what is RA as autoimmune disease and gout drugs used to treat RA and gout

1. MANAGEMENTOFRHEUMATOIDARTHRITIS
ANDGOUT
preparedby
• AyatollahAbdel-Sattar

2. What is Rheumatoid arthritis (RA) ?
• RA is a chronic, progressive inflammatory auto immune disease in
which the body attacks itself.
• characterized by polyarticular
symmetric joint involvement
and on long term leads to
systemic manifestations.

3. PATHOPHYSIOLOGYof RA :
• T cells are key initiators of the immune response involved in the
pathogenesis of RA .
• The immune system is activated by an unknown antigen.
• Antigens is recognized by MHC proteins on surface of Antigen-
presenting cells , resulting in activation of T cell which then
activates B cell .

4. • T cells secrete a variety of different cytokines such as IL-2, which
results in a further perpetuation of T cells. This results in the
production of more T cells.
• The T cells then proliferate, secrete a variety of proinflammatory
cytokines, and migrate to the synovial tissue .
• Activated T cells secrete IL-17
Which has been implicated
in neutrophil recruitment to
inflammation site .

5. • Activated T cells then activate B-cells and macrophages, neutrophils and
secrete a variety of proinflammatory cytokines such as tumor necrosis factor-α
(TNF-α),Interleukin-1 (IL-1),Interleukin-6 (IL-6) which stimulate further
activation of inflammatory processes and attract cells to areas of inflammation .
• Activated B cells produce plasma cells,
which form antibodies such as :
 Rheumatoid factor (RF ).
Anticyclic citrullinated peptide (ACCP).
• Macrophages are stimulated to release
pro-inflammatory cytokines,
chemokines, and growth factors, These
products can activate local
fibroblast-like synoviocytes (FLS)
in the lining of the synovium .

6. • Synovial tissue lining the joint capsule results in tissue proliferation (pannus
formation).
• Pannus is an abnormal layer of fibrovascular tissue that invades cartilage and
eventually the bone surface, producing erosions of bone and cartilage and
leading to joint destruction.
• End results may be loss of joint space and joint motion, bony fusion
(ankylosis), joint subluxation, tendon contractures, and chronic deformity.

7. CLINICALPRESENTATION:
Signs &symptoms :
• RA usually affects joint symmetrically (on both sides)
most frequently attacks the wrists ,hands ,elbow ,shoulders ,
knees and ankles.
• Tender, warm, swollen joints
• Fatigue , low grad fevers, a loss of energy.
• Morning stiffness “Gelling phenomenon” last >60 min.
• Firm nodules under the skin.
• Tender, warm, swollen joints .

8. Onset: over weeks to months.
Progression: RA progresses rapidly during 1st 6years .
• 80% of patient develop some permanent joint abnormality within 10 years.
Risk factors :

9. Extra articular manifestation (systematic)
• Eyes : Dry eyes , Scleritis.
• Skine: Rheumatoid nodules
• Blood vessles : Vasculitis.
• Lungs : Pleuritis , lung nodules formation .
• Heart : pericarditis ,
↑ risk of MI ,shock , heart attack.
• Spleen : Splenomegaly.
• Bone marrow Suppression : Anemia,
Thromocytosis, Neutropenia,
Thrombocytopenia.
• CNS :Peripheral neuropathy.

10. DIAGNOSIS:
• History& Examination : signs& symptoms as previously indicated
• Laboratory test :
* Rheumatoid Factor : (not confirmatory test)
(RF) is an antibody that is present eventually in the blood of most people with
rheumatoid arthritis.
• Not all people with rheumatoid arthritis test RF+ve20%, ( must repete )
• Some people test RF+ve , yet never develop the disease. (false +ve)
*Anti-CCP Antibodies: This blood test detects antibodies to cyclic citrullinated
peptide (anti-CCP). This test is positive in most people with rheumatoid arthritis.
It can even be positive years before RA symptoms develop.
*C-reactive protein (CRP) ,Erythrocyte sedimentation rate (ESR) markers for inflammation

