GOUT

GOUT

• Gout is a familial metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate crystals.

• The metatarsophalangeal joint of the first toe is often involved but other joints can also be affected.

• Uric acid calculi, tophi and nephritis may also occur.

GOUT

• Uric acid, a relatively insoluble compound is the end product of purine metabolism.

• Urate tend to crystallize in colder and acidic conditions.

• Neutrophils ingesting urate crystals secrete inflammatory mediators that lower the local pH and lead to further urate precipitation.

ACUTE GOUT

• The mainstay of the treatment during the acute attack of gout is the administration of NSAIDS, Glucocorticoids or Colchicine.

• Indomethacin, Naproxen, Sulindac and Celecoxib are effective in the treatment of acute gout.

• Aspirin is not used because it can inhibit urate excretion at low dose and can increase the risk of renal calculi at high dose.

ACUTE GOUT

• Glucocorticoids provide rapid relief within hours of the therapy.

• Prednisone or betamethasone are commonly used orally.

• Intravenous methylprednisolone and intraarticular triamcinolone have been found equally effective.

• ACTH injections are also considered.

ACUTE GOUT• Colchicine is the traditional and effective treatment, if

used early in the attack.• Colchicine a selective inhibitor of microtubule

assembly and inhibits cell division.• It also reduces leukocyte migration and phagocytosis;

and decrease free radical formation.• Colchicine can be used in low dose as a

prophylactic therapy to inhibit the recurrent attacks of acute gout during initial uricosuric therapy.

• Diarrhea is the commonly found adverse effect. It can severely damage kidney and liver. Overdose can be fatal.

GOUT PREVENTION OF RECURRENT ATTACKS• Serum uric acid levels < 5 mg / dL will prevent

recurrent gouty arthritis and eliminate tophaceous deposits entails long term hypouricemic therapy by

• 1. Uricosuric drugs - accelerating the renal excretion of uric acid. Eg., Probenecid, Sulfinpyrazone

• 2. reducing the conversion of purine to uric acid by xanthine oxidase. Eg., Allopurinol, Febuxostat

GOUTPROBENECID : PREVENTION OF RECURRENT ATTACKS

• Probenecid is an uricosuric drug that compete with uric acid for reabsorption in PCT of kidney.

• It is a good choice in underexcretors of uric acid when tophi present.

• It also can inhibit the secretion of penicillin and methotrexate.

• Increase urate stones due to probenecid can be prevented by making urine alkaline by sodium bicarbonate

• Probenecid can precipitate acute gout during their early phase and can be avoided by simultaneous administration of colchicine or NSAIDS.

GOUTALLOPURINOL : PREVENTION OF RECURRENT

ATTACKS

• Allopurinol is the preferred and standard therapy for chronic gout.

• Allopurinol and its metabolites are irreversible inhibitors of xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid.

• Allopurinol thus increase the concentration of more soluble hypoxanthine and xanthine and decrease the concentration of uric acid.

Allopurinol

GOUTALLOPURINOL• Allopurinol is also used as an adjunct to cancer

chemotherapy to slow the formation of uric acid by purines.

• Allopurinol inhibits the metabolism of mercaptopurine and azathioprine, that depend on xanthine oxidase.

• The serious toxicity includes hypersensitivity reactions like skin rashes and toxic epidermal necrosis and bone marrow suppression.

GOUTFEBUXOSTAT First nonpurine inhibitor of xanthine oxidase and

recently FDA approved for the prevention of chronic gout.

PEGLOTICASE is a recombinant uricase. Similarly to rasburicase, both enzymes metabolizes uric acid to allantoin. This reduces the risk of precipitates, since allantoin is five to ten times more soluble than uric acid.

It is indicated for severe refractory chronic gout

GOUT

Conclusions: • Acute gout : NSAIDS, steroids and

colchicine• Prophylaxis : Probenecid, allopurinol and

colchicine.

Rheumatoid arthritis• Rheumatoid arthritis is a chronic

inflammatory polyarthritis.• It is an autoimmune disease that results

in progressive joint destruction and deformity.

• NSAIDs alleviate the pain and inflammation but does not halt the loss of bone associated with RA.

• Disease modifying Anti-Rheumatic drugs ( DMARD) or Slow Acting Anti-Rheumatic Drugs (SAARD) are used to reduce and prevent the joint damage in rheumatoid arthritis

Rheumatoid arthritis IL-1

Rheumatoid arthritis

Characteristics Status Representative disease

Inflammation

Present Rheumatoid arthritis

Minimal present or absentOsteoarthritis (Acetaminophen is the first line)

Number of joint/s involved

Monoarticular Gout, osteoarthritis

Polyarticular ( > 5) Rheumatoid arthritis

Site of joint involvement

Distal interphalangeal Osteoarthritis ( not rheumatoid arthritis)

Metacarpophalangeal Rheumatoid arthritis ( not osteoarthritis)

First metatarsal phalangeal Gout, osteoarthritis

Rheumatoid arthritis

Disease modifying Anti-Rheumatic Drugs (DMARD) includes

• Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, Gold salts, Cyclosporine, Corticosteroids

Anti-cytokine therapy in Rheumatoid Arthritis

• Etanercept, Infliximab, Adalimumab, Anakinra

Rheumatoid arthritis

Disease modifying Anti-Rheumatic Drugs (DMARD) :

Methotrexate: It is now the first choice among DMARD in rheumatoid arthritis.

