THE IMMUNE RESPONSE

 The immune response occurs when immunologically competent cells are b. Biologic DMARDs
activated in response to foreign organisms or antigenic substances – TNF-alpha neutralizing agents: infliximab, etanercept, & adalimumab,
liberated during the acute or chronic inflammatory response. certolizumab, golimumab
 The outcome of the immune response for the host may be deleterious if – IL-1 neutralizing agents: anakinra
it leads to chronic inflammation without resolution of the underlying – Depletes B cells: rituximab
injurious process. – Interferes T cell activation: abatacept
 Chronic inflammation involves the release of multiple cytokines and – Anti-IL-6 receptor antibody: rocilizumab
chemokines plus a very complex interplay of immunoactive cells.
 The whole range of autoimmune diseases (eg, RA, vasculitis, SLE) and NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
inflammatory conditions (eg, gout) derive from abnormalities in this ✓ Salicylates and other similar agents used to treat rheumatic disease
cascade. share the capacity to suppress the signs and symptoms of inflammation
 The cell damage associated with inflammation acts on cell membranes including pain. These drugs also exert antipyretic effects.
to release leukocyte lysosomal enzymes; arachidonic acid is then
liberated from precursor compounds, and various eicosanoids are Chemistry & Pharmacokinetics
synthesized.  The NSAIDs are grouped in several chemical classes:
 The lipoxygenase pathway of arachidonate metabolism yields
leukotrienes, which have a powerful chemotactic effect on eosinophils, Indole derivative Indomethacin
neutrophils, and macrophages and promote bronchoconstriction and Fenamate Meclofenamic acid
alterations in vascular permeability. Pyrrolealkanoic acid derivative Tolmetin
 During inflammation, stimulation of the neutrophil membranes Pyrazolone derivative Phenylbutazone
produces oxygen-derived free radicals and other reactive molecules such Phenylacetic acid derivative Diclofenac
as hydrogen peroxide and hydroxyl radicals. Propionic acid derivative Ibuprofen
 The interaction of these substances with arachidonic acid results in the Phenylalkanoic acid derivative Flurbiprofen
generation of chemotactic substances, thus perpetuating the Oxicam Piroxicam
inflammatory process. Naphthylacetic acid prodrug Nabumetone

THERAPEUTIC STRATEGIES  All NSAIDs are weak organic acids except Nabumetone, which is a
Primary goals in the treatment of patients with inflammation: ketone prodrug that is metabolized to the acidic active drug.
1. relief of symptoms and the maintenance of function, which are usually  Most of these drugs are well absorbed, and food does not substantially
the major continuing complaints of the patient; change their bioavailability.
2. slowing or arrest of the tissue-damaging process.
 Most of the NSAIDs are highly metabolized, some by phase I followed by
phase II mechanisms and others by direct glucuronidation (phase II)
Indices used to define response in Rheumatoid arthritis:
alone. NSAID metabolism proceeds, in large part, by way of the CYP3A or
✓ DAS (Disease Activity Index)
CYP2C families of P450 enzymes in the liver.
✓ ACR Response (American College of Rheumatology Response Index)
 Renal excretion is the most important route for final elimination, nearly
 These indices often combine joint tenderness and swelling, patient
all undergo varying degrees of biliary excretion and reabsorption
response, and laboratory data.
(enterohepatic circulation).
 In fact, the degree of lower gastrointestinal (GI) tract irritation correlates
GENERAL APPROACHES
with the amount of enterohepatic circulation.
I. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
 Most of the NSAIDs are highly protein-bound (~ 98%), usually to
– Often results in relief of pain for significant periods
albumin.
– Appropriate for treatment of both acute & chronic inflammatory
 Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures,
conditions
– control the s/s of local inflammatory process and have minimal effect on except Naproxen, which is provided as a single enantiomer
the progression of the disease.  Few have no chiral center (eg, diclofenac).
 All NSAIDs can be found in synovial fluid after repeated dosing.
II. Glucocorticoids  Drugs with short half-lives remain in the joints longer than would be
– Powerful anti-inflammatory effects predicted from their half-lives
– Considered to be the ultimate answer to treatment of inflammatory  Drugs with longer half-lives disappear from the synovial fluid at a rate
arthritis proportionate to their half-lives.
– Low-dose corticosteroids have dse-modifying properties but toxicity
makes them less favored
– For long term treatment of arthritis

III. Disease modifying antirheumatic drugs (DMARDs)

– decrease inflammation, improve symptoms, & slow the bone damage
associated with RA
– affect more basic inflammatory mechanisms than do glucocorticoids or
the NSAIDs.
– more toxic than those alternative medications

a.Non-biologic DMARDs
a. Methotrexate, sulfasalazine, chloroquine & hydroxychloroquine,
leflunomide, cyclosporine, azathioprine, cyclophosphamide,
mycophenolate mofetil
b. Have the capacity to decrease elevated levels of acute phase reactants
→ modify inflammatory component & its destructive capacity
Pharmacodynamics ✓ OA
 NSAID anti-inflammatory activity is mediated chiefly through ✓ localized musculoskeletal syndromes (eg, sprains and strains, low
inhibition of prostaglandin biosynthesis. back pain)
✓ Gout (excep tolmetin, which appears to be ineffective in gout)
 Adverse effects are generally quite similar for all of the NSAIDs:
1. CNS: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis.
2. CVS: Fluid retention, hypertension, edema, and rarely, myocardial
infarction and congestive heart failure (CHF).
3. GI: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers
or bleeding.
4. Hematologic: Rare thrombocytopenia, neutropenia, or even
aplastic anemia.
5. Hepatic: Abnormal liver function test results and rare liver failure.
6. Pulmonary: Asthma.
7. Skin: Rashes, all types, pruritus.
8. Renal: Renal insufficiency, renal failure, hyperkalemia, and
proteinuria.