11. • Imaging Examination:
* Ultra sound
*X-rays
*MRI

12. Treatment:
**GoalsofTreatment:
*Relieve pain.
*Reduce inflammation.
*Slow down or stop joint damage.
*Improve a person’s sense of well-being and ability to function.
NONPHARMACOLOGIC THERAPY:
Adequate rest.
 weight reduction if obese.
physical therapy.
Patients with severe disease may
benefit from surgical procedures such
as tenosynovectomy,tendon repair,and
joint replacements.
Routine monitoring and ongoing care.
PHARMACOLOGIC THERAPY:
Two classes of medications are used in
treating RA:
I. Drugs used to try to slow
progression of the disease:Disease-
modifying antirheumatic drugs
(DMARDs) .
II. Drugs used to reduce
inflammation& pain such as: NSIDs
and corticosteroids.

13.  NonsteroidalAnti-inflammatoryDrugs:
• . NSAID inhibition of prostaglandin biosynthesis ,Various NSAIDs have additional possible mechanisms
of action, including inhibition of chemotaxis, down-regulation of IL-1 production, decreased
production of free radicals.
NONSELECTIVE COX INHIBITORS most GIT SE
• Diclofenac
• Indomethacin
• Ketoprofen
• Naproxen
COX-2 SELECTIVE INHIBITORS less GIT SE
• Celecoxib.
• Meloxicam
There is no best NSAID for all patients.
There is one or two best NSAIDs for a specific pt..

14. NonsteroidalAnti-inflammatoryDrugs

15.  Corticosteroids
• Corticosteroids have anti-inflammatory and immunosuppressive properties. interfere with
antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis,
and inhibit neutrophil and monocyte superoxide radical. eg, prednisone.
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (2 weeks to 6 months to become clinically
evident.)
Nonbiologic DMARDs Biologic DMARDs
• Immunosuppressant • Anti-TNF-α
Methotrexate, Mabs
Azathioprine, TNF-α inhibitors
Cyclophosphamide, • IL-1 receptor antagonist
cyclosporine,
• Chloroquine
hydroxychloroquine
• Sulfasalazine
• Leflunomide

16.  NonbiologicDMARDs: (Immunosuppressant)
Methotrexate,
the first-line DMARD for treating RA and is used in 50–70% of patients
• Mechanism of Action: at the low doses
relates to inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase
which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an
accumulation of AMP which converted extracellularly to adenosine, which is a potent
inhibitor of inflammation.
As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and
lymphocytes are suppressed.
There is some effect on dihydrofolate reductase and this affects lymphocyte and
macrophage function

17. • MTx Onset is as early as 2 to 3 weeks, Although the most common methotrexate
dosing regimen for the treatment of RA is 15–25 mg weekly, there is an
• increased effect up to 30–35 mg weekly.
• MTX’s serum half-life is usually only 6–9 hours.
• MTX is contraindicated in:
• pregnant and nursing women,
• chronic liver disease,
• immunodeficiency,
• leukopenia, thrombocytopenia,
• preexisting blood disorders.
• Adverse Effects: Nausea and mucosal ulcers .
• leukopenia, anemia, stomatitis, GI ulcerations, and alopecia .
• hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is
rare (<1%).

18.  SULFASALAZINE
• Mechanism of Action:
• Sulfasalazine, is metabolized to sulfapyridine and 5
Aminosali cylic acid.
• The sulfapyridine is probably the active moiety when treating RA (unlike inflammatory
bowel disease)
• sulfasalazine, also has an effect. Suppression of T-cell responses and inhibition of in
vitro B-cell proliferation
• sulfasalazine metabolites inhibit the release of inflammatory cytokines produced by
monocytes or macrophages, eg, IL-1, -6, and -12, and TNF-α.
• Indications:
Sulfasalazine is effective in RA and reduces radiologic disease progression.
The usual regimen is 2–3 g/d.
• Adverse Effects:
• nausea, vomiting, headache, and rash.
• Hemolytic anemia and methemoglobinemia
• Reversible infertility occurs in men, not affect fertility in
women.

