DRUGS USED IN GOUT AND RA
GOUT - a disorder of uric acid metabolism, characterized by hyperuricemia and recurrent attacks of acute
arthritis.
Uric acid - an end product of dietary purines or the breakdown of purines from nucleic acids during cell
turnover.
Hyperuricemia is associated with crystallization of monosodium urate in tissues.
Deposition of uric acid crystals in tissues initiate an inflammatory and an immune response  damaging
cartilage in joint.
Causes of hyperuricemia:
 overproduction of uric acid from excessive cell destruction or/and
 reduced renal excretion during renal failure and administration of drugs, that reduce tubular secretion of uric
acid
Characterization of acute attacks of gouty arthritis:
· rapid onset of excruciating pain, swelling and inflammation
· typically monoarticular at first
· most often affecting the first metatarsophalangeal joint (podagra)
· untreated attacks may last from 3 to 14 days
· attacks may be precipitated by stress, trauma, alcohol ingestion, infection, surgery, rapid lowering of
serum uric acid by ingestion of uric acid-lowering agents, and ingestion of certain drugs known to
elevate serum uric acid concentrations.
The goals in the treatment of gout:
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to terminate the acute attack by administration of antiinflammatory agents
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to prevent recurrent attacks of gouty arthritis
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to prevent complications associated with chronic deposition of urate crystals in tissues by lowering uric acid
levels in the plasma.
Treatment of acute gout
 NSAIDs (treatment of choice)
- indomethacin is most common used
∙ dosage: 75 mg given initially, followed by 50 mg every 6 hours for 2 days, then 50 mg every 8 hours
for 1 to 2 days.
∙ side effects unique to indomethacin: headache and dizziness
∙ other side effects: gastric ulceration and bleeding,
 Colchicine (is usually reserved for patients intolerated NSAIDs).
- it is not effective in reducing inflammation in other disorders.
- mechanism of action in gout:
∙ reducing production of chemotaxins  inhibiting leukocyte migration into inflamed tissue
∙ depolymerization of proteins in leukocyte microtubules by forming a complex with tubulin
- dosage: orally 1 mg initially, followed by 0,5 mg every 2 hours until (up to total dose of 8 mg has been
given)
- is effective in acute gouty arthritis when treatment is begun within 24 to 48 hours of the onset of joint
symptoms.
- pain relief usually begins after about 18 hours and is maximal by 48 hours.
- the major side effects: diarrhea, nausea, vomiting and abdominal pain
 intra-articular injection or oral corticoids (f.e. prednisolone) - reserved for resistant episodes of gout.
Prophylactic therapy – uric acid lowering therapy
Indications for prophylactic therapy:
- persistent hyperuricemia - elevated serum uric acid (over than 10 mg/dL)
- Attention! - patients with asymptomatic hyperuricemia should not be treated with hypouricemic agents
- severe attack of gouty arthritis
- frequent attacks of gouty arthritis (more than 2-3 per year) - even if the serum uric acid concentration is
normal or only minimally elevated
- uric acid lithiasis
- 24-hour urinary excretion of uric acid over than 1000 mg
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Uricosuric drugs
- increase renal excretion of urate
- mechanism of action:
∙ increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid
∙ increase the concentration of uric acid in urine  possible stone formation
prophylaxis of renal stones:
 maintenance of adequate urine flow (by administration of adequate amount of fluids –2.53.0 L/day)
 alkalinization of the urine with sodium bicarbonate solution or potassium citrate
- used in patients with normal renal function and no history of nephrolithiasis
- indicated in underexcretors (with 24-hour excretion of urate less than 600 mg/day)
- available uricosuric drugs:
∙ probenecid and sulfinpyrazone (commonly used in Europe, as well as in the USA)
∙ benzobromarone (available in Europe, but not in the USA)
- there may be a temporary increase in uric acid blood levels and increased risk of an acute gouty attack
prophylaxis of acute attack: beginning therapy with the administration of small dosages of
colchicines
Inhibitors of uric acid synthesis (Allopurinol)
- mechanism of action: xanthine oxidase inhibitor  blocks the conversion of hypoxanthine to xanthine
and xanthine to uric acid
- indications for allopurinol:
∙ drug of choice in patients with a history of urinary stones or impaired renal function
∙ useful in both
 patients with increased synthesis (who are overproducers - individuals who
excrete more than 600 mg/day on a purine-free diet)
 and decreased clearance of uric acid
∙ useful in patients with lymphoproliterative or myeloproliferative disorders
- the major side effects:
∙ skin rash (hypersensitivity reaction)
∙ bone marrow suppression (leucopenia)
∙ occasional GI toxicity
∙ increased frequency of acute gouty attacks with the initiation of therapy (should be started with
small doses of antiinflammatory agents)
- dosage – initially 100 mg once daily, up to 300 mg/d depending on the serum uric acid response.