CHOICE OF NSAID
✓ All NSAIDs, including aspirin, are about equally efficacious with a few
exceptions—tolmetin seems not to be effective for gout, and aspirin is
less effective than other NSAIDs (eg, indomethacin) for AS.
✓ Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-
effectiveness.
✓ For example, the GI and renal side effects of ketorolac limit its use.
Various NSAIDs have additional possible mechanisms of action, including: ✓ Some surveys suggest that indomethacin and tolmetin are the NSAIDs
✓ inhibition of chemotaxis associated with the greatest toxicity, while salsalate, aspirin, and
✓ down-regulation of IL-1 production ibuprofen are least toxic.
✓ decreased production of free radicals and superoxide ✓ For patients with renal insufficiency, nonacetylated salicylates may be
✓ interference with calcium-mediated intracellular events. best.
✓ Diclofenac and sulindac are associated with more liver function test
 Aspirin irreversibly acetylates and blocks platelet COX, while the non- abnormalities than other NSAIDs.
COX-selective NSAIDs are reversible inhibitors. ✓ The relatively expensive, selective COX-2 inhibitor celecoxib is probably
 Selectivity for COX-1 versus COX-2 is variable and incomplete for the safest for patients at high risk for GI bleeding but may have a higher risk
older NSAIDs, but selective COX-2 inhibitors have been synthesized. of cardiovascular toxicity.
 The selective COX-2 inhibitors do not affect platelet function at their ✓ Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may
usual doses. be appropriate in patients at highest risk for GI bleeding; in this
 The efficacy of COX-2-selective drugs equals that of the older NSAIDs, subpopulation of patients, they are cost-effective despite their high
while GI safety may be improved. acquisition costs.
 Sselective COX-2 inhibitors increase the incidence of edema, ✓ The choice of an NSAID thus requires a balance of efficacy, cost-
hypertension, and possibly myocardial infarction. effectiveness, safety, and numerous personal factors (eg, other drugs
 As of August 2011, celecoxib and the less selective meloxicam were the also being used, concurrent illness, compliance, medical insurance
only COX-2 inhibitors marketed in the USA. coverage), so that there is no best NSAID for allpatients. There may,
 Celecoxib has an FDA-initiated “black box” warning concerning however, be one or two best NSAIDs for a specific person.
cardiovascular risks. It has been recommended that all NSAID product
labels be revised to mention cardiovascular risks.
 The NSAIDs decrease the sensitivity of vessels to bradykinin and
histamine, affect lymphokine production from T lymphocytes, and
reverse the vasodilation of inflammation.
 All newer NSAIDs are analgesic, anti-inflammatory, and antipyretic
 All inhibits platelet aggregation except the COX-2-selective agents and
the nonacetylated salicylates
 NSAIDs are all gastric irritants and can be associated with GI ulcers and
bleeds as well, although as a group the newer agents tend to cause less
GI irritation than aspirin.
 Nephrotoxicity, reported for all NSAIDs, is due, in part, to interference
with the autoregulation of renal blood flow, which is modulated by
prostaglandins.
 Hepatotoxicity can also occur with any NSAID.
 Although these drugs effectively inhibit inflammation, there is no
evidence that—in contrast to drugs such as methotrexate, biologics, and
other DMARDs—they alter the course of any arthritic disorder.
 Several NSAIDs (including aspirin) reduce the incidence of colon cancer
when taken chronically (50% reduction in relative risk for this neoplasm
when the drugs are taken for 5 years or longer)
 Although not all NSAIDs are approved by the FDA for the whole range of
rheumatic diseases, most are probably effective in:
✓ RA
✓ Sero-negative spondyloarthropathies (eg, PA and arthritis
associated with inflammatory bowel disease)
NONACETYLATED SALICYLATES
Magnesium choline salicylate ▪ All nonacetylated salicylates are effective anti-inflammatory drugs, although they may be less effective analgesics than aspirin.
Sodium salicylate ▪ Do not inhibit platelet aggregation, they may be preferable when COX inhibition is undesirable such as in patients with asthma, those with
Salicyl salicylate bleeding tendencies, and even (under close supervision) those with renal dysfunction.
▪ The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate
measurements.

COX-2 SELECTIVE INHIBITORS

✓ inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isozyme found in
the GI tract, kidneys, and platelets.
✓ COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme.
✓ Inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium.
✓ As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs.
✓ Recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs.
✓ Clinical data suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the
market.
Celecoxib ▪ It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9.
▪ selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1.
▪ It does not affect platelet aggregation at usual doses.
▪ Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs.
▪ Probably because it is a sulfonamide, celecoxib may cause rashes
Meloxicam ▪ enolcarboxamide related to piroxicam
▪ preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d.
▪ not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective.
▪ It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen.
▪ Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses, its blockade of thromboxane
A2 does not reach levels that result in decreased in vivo platelet function
NONSELECTIVE COX INHIBITORS
Aspirin ✓ Aspirin’s long use and availability without prescription diminishes its glamour compared with that of the newer NSAIDs.
(acetylsalicylic ✓ rarely used as an anti-inflammatory medication
✓ Antiplatelet effects: 81–325 mg once daily
acid; ASA)
Pharmacokinetics Clinical uses:
▪ Salicylic acid is a simple organic acid with a pKa of 3.0. ▪ Aspirin decreases the incidence of transient ischemic attacks, unstable angina,
▪ Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 coronary artery thrombosis with myocardial infarction, and thrombosis after coronary
▪ Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 artery bypass grafting.
inutes) to acetic acid and salicylate by esterases in tissue and blood. ▪ Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated
▪ Salicylate is nonlinearly bound to albumin. with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.
▪ Alkalinization of the urine increases the rate of excretion of free Adverse effects:
salicylate and its water-soluble conjugates. ▪ Main adverse effects at antithrombotic doses are gastric upset (intolerance) and
MOA: gastric and duodenal ulcers.
▪ Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet ▪ Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at
effect lasts 8–10 days (the life of the platelet). antithrombotic doses.
▪ In other tissues, synthesis of new COX replaces the inactivated enzyme ▪ The antiplatelet action of aspirin contraindicates its use by patients with hemophilia.
so that ordinary doses have a duration of action of 6–12 hours. Although previously not recommended during pregnancy, aspirin may be valuable in
treating preeclampsia-eclampsia.
Diclofenac ▪ Phenylacetic acid derivative; relatively nonselective ▪ Elevation of serum aminotransferases occurs more commonly with this drug than
▪ Gastrointestinal ulceration may occur less frequently than with with other NSAIDs.
some other NSAIDs. ▪ A 0.1% ophthalmic preparation is promoted for prevention of postoperative
▪ A preparation combining diclofenac and misoprostol decreases ophthalmic inflammation and can be used after intraocular lens implantation and
upper gastrointestinal ulceration but may result in diarrhea. strabismus surgery.
▪ Another combination of diclofenac and omeprazole was also ▪ A topical gel containing 3% diclofenac is effective for solar keratoses.
effective with respect to the prevention of recurrent bleeding, but ▪ Diclofenac in rectal suppository form can be considered for preemptive analgesia
renal adverse effects were common in high-risk patients. and postoperative nausea.
▪ Diclofenac, 150 mg/d, appears to impair renal blood flow and ▪ In Europe, diclofenac is also available as an oral mouthwash and for intramuscular
glomerular filtration rate. administration.
Diflunisal ▪ Although diflunisal is derived from salicylic acid, it is not ▪ RA recommended dose: 500–1000 mg daily in two divided doses.
metabolized to salicylic acid or salicylate. ▪ Effective for cancer pain with bone metastases and for pain control in dental (third
▪ It undergoes an enterohepatic cycle with reabsorption of its molar) surgery.
glucuronide metabolite followed by cleavage of the glucuronide to ▪ 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions.
again release the active moiety. ▪ Because its clearance depends on renal function as well as hepatic metabolism,
▪ Diflunisal is subject to capacity-limited metabolism, with serum half- diflunisal’s dosage should be limited in patients with significant renal impairment.
lives at various dosages approximating that of salicylates.