19.  CYCLOSPORINE
Mechanism of Action: Cyclosporine is a peptide antibiotic but is considered a nonbiologic
DMARD through regulation of gene transcription,
• it inhibits IL-1 and IL-2 receptor production .
• inhibits macrophage-T-cell interaction
• and T-cell responsiveness
• T-cell-dependent B-cell function is also affected.
. Indications: it retards the appearance of new bony erosions.
Its usual dosage is 3–5 mg/kg/d divided
into two doses.
Adverse Effects:
• Leukopenia, thrombocytopenia.
• High doses can be cardiotoxic
• Sterility may occur after chronic dosing
at anti-rheumatic doses,
especially in women.

20.  AZATHIOPRINE
Mechanism of Action: Azathioprine is a synthetic nonbiologic DMARD that acts
through its it’s metabolite, 6-thioguanine which suppresses
• T-cell function and B-cell leads to suppresses immunoglobulin production
• IL-2 secretion
Indications: Azathioprine is use in RA at a dosage of 2 mg/kg/d.
Adverse Effects:
• Bone marrow suppression,
• GI disturbances,
• increase in infection risk.

21.  Hydroxychloroquine &chloroquine
• • Mechanism of Action:. The following mechanisms have been proposed:
• suppression of T-lymphocyte responses to mitogens,
• inhibition of leukocyte chemotaxis,
• stabilization of lysosomal enzymes,
• inhibition of DNA andRNA synthesis.
Indications: usual dosages
(up to 6.4 mg/kg/d for hydroxychloroquine or
200 mg/d for chloroquine).
• It usually takes 3–6 months to obtain a response
Adverse Effects:
• ocular toxicity may occur at dosages greater than usual dosages
ophthalmologic monitoring every 12 months is advised.
• nausea, vomiting, abdominal pain, rashes, and nightmares

22.  LEFLUNOMIDE
Mechanism of Action: its active metabolite, A77-1726.
• This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in
ribonucleotide synthesis
• inhibits T-cell proliferation
• reduces production of autoantibodies by B cells.
Indications: Leflunomide is as effective as methotrexate in RA, including inhibition
of bony damage, combined therapy have better results .
Adverse Effects:
• Diarrhea 25% of pt.
• Elevation in liver enzymes can occur.
• Both effects can be reduced by decreasing
thedose of leflunomide..
• This drug is contraindicated in pregnancy.

23.  BiologicDMARDs
•Adalimumab
Mechanism of Action: Adalimumab is a fully human IgG1 anti-TNF monoclonal
antibody.
• This compound complexes with soluble TNF-α and prevents its cell surface
receptors.
• This results in down-regulation of macrophage and T-cell function.
• 40% in the presence of methotrexate, and the formation of human anti-
monoclonal antibody is decreased when methotrexate is given at the same time.
• The usual dose in RA is 40 mg every other week
. Indications: The compound is approved for RA,
It decreases the rate of formation of new erosions.
• It is effective both as monotherapy and
in combination with methotrexate
and other nonbiologicDMARDs.

24. TNF-α Inhibitors
• Etanercept
Mechanism of Action: Etanercept is a recombinant fusion protein consisting of two
soluble TNF p75 receptor moieties linked to the Fc portion of human IgG1; it binds
TNF-α molecules.
Indications:
• it given sc INJ as 25 mg twice weekly or 50 mg weekly.
• Etanercept decreases the rate of formation of new erosions relative to
methotrexate alone.
• Combination yherapy with
MTX have good result.

25. AdverseEffectsofAntiTNF-α
• The risk of bacterial infections and macrophage-dependent infection
• (including tuberculosis, fungal, and other opportunistic infections) is
increased,
• Nevertheless, all patients should be screened for latent or active tuberculosis
before starting TNF-α-blocking agents.
• increased risk of HBV reactivation and screening for HBV is important before
starting the treatment.
• TNF-α-blocking agents increase the risk of skin cancers r lymphomas .

26.  IL-1receptorantagonist
Anakinra
Mechanism of Action: it blocks the effect of IL-1on IL-1 receptors,
hence decreasing the immune response in inflammatory diseases.
Indications: The recommended dose in the treatment of RA
is 100 mg daily.
• Anakinra is effective in gout.