In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, but rather the inhibition of other enzymes like aminoimidazole carboxamide ribonucleotide transformylase (AICAR), leading to accumulation of adenosine, or the inhibition of thymidylate synthetase, with secondary effects on chemotaxis.

It is also used in psoriasis and SLE Dose related hepatotoxicity occurs frequently.

METHOTREXATE

Rheumatoid arthritis

Disease modifying Anti-Rheumatic Drugs (DMARD)

Sulfasalazine : It is approved for the treatment of RA and inflammatory bowel diseases.

• It is a prodrug which is converted into sulfapyridine and 5-aminosalicylic acid (5-ASA).

• It also inhibits effects of IL-1 and TNF-alfa.

• It is more effective than hydroxychloroquine.

• Stevens Johnson syndrome and aplastic anemia are toxic effects.

Rheumatoid arthritis

Disease modifying Anti-Rheumatic Drugs (DMARD) :

Hydroxychloroquine : • Interfere with the activity of T

lymphocytes• Decrease leucocytes chemotaxis • Stabilizes the lysosomal membranes• Interfere with DNA and RNA synthesis

and trap free radicals.• Less toxic than chloroquine but long

term use can cause retinopathy or corneal deposits.

Rheumatoid arthritis Disease modifying Anti-Rheumatic

Drugs Leflunomide : It is an immunomodulatory

agent that cause inhibition of dihydroorotate dehydrogenase the key enzyme in the pyrimidine synthesis – deprives the cell of UMP, a necessary component of RNA and DNA, thus inhibition of T-lymphocytes proliferation.

It is indicated for RA and psoritic arthritis. It can be used as a monotherapy or in

combination with methotrexate. Serious liver damage and bone marrow

suppression.

Rheumatoid arthritis

Dehydrogenase

Rheumatoid arthritis

Anti-cytokine therapy in Rheumatoid Arthritis:

o Failure to respond to two DMARD.o Prior to initiation of anti-cytokine

therapy, screening for TB is done as it can cause activation of latent TB.

Rheumatoid arthritisAnti cytokine drugs

Infliximab Etanercept Adalimumab Anakinra Abatacept

Chimeric IgG 25% mouse, 75% human

Recombinant fusion protein

Fully human IgG

Recombinant IL-1 receptor antagonist

Recombinant fusion protein

Mechanism of action

Blocks TNF-α Blocks TNF α & β

Blocks TNF-α IL-1 receptor antagonist

Blocks costimulationPrevents CD28 from binding CD80/86

Uses RA, psoriasis, crohn’s disease

RA, psoriasis RA, psoriasis, crohn’s disease

RA (when not responding to other drugs)

RA (when not responding to other drugs)

Questions• A 30-year-old man suddenly develops pain, redness, and

swelling of his right first metatarsophalangeal joint. There is no history of injury. Serum uric acid concentration is 8 mg/dl (normal, < 5mg/dl). Examination of joint aspirate shows birefringent crystals. Which of the following drugs is MOST APPROPRIATE & SAFE to treat the acute symptoms in this patient?

• Allopurinol• Low dose Aspirin• Meperidine• Naproxen• Probenecid

Questions• A 54-year-old woman presents to her primary care physician with

signs and symptoms consistent with the early stages of rheumatoid arthritis. She was started on hydroxychloroquine and methotrexate therapy, which provided adequate relief. However, after several years of therapy, her symptoms began to worsen. Radiologic studies show progressive destruction in the joints of several fingers. Treatment with a biological response modifier and anticytokine agent was considered. Which one of the following agents used in rheumatoid arthritis acts by blocking tumor necrosis factor alpha (TNF-)?

• Etanercept• Hydroxychloroquine• Leflunomide• Methotrexate• Sulfasalazine

Questions• The new 2009 clinical guidelines for the treatment of

Rheumatoid arthritis recommends that a combination of disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate and one other DMARD to be started within 3 months of the onset of persistent symptoms. The disease modifying antirheumatic drug, anakinra (kineret) acts by which of the following mechanisms?

• Block spindle fiber formation in synovial cells• Block TNF- binding to its receptor• Block IL-2 binding to its receptor• Block CD80 (B7-1) and CD86 (B7-2) binding to CD28 on T

cells• Block IL-1 binding to its receptor