Etodolac ▪ racemic acetic acid derivative with an intermediate half-life

▪ Analgesic dosage of etodolac is 200– 400 mg three to four times daily.
▪ Recommended dose in OA and RA is 300 mg twice or three times a day up to 500 mg twice a day initially followed by a maintenance of 600 mg/d.
Flurbiprofen ▪ propionic acid derivative with a possibly more complex mechanism ▪ Available in a topical ophthalmic formulation for inhibition of intraoperative
of action than other NSAIDs. miosis.
▪ Its (S)(−) enantiomer inhibits COX nonselectively, but it has been ▪ Intravenously is effective for perioperative analgesia in minor ear, neck, and nose
shown in rat tissue to also affect tumor necrosis factor-α (TNF-α) surgery and in lozenge form for sore throat.
and nitric oxide synthesis. ▪ Although its adverse effect profile is similar to that of other NSAIDs in most ways,
▪ Hepatic metabolism is extensive; its (R)(+) and (S) (−) enantiomers flurbiprofen is also rarely associated with cogwheel rigidity, ataxia, tremor, and
are metabolized differently, and it does not undergo chiral myoclonus.
conversion.
▪ It does demonstrate enterohepatic circulation.
Ibuprofen ▪ Phenylpropionic acid derivative ▪ Liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and good
▪ In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of overall efficacy in postsurgical dental pain.
aspirin in anti-inflammatory effect. ▪ In comparison with indomethacin, ibuprofen decreases urine output less and also
▪ Oral ibuprofen is often prescribed in lower doses (<2400 mg/d), at causes less fluid retention.
which it has analgesic but not anti-inflammatory efficacy. ▪ Relatively contraindicated in individuals with nasal polyps, angioedema, and
▪ It is available over the counter in low-dose forms under several trade bronchospastic reactivity to aspirin. Aseptic meningitis (particularly in patients
names. with SLE), and fluid retention have been reported.
▪ Ibuprofen oral and IV is effective in closing patent ductus arteriosus ▪ Concomitant administration of ibuprofen and aspirin:
in preterm infants, with much the same efficacy and safety as ✓ antagonizes the irreversible platelet inhibition induced by aspirin
indomethacin. (treatment with ibuprofen in patients with increased cardiovascular risk
▪ Topical cream preparation appears to be absorbed into fascia and may limit the cardioprotective effects of aspirin.
muscle; ibuprofen cream was more effective than placebo cream in ✓ decrease the total anti-inflammatory effect.
the treatment of primary knee OA. ▪ Rare hematologic effects include agranulocytosis and aplastic anemia.
Indomethacin ▪ indole derivative
▪ potent nonselective COX inhibitor and may also inhibit ▪ An ophthalmic preparation is efficacious for conjunctival inflammation and to
phospholipase A and C, reduce neutrophil migration, and decrease reduce pain after traumatic corneal abrasion.
T-cell and B-cell proliferation. ▪ Gingival inflammation is reduced after administration of indomethacin oral rinse.
▪ Indomethacin differs somewhat from other NSAIDs in its indications ▪ Epidural injections produce a degree of pain relief similar to that achieved with
and toxicities. methylprednisolone in postlaminectomy syndrome.
▪ It has been used to accelerate closure of patent ductus arteriosus. ▪ The GI effects may include pancreatitis.
▪ Indomethacin has been tried in numerous small or uncontrolled ▪ Headache is experienced by 15–25% of patients and may be associated with
trials for many other conditions, including Sweet’s syndrome, dizziness, confusion, and depression.
juvenile RA, pleurisy, nephrotic syndrome, diabetes insipidus, ▪ Renal papillary necrosis has also been observed.
urticarial vasculitis, postepisiotomy pain, and prophylaxis of
heterotopic ossification in arthroplasty.

Ketoprofen ▪ propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase.
▪ Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.
▪ The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs.
▪ Its major adverse effects are on the GI tract and the central nervous system.
Nabumetone ▪ only nonacid NSAID in current use
▪ it is given as a ketone prodrug and resembles naproxen in structure.
▪ Its half-life of more than 24 hours permits once-daily dosing, and the drug does not appear to undergo enterohepatic circulation.
▪ Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve.
▪ Its properties are very similar to those of other NSAIDs, though it may be less damaging to the stomach.
▪ Unfortunately, higher dosages (eg, 1500–2000 mg/d) are often needed, and this is a very expensive NSAID.
▪ Like naproxen, nabumetone has been associated with pseudoporphyria and photosensitivity in some patients.

Naproxen ▪ naphthylpropionic acid derivative.

▪ The incidence of upper GI bleeding in over-the-counter use is low but still double that
▪ the only NSAID presently marketed as a single enantiomer.
of over-the-counter ibuprofen (perhaps due to a dose effect).
▪ Naproxen’s free fraction is significantly higher in women than in
▪ Rare cases of allergic pneumonitis, leukocytoclastic
men, but half-life is similar in both sexes.
▪ vasculitis, and pseudoporphyria as well as the common
▪ Effective for the usual rheumatologic indications
▪ NSAID-associated adverse effects have been noted.
▪ Available in a slow-release formulation, as an oral suspension, and
over the counter, topical preparation and an ophthalmic solution

Oxaprozin ▪ propionic acid derivative

▪ its major difference from the other members of this subgroup is a very long half-life (50–60 hours),
▪ although oxaprozin does not undergo enterohepatic circulation.
▪ It is mildly uricosuric.
▪ Otherwise, the drug has the same benefits and risks that are associated with other NSAIDs.
Piroxicam ▪ oxicam
▪ nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits
lymphocyte function.
▪ Its long half-life permits once-daily dosing.
▪ Piroxicam can be used for the usual rheumatic indications.
▪ When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered—as much as 9.5 times higher than
with other NSAIDs
Sulindac ▪ sulfoxide prodrug.
▪ reversibly metabolized to the active sulfide metabolite, which is excreted in bile and then reabsorbed from the intestine.
▪ The enterohepatic cycling prolongs the duration of action to 12–16 hours.
▪ In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis
▪ it may inhibit the development of colon, breast, and prostate cancer in humans.
▪ Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have
all been observed.
▪ It is sometimes associated with cholestatic liver damage.
Tolmetin ▪ nonselective COX inhibitor with a short half-life (1–2 hours) and is not often used.
▪ It is ineffective (for unknown reasons) in the treatment of gout.

Azapropazone ▪ rarely used

carprofen
meclofenamate
tenoxicam
 ✓ The effects of disease-modifying therapies may take 2 weeks to 6 months to become clinically evident.