27.  GOUT :
PHARMACOTHERAPY OF GOUT
Gout is a metabolic disease characterized
by recurrent episodes of acute arthritis
due to deposits of monosodium urate
in joints and cartilage.
Acute gout usually causes painful
distal monoarthritis and
also can cause joint destruction, and renal calculi and damage.
In most patients with gout,

28. PATHOPHYSIOLOGYofgout
• Hyperuricemia arises from underexcretion rather than overproduction of
urate.
• Mutations of one of the renal urate transporters, URAT-1, are associated
with hypouricemia.
• Monosodium urate crystals activate monocytes/macrophage
• This results in the secretion of cytokines, including IL-1 β and TNF-α;
endothelial activation; and attraction of neutrophils to the site of
inflammation.
• Neutrophils secrete inflammatory mediators that lower the local pH and lead
to further urate precipitation.

29. The aims of treatment are to:
• Decrease the symptoms of an acute attack.
• Decrease the risk of recurrent attacks.
• Lower serum urate levels.
The substances available for these purposes are:
• Drugs that relieve inflammation and pain (NSAIDs, colchicine,
glucocorticoids)
• Drugs that prevent inflammatory responses to crystals (colchicine
and NSAIDs)
• Drugs that act by inhibition of urate formation (allopurinol,
febuxostat) .
• Drugs that increses urate excretion (probenecid)

30. COLCHICINE.
Colchicine isconsidered second-line therapy because it has a narrow therapeutic
window and a
high rate of side effects, particularly at higher doses.
MECHANISM OF ACTION.
• It has antimitotic effects, arresting cell division in G1 by interfering with microtubule
and spindle formation .This effect is greatest on cells (e.g., neutrophils, alter neutrophil
motility and decreases the secretion of chemotactic factors by activated neutrophils.
• Colchicine inhibits the release of histamine-containing granules from mast cells,
• THERAPEUTIC USES.
• Acute Gout. Colchicine dramatically
relieves acute attacks of gout if given
within 24 h of attack onset.
• Pain, swelling, and redness
completely gone within 48-72 h.
• Prevention of Acute Gout
• ADVERSE EFFECTS.
• Nausea, vomiting, diarrhea,
• and abdominal pain,
• hemorrhagic gastropathy,

31. ALLOPURINOL
Allopurinol inhibits xanthine oxidase (XO) and prevents the synthesis of urate
from hypoxanthine and xanthine.
• Allopurinol is an analog of hypoxanthine.
MECHANISM OF ACTION. Both allopurinol and its primary metabolite, oxypurinol
(alloxanthine),reduce urate production by inhibiting XO, which converts xanthine
to uric acid.
Allopurinol competitively inhibits XO at low concentrations and is a
noncompetitive inhibitor at high
Allopurinol facilitates the dissolution of tophi and prevents the development or
progression of chronic gouty arthritis
ADVERSE EFFECTS.
The most common adverse effects
are hypersensitivity

32. FEBUXOSTAT
Febuxostat is an XO inhibitor approved for treatment of hyperuricemia in
patientswith gout.
MECHANISM OF ACTION
• . Febuxostat is a nonpurine inhibitor of XO. Unlike oxypurinol, the active
metabolite of allopurinol
• febuxostat forms a stable complex with both the reduced and oxidized
enzymes and inhibits catalytic function in both states.
THERAPEUTIC USE.
• used forhyperuric patients with
gout attacks,
ADVERSE effects
• liver function abnormalities,
• nausea, joint pain, and rash.
• There was a higher rate of myocardial infarction and stroke in patients on
febuxostat than on allopurinol.

33. URICOSURICAGENTS
• Uricosuric agents increase the rate of excretion of uric acid.
• urate is filtered, secreted, and reabsorbed by the kidneys.
• Reabsorption is mediated by an organic anion transporter URAT-1,
which can be inhibited.
Uricosuric drugs such as probenecid, sulfinpyrazone, benzbromarone,
and losartan compete with urate for the transporter,
• thereby inhibiting itsreabsorption via the urate–anion exchanger .

34. PROBENECID.
• ADVERSE EFFECTS.
• Hypersensitivity reactions,,
• overdosage with probenecid results in CNS stimulation,
• convulsions, and death from respiratory failure.
BENZBROMARONE
• Benzbromarone is a potent uricosuric agent widely used
• Adverse effects
• Hepatotoxic drug..