RHEUMATOID ARTHRITIS (RA) - a chronic, systemic inflammatory disorder involving peripheral joints
(an inflammation in the synovial tissue) and extraarticular tissues and organs.
The pathogenesis of RA is unknown, probably - an autoimmune disease. The activation of T cells and increased
levels of t cell-derived cytokines (IL-1 and TNF-) are present.
Signs and symptoms: pain, swelling, warmth, tenderness, stiffness, limitation of motion of joints, general signs weakness, anorexia, weight loss, fever.
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The major goals of treatment are to
reduce pain and discomfort,
reduce inflammation
prevent deformities and loss of joint function,
prevent the disease progression (to the extent possible)
maintain a productive and active life.
Drug classes used in the treatment of RA:
 non-steroidal anti-inflammatory agents (NSAIDs),
 corticosteroids,
 disease modifying anti-rheumatic drugs (DMARDs)
The mechanism of action of many of therapeutic agents, effective in RA, is uncertain!!
NSAIDs - short onset of action, rapidly relieve signs and symptoms, have no effect on the progression of the
disease.
- Effects: reduce acute inflammation, decrease pain (mild to moderate analgesic properties).
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Time required to achieving maximal effect – few hours to 1 month.
Corticosteroids - short onset of action, inflammatory and immunoregulatory activity.
- Systemic corticosteroids:
 indicated when there is an increase of inflammation in multiple sites
 usually given orally in small doses (10 mg of prednisone/or its equivalents/ daily)
 tapering of corticosteroid should be done slowly (over a few weeks)
 side effects of prolonged systemic treatment:
 weight gain, cushingoid syndrome,
 osteoporosis (particularly at doses  10 mg of prednisone daily).
Prophylaxis: bone densitometry to assess fracture risk, hormone replacement
therapy, bisphosphonates.
 hypothalamic-pituitary-adrenal suppression.
Prophylaxis: once a day dosing of prednisone, given before 9 AM.
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Intra-articular corticosteroids
 e.g., triamcinolone - 40 mg in a knee, 20 mg in a shoulder, or 2 mg in a finger
 for controlling a local inflammation, if only one or two joints are involved.
Disease Modifying Anti-Rheumatic Drugs (DMARDs)
- agents with delayed onset of action (the appearance of benefit from DMARD therapy is usually delayed for
weeks or months)
- may alter the disease course and improve long term outcomes.
- exert minimal direct nonspecific anti-inflammatory or analgesic effects  NSAIDs must be continued
during their administration
- improve serologic and biochemical evidences of disease activity (f.e. rheumatoid factor, C-reactive protein,
the erythrocyte sedimentation rate are decline).
- retard the development of bone erosions
- indications:
 all patients with confirmed diagnosis of RA
 should be started as soon as possible after diagnosis – within first 3 months
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The currently available drugs include:
1. Classical (chemical) agents:
methotrexate
leflunomide
hydroxychloroquine and chloroquine (antimalarials)
sulfasalazine
intramuscular gold salts
cytotoxic agents (cyclosporine A, azathioprine, and cyclophosphamide)
2. „biological” agents:
tumor necrosis factor inhibitors (TNFα inhibitors)
etanercept, infliximab, adalimumab
antagonists of interleukin–1 (IL–1) – anakinra
antagonists of interleukin–6 (IL–1) – tocilizumab
abatacept („inhibitor” of T-cells)
rituximab („inhibitor” of B-cells)
Methotrexate
- early onset of action (4-6 weeks)
- high patient tolerability
- Dosage: an initial dosage of 7.5 mg orally once weekly. If no effect after 4 to 6 weeks - the dose can be
increased up to 25mg weekly (in the elderly or in partial responders)
- in patients who experience serious GI side effects - IM injections
- contraindications: renal insufficiency, liver disease, alcohol abuse, leukopenia, thrombocytopenia,
untreated folate deficiency, obesity, diabetes, hepatitis B or C – increase methotrexate hepatotoxicity.