Nonbiologic DMARDS include small molecule drugs such as: Biologics agents are large-molecule therapeutic agents, usually proteins,
✓ Methotrexate that are often produced by recombinant DNA technology
✓ Azathioprine
✓ chloroquine and hydroxychloroquine The biologic DMARDs approved for RA include:
✓ cyclophosphamide ✓ Abatacept – T-cell - modulating
✓ cyclosporine ✓ rituximab – B-cell cytotoxic agent
✓ leflunomide ✓ Tocilizumab – anti-IL-6 receptor antibody
✓ mycophenolate mofetil ✓ Anakinra, rilonacept, canakinumab – IL-1- inhibiting agents
✓ sulfasalazine ✓ TNF-α-blocking agents
✓ Tofacitinib, though marketed as a biologic, is actually a well-tolerated nonbiologic DMARD. Adalimumab
✓ Gold salts, which were once extensively used, are no longer recommended because of their significant Certolizomab
toxicities and questionable efficacy Etanercept
✓ Penicillamine Golimumab
Infliximab
COMBINATION THERAPY WITH DMARDS
✓ Combinations of DMARDs can be designed rationally on the basis of complementary mechanisms of action, onoverlapping pharmacokinetics, and nonoverlapping toxicities.
✓ When added to methotrexate background therapy, cyclosporine, chloroquine, hydroxychloroquine, leflunomide, infliximab, adalimumab, rituximab, and etanercept have all shown
improved
✓ efficacy.
✓ Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine appears to be as effective as etanercept and methotrexate.
✓ In contrast, azathioprine or sulfasalazine plus methotrexate results in no additional therapeutic benefit.
✓ While it might be anticipated that combination therapy could result in more toxicity, this is often not the case.
✓ Combination therapy for patients not responding adequately to monotherapy is now the rule in the treatment of RA.
NONBIOLOGICS
Mechanism of Action Pharmacokinetics Indication Adverse Effects:
Methotrexate ▪ inhibition of amino- ▪ approximately 70% absorbed after ▪ nonbiologic antimetabolite ▪ Nausea and mucosal ulcers are the
imidazolecarboxamide ribonucleotide oral administration ▪ first line DMARD for treating RA most common toxicities.
(AICAR) transformylase and ▪ metabolized to a less active ▪ It is active in this condition at ▪ Leukopenia, anemia, stomatitis, GI
thymidylate synthetase. hydroxylated product. much lower doses than those ulcerations, and alopecia are probably
▪ AICAR, which accumulates ▪ Both the parent compound and the needed in cancer chemotherapy the result of inhibiting cellular
intracellularly, competitively inhibits metabolite are polyglutamated ▪ Although the most common proliferation.
AMP deaminase, leading to an within cells where they stay for methotrexate dosing regimen for ▪ Progressive dose-related
accumulation of AMP. prolonged periods. the treatment of RA is 15–25 mg hepatotoxicity in the form of enzyme
▪ The AMP is released and converted ▪ Methotrexate’s serum half-life is weekly, there is an increased elevation occurs frequently, but
extracellularly to adenosine, which is usually only 6–9 hours. effect up to 30–35 mg weekly. cirrhosis is rare (<1%).
a potent inhibitor of inflammation. ▪ Hydroxychloroquine can reduce the ▪ The drug decreases the rate of ▪ Liver toxicity is not related to serum
▪ As a result, the inflammatory clearance or increase the tubular appearance of new erosions. methotrexate concentrations.
functions of neutrophils, reabsorption of methotrexate. ▪ Evidence supports its use in ▪ A rare hypersensitivity-like lung
macrophages, dendritic cells, and ▪ Methotrexate is excreted principally juvenile chronic arthritis, and it reaction with acute shortness of
lymphocytes are suppressed. in the urine, but up to 30% may be has been used in psoriasis, PA, breath has been documented, as have
▪ Methotrexate has secondary effects excreted in bile. AS, polymyositis, pseudo-lymphomatous reactions.
on polymorphonuclear chemotaxis. dermatomyositis, Wegener’s ▪ The incidence of GI and liver function
▪ There is some effect on dihydrofolate granulomatosis, giant cell test abnormalities can be reduced by
reductase and this affects lymphocyte arteritis, SLE, and vasculitis. the use of leucovorin 24 hours after
and macrophage function, but this is each weekly dose or by the use of
not its principal mechanism of action. folic acid, although may decrease the
▪ direct inhibitory effects on efficacy of the methotrexate by about
proliferation and stimulates apoptosis 10%.
in immune-inflammatory cells. ▪ This drug is contraindicated in
▪ it inhibits proinflammatory cytokines pregnancy.
linked to rheumatoid synovitis.

Azathioprine ▪ Azathioprine is a synthetic nonbiologic ▪ Azathioprine can be given orally or ▪ RA at a dosage of 2mg/kg/d ▪ bone marrow suppression, GI
DMARD that acts through its major parenterally. ▪ Prevention of kidney transplant disturbances, and some increase in
metabolite, 6-thioguanine. ▪ Its metabolism is bimodal in humans, rejection in combination with infection risk.
▪ 6-Thioguanine suppresses inosinic with rapid metabolizers clearing the other immune suppressants. ▪ lymphomas may be increased with
acid synthesis, B-cell and T-cell drug four times faster than slow ▪ PA, reactive arthritis, azathioprine use.
function, immunoglobulin production, metabolizers. polymyositis, SLE, maintenance of ▪ Rarely, fever, rash, and hepatotoxicity
and IL-2 secretion ▪ Production of 6-thioguanine is remission in vasculitis, and signal acute allergic reactions.
dependent on thiopurine Behçet’s disease.
methyltransferase (TPMT), and ▪ used in scleroderma
patients with low or absent TPMT ▪ however, in one study, it was
activity (0.3% of the population) are found to be less effective than
at particularly high risk of cyclophosphamide in controlling
myelosuppression by excess the progression of scleroderma
concentrations of the parent drug, if lung disease.
dosage is not adjusted.

Cyclophosphamide ▪ Its major active metabolite is ▪ Used regularly at 2 mg/kg/d to

phosphoramide mustard, which cross- treat SLE, vasculitis, Wegener’s
links DNA to prevent cell replication. granulomatosis, and other
▪ It suppresses T-cell and B-cell function ▪ severe rheumatic diseases.
by 30–40%;
▪ T-cell suppression correlates with
clinical response in the rheumatic
diseases.
Chloroquine and ▪ The following mechanisms have been ▪ Antimalarials are rapidly absorbed ▪ mainly used for malaria and in the ▪ Although ocular toxicity may occur at
proposed: ▪ 50% protein-bound in the plasma. rheumatic diseases. dosages greater than 250 mg/d for
hydroxychloroquine ▪ suppression of T-lymphocyte ▪ They are very extensively tissue- ▪ Antimalarials are approved for chloroquine and greater than 6.4
responses to mitogens bound, particularly in melanin- RA, but they are not considered mg/kg/d for hydroxychloroquine, it
▪ inhibition of leukocyte chemotaxis containing tissues such as the eyes. very effective DMARDs. rarely occurs at lower doses.
▪ stabilization of lysosomal enzymes ▪ The drugs are deaminated in the ▪ Dose-loading may increase rate of ▪ Nevertheless, ophthalmologic
▪ processing through the Fc-receptor liver and have blood elimination half- response. monitoring every 12 months is
▪ inhibition of DNA and RNA synthesis lives of up to 45 days. ▪ There is no evidence that these advised.
▪ trapping of free radicals compounds alter bony damage in ▪ Other toxicities include dyspepsia,
RA at their usual dosages (up to nausea, vomiting, abdominal pain,
6.4 mg/kg/d for rashes, and nightmares.
hydroxychloroquine or 200 mg/d ▪ These drugs appear to be relatively
for chloroquine). safe in pregnancy.
▪ It usually takes 3–6 months to
obtain a response.
▪ Antimalarials are used very
commonly in SLE because they
decrease mortality and the skin
manifestations, serositis, and
joint pains of this disease.
▪ Sjögren’s syndrome.

