Naprosyn, Anaprox, Aleve)
 Naproxen/Esomeprazole (Vimovo)
 Naproxen/Lansoprazole (Prevacid NapraPAC)
 Oxaprozin (Daypro)
 Piroxicam (Feldene)
 Salsalate
 Sulindac
 Tolmetin
Biologic Agents
Biological drugs are proteins manufactured using recombinant DNA technology. They are
immunosuppressants that target and block the action of cells or chemicals that enable
the immune system to cause inflammation and other symptoms of RA. Biological agents are
called disease-modifying antirheumatic drugs (DMARDs) because by suppressing components
of the immune system they reduce symptoms and reverse the course of RA.
 Abatacept (Orencia)
 Adalimumab (Humira)
 Anakinra (Kineret)
 Certolizumab (Cimzia)
 Etanercept (Enbrel)
 Golimumab (Simponi)
 Infliximab (Remicade)
 Rituximab (Rituxan)
 Tocilizumab (Actemra)
Janus Kinase (JAKs) Inhibitor
JAK inhibitors are the newest class of drugs used to treat RA. They work by blocking Janus
kinase JAKs) enzymes located within stem cells and other cells. JAKs enzymes are involved in
stimulating immune responses that contribute to symptoms of RA. Therefore, inhibiting JAKs
enzymes reduces symptoms of RA.
Tofacitinib (Xeljanz) is an oral drug and is the first JAKs inhibitor approved by the FDA.
Corticosteroids
Corticosteroids are synthetic versions of anti-inflammatory chemicals normally produced in the
body. They are powerful, but long-term use can result in severe side effects, including weaker
bones and a depressed immune system.
 Cortisone

11.  Dexamethasone
 Hydrocortisone (Cortef)
 Ethamethasoneb (Celestone)
 Fludrocortisone (Florinef)
 Methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol)
 Prednisone
 Prednisolone (Prelone)
 Triamcinolone (Aristospan, Kenalog)
Disease-Modifying Antirheumatic Drugs (DMARDs)
DMARDs don't just relieve pain and/or inflammation of RA, they actually can alter the course of
the chronic disease, and help stop some of the damage from getting worse. DMARDs include the
biological drugs listed above as well as non-biological drugs listed below.
 Methotrexate, a cancer drug, is one of the most popular and effective drugs in this class.
 Azathioprine (Imuran)
 Auranofin (Ridaura)
 Chloroquine (Aralen)
 Cyclophosphamide (Cytoxan)
 Cyclosporine (Gengraf, Sandimmune)
 Gold sodium thiomalate (Myochrysine, Solganal)
 Hydroxychloroquine (Plaquenil)
 Leflunomide (Arava)
 Methotrexate (Rheumatrex)
 Minocycline (Minocin)
 Mycophenolate (CellCept)
 Penicillamine (Cuprimine)
 Sulfasalazine (Azulfidine)