- Usual Time to Effect: 4 to 6 weeks, with 70% of patients having some response.
Side Effects
 rare: hepatic cirrhosis, interstitial pneumonitis and severe myelosuppression
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common: stomatitis, mild alopecia and GI upset - are related to folic acid antagonism
(prophylaxis: folic acid supplementation).
 increased risk of localized herpes zoster infection, teratogenic effect (effective birth control is
needed).
Leflunomide (Arava™)
- The mechanism of action: inhibition of tyrosine kinase activity, inhibition of de novo pyrimidine
biosynthesis by the inhibition of dihydroorotate dehydrogenase, inhibition of mitogen and IL-2 stimulated T
cells.
- An alternative drug to patients who have failed or were intolerant to methotrexate.
- pharmacokinetic:
 half-life - 15 days – for original compound, up to 2 years (!) – for active metabolites.
 extensively protein bound
 undergoes enterohepatic recycling.
In patients, who must rapidly discontinue therapy (i.e. women wishing to become pregnant;
toxicity): “washing” from the body by cholestyramine (8 g 3 times daily for 11 days) to
achieve documented serum concentration of leflunomide less than 0.02 mg/L).
- Usual time to maximal effect: 4-8 weeks.
- Side Effects: liver transaminase elevations, mild diarrhea, GI upset, alopecia (hair loss), teratogenic effects
Soluble Interleukin–1 (IL–1) Receptor
Anakinra (Kineret™)
- a human recombinant IL–1 receptor antagonist.
- blocks the biologic activity of IL–1 by binding to IL-1R type I.
- Side Effects:
 injection site reactions
 decreasing of immunity  increased risk of serious infection
 neutropenia (severe neutropenia is especially high in the combination anakinra/anti-TNF
agents)
Tumor necrosis factor (TNF) inhibitors
(TNF- - is a pro-inflammatory cytokine produced by macrophages and lymphocytes)
Mechanism: binds TNF- at high affinity in the circulation, preventing interaction with the cell surface TNF-
receptors and clears TNF- from the circulation.
Currently used only in combination with methotrexate or other first line DMARDs.
Usual time to maximal effect: 1-2 weeks, with some continued improvement over the next 4 weeks.
Very expensive.
Etanercept (Enbrel™)
- human fusion protein – a soluble receptor for TNFα
- a low potential for immunogenicity
- Side effects: injection site reactions, infection symptoms (most commonly - mild upper respiratory
system infections)
Infliximab (Remicade™)
- a chimeric monoclonal antibody
- Side effects:
 development of human anti-chimeric antibodies (HACA) which would block infliximab
from binding TNF-.
 "cytokine release syndrome" (fever, chills, headache after the infusion of the antibody)
 a risk of infections (especially on concomitant immunosuppressive therapy)
Adalimumab (Humira)
- entirely human monoclonal antibody
Antimalarials
Hydroxychloroquine (Plaquenil, 200mg tablets) and Chloroquine (because of great ocular toxicity is not
recommended)
- relatively safe, well-tolerated and effective in the treatment of RA (of mild to moderate severity).
- Mechanism of action in the treatment of RA is unknown.
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usual time to maximal effect: 3 to 6 months
Side Effects: ocular toxicity: corneal deposits, extraocular muscular weakness, loss of accommodation,
retinopathy (ophthalmologic examination before and during the period of treatment is needed).
Gold (Myochrysine, Solganal – intramuscular)
- Mechanism in RA is unknown.
- Dosage: initially 10 mg intramuscularly, 25mg - given the second week, then 50mg is given weekly until a
response has occurred or until a total of 1 g has been given.
If there is a favorable response – 50 mg every 2 weeks for 3 months, then every 3 weeks for 3 months and
then finally to a maintenance monthly dose (continued indefinitely).
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Usual Time to Maximal Effect: 4 to 6 months.
Side Effects: rash , ulcerations and mucositis of the mouth, tongue, and pharynx , altering renal function
(most often - mild proteinuria, rarely - nephrotic syndrom), immune thrombocytopenia, granulocytopenia, and
aplastic anemia
Immunosuppressive and other cytotoxic agents
azathioprine (Imuran) - a purine analog
cyclophosphamide (Cytoxan) - an alkylating agent
cyclosporin A - an immunosuppressive agent
- used in aggressive disease or extra-articular manifestations
- serious toxicity’s including bone marrow suppression, infection, secondary malignancy, renal insufficiency.
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