Cyclosporine ▪ Cyclosporine is a peptide antibiotic ▪ Cyclosporine absorption is ▪ Approved for use in RA and ▪ Leukopenia, thrombocytopenia, and
but is considered a nonbiologic incomplete and somewhat erratic, retards the appearance of new to a lesser extent, anemia are
DMARD. although a microemulsion bony erosions. predictable.
▪ Through regulation of gene formulation improves its consistency ▪ Its usual dosage is 3–5 mg/kg/d ▪ High doses can be cardiotoxic and
transcription, it inhibits IL-1 and IL-2 and provides 20–30% bioavailability. divided into two doses. sterility may occur after chronic
receptor production and secondarily ▪ Grapefruit juice increases ▪ Anecdotal reports suggest that it dosing at antirheumatic doses,
inhibits macrophage-T-cell interaction cyclosporine bioavailability by as may be useful in SLE, polymyositis especially in women.
and T-cell responsiveness T- much as 62%. and dermatomyositis, Wegener’s ▪ Bladder cancer is very rare but must
celldependent B-cell function is also ▪ Cyclosporine is metabolized by granulomatosis, and juvenile be looked for, even 5 years after
affected. CYP3A and consequently is subject to chronic arthritis. cessation of use.
a large number of drug interactions
Leflunomide ▪ undergoes rapid conversion, both in ▪ Leflunomide is completely absorbed ▪ Leflunomide is as effective as ▪ Diarrhea occurs in approximately 25%
the intestine and in the plasma, to its from the gut and has a mean plasma methotrexate in RA, including of patients given leflunomide,
active metabolite, A77-1726. half-life of 19 days. inhibition of bony damage. although only about 3–5% of patients
▪ This metabolite inhibits ▪ Its active metabolite, A77-1726, has ▪ In one study, combined treatment discontinue the drug because of this
dihydroorotate dehydrogenase, approximately the same half-life and with methotrexate and side effect.
leading to a decrease in ribonucleotide is subject to enterohepatic leflunomide resulted in a 46.2% ▪ Elevation in liver enzymes can occur.
synthesis and the arrest of stimulated recirculation. ACR20 response compared with ▪ Both effects can be reduced by
cells in the G1 phase of cell growth. ▪ Cholestyramine can enhance 19.5% in patients receiving decreasing the dose of leflunomide.
▪ Consequently, leflunomide inhibits T- leflunomide excretion and increases methotrexate alone. ▪ Other adverse effects associated with
cell proliferation and reduces total clearance by approximately leflunomide are mild alopecia, weight
production of autoantibodies by B 50%. gain, and increased blood pressure.
cells. ▪ Leukopenia and thrombocytopenia
▪ Secondary effects include increases of occur rarely.
IL-10 receptor mRNA, decreased IL-8 ▪ This drug is contraindicated in
receptor type A mRNA, and decreased pregnancy.
TNF-α-dependent nuclear factor kappa
B (NF-κB) activation.

Mycophenolate ▪ a semisynthetic DMARD ▪ MMF is effective for the ▪ nausea, dyspepsia, and abdominal
▪ converted to mycophenolic acid, the treatment of renal disease due to pain.
mofetil active form of the drug. SLE and may be useful in ▪ Hepatotoxicity
▪ The active product inhibits inosine vasculitis and Wegener’s ▪ leukopenia, thrombocytopenia, and
monophosphate dehydrogenase, granulomatosis. anemia.
leading to suppression of T- and B- ▪ Although MMF is occasionally ▪ associated with an increased
lymphocyte proliferation. used at a dosage of 2 g/d to treat incidence of infections.
▪ Downstream, it interferes with RA, there are no well-controlled ▪ It is only rarely associated with
leukocyte adhesion to endothelial data regarding its efficacy in this malignancy.
cells through inhibition of E-selectin, disease.
P-selectin, and intercellular adhesion
molecule 1.

Sulfasalazine ▪ a synthetic nonbiologic DMARD ▪ Only 10–20% of orally administered ▪ Sulfasalazine is effective in RA ▪ Common : nausea, vomiting,
▪ metabolized to sulfapyridine and 5- sulfasalazine is absorbed, although a and reduces radiologic disease headache, and rash.
aminosalicylic acid. fraction undergoes enterohepatic progression. ▪ Hemolytic anemia and
▪ The sulfapyridine is probably the recirculation into the bowel where it ▪ It has also been used in juvenile methemoglobinemia also occur, but
active moiety when treating RA Some is reduced by intestinal bacteria to chronic arthritis, PA, rarely.
authorities believe that the parent liberate sulfapyridine and 5- inflammatory bowel disease, AS, ▪ Neutropenia occurs in 1–5% of
compound, sulfasalazine, also has an aminosalicylic acid. and spondyloarthropathy- patients, while thrombocytopenia is
effect. ▪ Sulfapyridine is well absorbed while associated uveitis. very rare.
▪ Suppression of T-cell responses to 5-aminosalicylic acid remains ▪ The usual regimen is 2–3 g/d. ▪ Pulmonary toxicity and positive
concanavalin and inhibition of in vitro unabsorbed. double- stranded DNA (dsDNA) are
B-cell proliferation are documented. ▪ Some sulfasalazine is excreted occasionally seen, but drug-induced
▪ In vitro, sulfasalazine or its unchanged in the urine whereas lupus is rare.
metabolites inhibit the release of sulfapyridine is excreted after ▪ Reversible infertility occurs in men,
inflammatory cytokines produced by hepatic acetylation and but sulfasalazine does not affect
monocytes or macrophages, eg, IL-1, - hydroxylation. fertility in women.
6, and -12, and TNF-α. ▪ Sulfasalazine’s half-life is 6–17 hours. ▪ The drug does not appear to be
teratogenic.
BIOLOGICS
Mechanism of Action Pharmacokinetics Indication Adverse Effects:
Abatacept ▪ Co-stimulation modulator ▪ Recommended dose: Tx of adult ▪ monotherapy or in combination ▪ Slightly increased risk of infection (as with
biologic that inhibits the patients with RA: three intravenous with methotrexate or other other biologic DMARDs), predominantly of
activation of T cells. infusion induction” doses (day 0, week DMARDs in patients with the upper respiratory tract.
▪ After a T cell has engaged an 2, and week 4), followed by monthly moderate to severe RA or severe ▪ Concomitant use with TNF-α antagonists or
antigen-presenting cell (APC), a infusions. PJIA. other biologics is not recommended due to
second signal is produced by ▪ The dose is based on body weight; ▪ It is being tested in early RA and the increased incidence of serious
CD28 on the T cell that interacts patients weighing : methotrexate-naïve patients. infection.
with CD80 or CD86 on the APC, o less than 60 kg - 500 mg, ▪ All patients should be screened for latent
leading to T-cell activation. o 60–100 kg - 750 mg tuberculosis and viral hepatitis before
▪ Abatacept (which contains the o more than 100 kg – 1000 mg starting this medication.
endogenous ligand CTLA-4) ▪ available as a SQ formulation and is ▪ Live vaccines should be avoided in patients
binds to CD80 and 86, thereby given as 125 mg subcutaneously once while taking abatacept and up to 3 months
inhibiting the binding to CD28 weekly. after discontinuation.
and preventing the activation of ▪ JIA can also be treated with abatacept ▪ Infusionrelated reactions and
T cells. with an induction schedule at day 0, hypersensitivity reactions, including
week 2, and week 4, followed by anaphylaxis, have been reported but are
intravenous infusion every 4 weeks. rare.
▪ Rec. dose for patients 6–17 years of ▪ Anti-abatacept antibody formation is
age and weighing less than 75 kg is 10 infrequent (<5%) and has no effect on
mg/kg, while those weighing 75 kg or clinical outcomes.
more follow the adult intravenous ▪ There is a possible increase in lymphomas
doses to a maximum not to exceed but not other malignancies when using
1000 mg. abatacept.
▪ terminal serum half-life is 13–16 days
▪ Co-administration with methotrexate,
NSAIDs, and corticosteroids does not
influence abatacept clearance.
▪ Most patients respond to abatacept
within 12–16 weeks after the initiation
of the treatment;
▪ however, some patients can respond
in as few as 2–4 weeks.
▪ A study showed equivalence between
adalimumab and abatacept.
▪
rituximab ▪ Rituximab is a chimeric ▪ Given as two intravenous infusions of ▪ moderately to severely active ▪ About 30% of patients develop rash with the
monoclonal antibody biologic 1000 mg, separated by 2 weeks. RA in combination with first 1000 mg treatment;
agent that targets CD20 B ▪ It may be repeated every 6–9 months, methotrexate in patients with ▪ this incidence decreases to about 10% with
lymphocytes. as needed. an inadequate response to one the second infusion and progressively
▪ Depletion of these cells takes ▪ Repeated courses remain effective. or more TNF-α antagonists. decreases with each course of therapy
place through cell-mediated and ▪ Pretreatment with acetaminophen, an ▪ Rituximab in combination with thereafter.
complement-dependent antihistamine, and intravenous glucocorticoids is also approved ▪ These rashes do not usually require
cytotoxicity and stimulation of glucocorticoids (usually 100 mg of for the treatment of adult discontinuation of therapy, although an
cell apoptosis. methylprednisolone) given 30 minutes patients with Wegener’s urticarial or anaphylactoid reaction
▪ Depletion of B lymphocytes prior to infusion decreases the granulomatosis (also known as precludes further therapy.
reduces inflammation by incidence and severity of infusion granulomatosis with ▪ Immunoglobulins (particularly IgG and IgM)
decreasing the presentation of reactions. polyangiitis) and microscopic may decrease with repeated courses of
antigens to T lymphocytes and polyangiitis therapy and infections can occur, although
inhibiting the secretion of ▪ used in other forms of vasculitis they do not seem directly associated with
proinflammatory cytokines. the decreases in immunoglobulins.
▪ Rituximab rapidly depletes ▪ Serious, and sometimes fatal, bacterial,
peripheral B cells, although this fungal, and viral infections are reported for
depletion correlates neither up to one year of the last dose of rituximab
with efficacy nor with toxicity. ▪ patients with severe and active infections
should not receive rituximab.
▪ Rituximab is associated with reactivation of
hepatitis B virus (HBV) infection, which
requires monitoring before and several
months after the initiation of the treatment.
▪ Rituximab has not been associated with
either activation of tuberculosis or the
occurrence of lymphomas or other tumors.
▪ Fatal mucocutaneous reactions have been
reported in patients receiving rituximab.
▪ Different cytopenias can occur, which
require complete blood cell monitoring
every 2–4 months in RA patients.
▪ Other adverse effects, such as cardiovascular
events, are rare.
Tocilizumab ▪ Tocilizumab, a newer biologic ▪ half-life of tocilizumab is dose ▪ For adult patients with ▪ Serious infections including tuberculosis,
humanized antibody, binds to dependent, approximately 11 days for moderately to severely active RA fungal, viral, and other opportunistic
soluble and membrane-bound the 4 mg/kg dose and 13 days for the 8 who have had an inadequate infections have occurred.
IL-6 receptors, and inhibits the mg/kg dose. response to one or more ▪ Screening for tuberculosis should be done
IL-6-mediated signaling via these ▪ IL-6 can suppress several CYP450 DMARDs. prior to beginning tocilizumab.
receptors. isoenzymes; thus, inhibiting IL-6 may ▪ Patients who are older than 2 ▪ MC adverse reactions: upper respiratory
▪ IL-6 is a proinflammatory restore CYP450 activities to higher years with active SJIA or active tract infections, headache, hypertension,
cytokine produced by different levels. PJIA. and elevated liver enzymes.
cell types including T cells, B ▪ This may be clinically relevant for ▪ A recent study showed that it is ▪ Neutropenia and reduction in platelet
cells, monocytes, fibroblasts, drugs that are CYP450 substrates and slightly more effective than counts occur occasionally, and lipids (eg,
and synovial and endothelial have a narrow therapeutic window adalimumab. cholesterol, triglycerides, LDL, and HDL)
cells. (eg, cyclosporine or warfarin), and should be monitored.
▪ IL-6 is involved in a variety of dosage adjustment of these ▪ GI perforation has been reported when
physiologic processes such as T- medications may be needed. using tocilizumab in patients with
cell activation, hepatic acute- ▪ Tocilizumab can be used in diverticulitis and in those using
phase protein synthesis, and combination with nonbiologic corticosteroids, although it is not clear that
stimulation of the inflammatory DMARDs or as monotherapy. this adverse
processes involved in diseases ▪ (US) Recommended starting dose for ▪ effect is more common than with TNF-α-
such as RA. RA is 4 mg/kg intravenously every 4 blocking agents.
weeks followed by an increase to 8 ▪ Demyelinating disorders including multiple
mg/kg (not exceeding 800 sclerosis are rarely associated with
mg/infusion) dependent on clinical tocilizumab use.
response. ▪ fewer than 1% of the patients taking
▪ In Europe, the starting dose of tocilizumab develop anaphylactic reaction.
tocilizumab is 8 mg/kg up to 800 mg. ▪ Anti-tocilizumab antibodies develop in 2% of
▪ Tocilizumab dosage in SJIA or PJIA the patients, and these can be associated
follows an algorithm that accounts for with hypersensitivity reactions requiring
body weight. discontinuation.
▪ Additionally, dosage modifications are
recommended on the basis of certain
laboratory changes such as elevated
liver enzymes, neutropenia, and
thrombocytopenia.
Belimumab ▪ an antibody that specifically ▪ Recommended dose: ▪ Approved only for the treatment ▪ MC: nausea, diarrhea, and respiratory tract
inhibits B-lymphocyte stimulator 10 mg/kg at weeks 0, 2, 4, and every 4 of adult patients infection.
(BLyS). weeks thereafter. with active, seropositive SLE ▪ As with other biologic DMARDs, there is a
▪ It is administered as an ▪ distribution half-life: 1.75 days who are receiving standard slight increase in the risk of infection
intravenous infusion. ▪ terminal half-life: 19.4 days. treatment. including serious infections.
▪ Belimumab should not be used ▪ The drug was approved after a ▪ Cases of depression and suicide have been
in patients with active renal or protracted series of clinical reported in patients receiving belimumab,
neurological manifestations of trials, and its place in the SLE although these patients may have had
SLE, as there are no data for armamentarium is not clear. neurologic SLE, thus confounding the causal
these conditions. relationship.
▪ Infusion reactions including anaphylaxis are
among the other adverse effects.
▪ A very small percentage of patients develop
antibodies toward belimumab; their clinical
significance however is not clear
Tofacitinib ▪ Tofacitinib is a synthetic small ▪ Tofacitinib is an oral, targeted DMARD. ▪ originally developed to prevent ▪ As with biologic DMARDs, tofacitinib slightly
molecule that selectively inhibits ▪ Recommended dose in the treatment solid organ allograft rejection. increases the risk of infection
all members of the Janus kinase of RA is 5 mg twice daily; ▪ It has also been tested for the ▪ should not be used with potent
family to varying degrees. ▪ there is a clear trend to increased treatment of inflammatory immunosuppressants or biologic DMARDs
▪ At therapeutic doses, tofacitinib response (and increased toxicity) at bowel disease, spondyloarthritis, due to added immunosuppressive effects.
exerts its effect mainly by double this dose. psoriasis, and dry eyes. ▪ URTI and UTI represent the most common
inhibiting JAK3, and to a lesser ▪ absolute oral bioavailability of 74%, ▪ To date, tofacitinib is approved in infections.
extent JAK1, hence interrupting ▪ high-fat meals do not affect the AUC the USA for the treatment of ▪ More serious infections are also reported,
the JAK-STAT signaling pathway. ▪ elimination half-life is about 3 hours adult patients with moderately including pneumonia, cellulitis, esophageal
▪ This pathway plays a major role ▪ Metabolism (of 70%) occurs in the liver, to severely active RA who have candidiasis, and other opportunistic
in the pathogenesis of mainly by CYP3A4 and to a lesser extent failed or are intolerant to infections.
autoimmune diseases including by CYP2C19. methotrexate. ▪ All patients should be screened for latent or
RA. ▪ The remaining 30% is excreted ▪ It is not approved in Europe for active tuberculosis before the initiation of
▪ The JAK3/JAK1 complex is unchanged by the kidneys. this indication. treatment.
responsible for signal ▪ Patients taking CYP enzyme inhibitors ▪ It can be used as a monotherapy ▪ Lymphoma and other malignancies such as
transduction from the common and those with moderate hepatic or or in combination with other lung and breast cancer have been reported in
γ-chain receptor (IL-2RG) for IL-2, renal impairment require dose nonbiologic DMARDs, including patients taking tofacitinib, although some
-4, -7, -9, -15, and -21, which reduction to 5 mg once daily. methotrexate. studies discuss the potential use of JAK
subsequently influences ▪ It should not be given to patients with inhibitors to treat certain lymphomas.
transcription of several genes severe hepatic disease ▪ Dose-dependent increases in the levels of
that are crucial for the l(LDL), (HDL), and total cholesterol have been
differentiation, proliferation, and found in patients receiving tofacitinib, often
function of NK cells and T and B beginning about 6 weeks after starting
lymphocytes. treatment; therefore, lipid levels should be
▪ In addition, JAK1 (in combination monitored.
with other JAKs) controls signal ▪ Although tofacitinib causes a dose-
transduction from IL-6 and dependent increase in CD19 B cells and CD4 T
interferon receptors. cells plus a reduction in CD16/ CD56 NK cells,
▪ RA patients receiving tofacitinib the clinical significance of these changes
rapidly reduce the C-reactive remains unclear.
protein. ▪ Drug-related neutropenia and anemia occur,
requiring drug discontinuation.
▪ Headache, diarrhea, elevation of liver
enzymes, and gastrointestinal perforation
TNF-α-blocking agents
✓ Cytokines play a central role in the immune response and in RA. Although a wide range of cytokines are expressed in the joints of RA patients, TNF-α appears to be particularly
important in the inflammatory process.
✓ TNF-α affects cellular function via activation of specific membrane-bound TNF receptors (TNFR1, TNFR2).
✓ Five biologic DMARDs interfering with TNF-α have been approved for the treatment of RA and other rheumatic diseases
Mechanism of Action Pharmacokinetics Indication Adverse Effects:
Adalimumab ▪ Fully human IgG1 anti-TNF monoclonal ▪ given subcutaneously ▪ The compound is approved for TNF-α-blocking agents have
antibody ▪ half-life of 10–20 days RA, AS, PA, JIA, plaque psoriasis, multiple adverse effects in
▪ This compound complexes with soluble ▪ clearance is decreased by more than Crohn’s disease, and ulcerative common.
TNF-α and prevents its interaction with 40% in the presence of methotrexate colitis. ▪ The risk of bacterial infections
p55 and p75 cell surface receptors. ▪ formation of human anti-monoclonal ▪ It decreases the rate of formation and macrophage dependent
▪ This results in down-regulation of antibody is decreased when of new erosions. infection (including
macrophage and T-cell function. methotrexate is given at the same ▪ It is effective both as tuberculosis, fungal, and other
time. monotherapy and in combination opportunistic infections) is
▪ Usual dose in RA is 40 mg every other with methotrexate and other increased, although it remains
week, but dosing is frequently nonbiologic DMARDs. very low.
increased to 40 mg weekly. ▪ Based only on case reports ▪ Activation of latent
▪ In psoriasis, and case series, adalimumab has tuberculosis is lower with
 80 mg is given at week 0, also been found to be effective in etanercept than with other
 40 mg at week 1, and then the treatment of Behçet’s disease, TNF-α-blocking agents.
 40 mg every other week thereafter. sarcoidosis, and notably, ▪ Nevertheless, all patients
▪ Initial dose in inflammatory bowel noninfectious uveitis. should be screened for latent
disease is higher; or active tuberculosis before
 160 mg at week 0 starting TNF-α-blocking
agents.
 80 mg 2 weeks later,
▪ The use of TNF-α-blocking
 followed by a 40 mg maintenance agents is also associated with
dose every other week. increased risk of HBV
▪ Patients with ulcerative colitis should reactivation and screening for
continue maintenance treatment HBV is important before
beyond 8 weeks if they show evidence starting the treatment.
of remission by that time. ▪ TNF-α-blocking agents
▪ Adalimumab dose depends on the increase the risk of skin
body weight in patients with JIA; 20 cancers— including
mg every other week for patients melanoma—which
weighing 15–30 kg, and 40 mg every necessitates periodic skin
other week in patients weighing 30 kg examination, especially in
or more. high-risk patients.
▪ On the other hand, there is no
Certolizumab ▪ Certolizumab is a recombinant, ▪ Given subcutaneously ▪ indicated for the treatment of clear evidence of increased
humanized antibody Fab fragment ▪ half-life: 14 days. ▪ adults with moderately to risk of solid malignancies or
conjugated to a polyethylene glycol ▪ Methotrexate decreases the severely active RA. It can be lymphomas with TNF-α-
(PEG) with specificity for human TNF-α. appearance of anti-certolizumab used as blocking agents, and their
▪ Certolizumab neutralizes membrane- antibodies. ▪ monotherapy or in combination incidence may not be different
bound and soluble TNF-α in a dose- ▪ The usual dose for RA is with nonbiologic DMARDs. compared with other DMARDs
dependent manner. 400 mg initially and at weeks 2 and 4, ▪ Additionally, certolizumab is or active RA itself.
▪ does not contain an Fc region, found on followed by approved in adult patients with ▪ A low incidence of newly
a complete antibody, and does not fix 200 mg every other week, or 400 mg ▪ Crohn’s disease, active PA and formed dsDNA antibodies and
complement or cause antibody every 4 weeks. active AS. antinuclear antibodies (ANAs)
dependent cell-mediated cytotoxicity in has been documented when
vitro. using TNF-α-blocking agents,
Etanercept ▪ recombinant fusion protein consisting of ▪ given subcutaneously as 25 mg twice ▪ Approved for the treatment of but clinical lupus is extremely
two soluble TNF p75 receptor moieties weekly or 50 mg weekly. RA, juvenile chronic arthritis, rare and the presence of ANA
linked to the Fc portion of human ▪ In psoriasis, 50 mg is given twice psoriasis, PA, and AS. and dsDNA antibodies per se
▪ it binds TNF-α molecules and also weekly for 12 weeks and then is ▪ It can be used as monotherapy, does not contraindicate the
inhibits lymphotoxin-α. followed by 50 mg weekly. although over 70% of patients use of TNF-α-blocking agents.
▪ The drug is slowly absorbed, with taking etanercept are also using ▪ In patients with borderline or
peak concentration 72 hours after methotrexate. overt heart failure (HF), TNF-
drug administration. ▪ decreases the rate of formation α-blocking agents can
▪ Etanercept has a mean serum of new erosions relative to exacerbate HF.
elimination half-life of 4.5 days. methotrexate alone. ▪ TNF-α-blocking agents can
▪ A recent study demonstrated ▪ It is also being used in other induce the immune system to
▪ a reduction of radiographic rheumatic syndromes such as develop anti-drug antibodies
progression with the use of scleroderma, granulomatosis in about 17% of cases.
50 mg of etanercept weekly. with polyangiitis (Wegener’s ▪ These antibodies may
granulomatosis), giant cell interfere with drug efficacy
arteritis, Behçet’s disease, and correlate with infusion
uveitis, and sarcoidosis. site reactions.
Golimumab ▪ human monoclonal antibody with a high ▪ administered subcutaneously ▪ Golimumab with methotrexate ▪ Injection site reactions occur
affinity for soluble and membrane- ▪ half-life: approximately 14 days. is indicated for the treatment of in 20–40% of patients,
bound TNF-α. ▪ Concomitant use with methotrexate moderately to severely active RA although they rarely result in
▪ Golimumab effectively neutralizes the increases golimumab serum levels in adult patients. discontinuation of therapy.
inflammatory and decreases anti-golimumab ▪ It is also indicated for the ▪ Cases of alopecia areata,
effects produced by TNF-α seen in antibodies. treatment of PA and AS hypertrichosis, and erosive
diseases such as RA. ▪ Recommended dose for the and moderate to severe lichen planus have been
treatment of RA, PA, and AS is 50 mg ulcerative colitis. reported.
given every 4 weeks. ▪ Cutaneous pseudo lymphomas
▪ A higher dose of golimumab is used are reported rarely with TNF-
for the treatment of ulcerative colitis α-blocking agents, especially
as follows: 200 mg initially at week 0 infliximab.
followed by 100 mg at week 2 and
every 4 weeks thereafter.
Infliximab ▪ Chimeric (25% mouse, 75% human) IgG1 ▪ Infliximab is given as an intravenous ▪ Approved for use in RA, AS, PA, ▪ TNF-α-blocking agents may
monoclonal antibody that binds with infusion with “induction” at 0, 2, and Crohn’s disease, ulcerative colitis, increase the risk of
high affinity to soluble and possibly 6 weeks and maintenance every 8 pediatric inflammatory bowel gastrointestinal ulcers and
membranebound TNF-α. weeks thereafter. disease, and psoriasis. large bowel perforation
▪ Its mechanism of action probably is the ▪ Dosing is 3–10 mg/kg, ▪ It is being used off-label in other including diverticular and
same as that of adalimumab. ▪ Usual dose is 3–5 mg/kg every 8 diseases, including appendiceal perforation.
weeks granulomatosis with polyangiitis ▪ Nonspecific interstitial
▪ There is a relationship between (Wegener’s granulomatosis), giant pneumonia, psoriasis, and
serum concentration and effect, cell arteritis, Behçet’s disease, sarcoidosislike syndrome are
although individual clearances vary uveitis, and sarcoidosis. among the rare reported
markedly. ▪ In RA, infliximab plus toxicities associated with TNF-
▪ terminal half-life is 9–12 days methotrexate decreases the rate α blockers.
without accumulation after repeated of formation of new erosions. ▪ Rare cases of leukopenia,
dosing at the recommended interval ▪ Although it is recommended that neutropenia,
of 8 weeks. methotrexate be used in thrombocytopenia, and
▪ After intermittent therapy, infliximab conjunction with infliximab, a pancytopenia have been
elicits human antichimeric antibodies number of other nonbiologic reported.
in up to 62% of patients. DMARDs, including ▪ The precipitating drug should
▪ Concurrent therapy with antimalarials, azathioprine, be discontinued in such cases.
methotrexate markedly decreases leflunomide, and cyclosporine,
the prevalence of human can be used as background
antichimeric therapy for this drug.
antibodies ▪ Infliximab is also used as
monotherapy.

IL-1- inhibiting agents

✓ IL-1α plays a major role in the pathogenesis of several inflammatory and autoimmune diseases including RA.
✓ IL-1β and IL-1 receptor antagonist (IL-1RA) are other members of the IL-1 family.
✓ All three bind to IL-1 receptors in the same manner.
✓ However, IL-1RA does not initiate the intracellular signaling pathway and thus acts as a competitive inhibitor of the proinflammatory IL-1α and IL-1β.

Anakinra ▪ Anakinra is the oldest drug in this ▪ administered subcutaneously ▪ approved for the treatment of ▪ MC adverse effects are
family ▪ reaches a maximum plasma moderately to severely active RA injection site reactions (up to
▪ but is now rarely used for RA. concentration after 3–7 hours. in adult patients, but it is not very 40%) and upper respiratory
▪ recombinant IL-1RA; ▪ absolute bioavailability of anakinra is effective and is rarely used for this tract infections.
▪ it blocks the effect of IL-1α and IL-1β 95% indication. ▪ Serious infections occur rarely
on IL-1 receptors, ▪ terminal half-life: 4- to 6-hour ▪ drug of choice for CAPS in patients given IL-1 inhibitors.
▪ hence decreasing the immune ▪ recommended dose: treatment of RA is particularly the neonatal- onset ▪ Headache, abdominal pain,
response in inflammatory diseases. 100 mg daily. multisystem inflammatory disease nausea, diarrhea, arthralgia,
▪ The dose of anakinra depends on the (NOMID) subtype. and flu-like illness have all
body weight in the treatment of been reported, as well as
cryopyrin-associated periodic
▪ effective in gout hypersensitivity reactions.
syndrome (CAPS), starting with 1–2 ▪ Behçet’s disease and adult onset ▪ Patients taking IL-1 inhibitors
mg/kg/d to a maximum of 8 mg/kg/d. JIA. may experience transient
▪ Reduction in the frequency of ▪ Its use for giant cell arteritis is neutropenia, which requires
administering anakinra to every other controversial. regular monitoring of
day is recommended in patients with neutrophil counts.
renal insufficiency.

canakinumab ▪ Canakinumab is a human IgG1/κ ▪ given as subcutaneous injections. ▪ for active SJIA in children 2 years
monoclonal antibody against IL- ▪ reaches peak serum concentrations 7 or older.
1β. days after a single subcutaneous ▪ used to treat CAPS, particularly
▪ It forms a complex with IL-1β, injection. the familial cold
preventing its binding to IL-1 ▪ absolute bioavailability of 66% autoinflammatory syndrome and
receptors. ▪ 26-day mean terminal half-life Muckle-Wells syndrome
▪ recommended dose for patients with subtypes for adults and children
SJIA who weigh more than 7.5 kg is 4 4 years or older.
mg/kg every 4 weeks. ▪ Canakinumab is also used to
▪ There is a weight adjusted algorithm treat gout
for treating CAPS.
rilonacept ▪ Rilonacept is the ligand-binding ▪ subcutaneous dose of rilonacept for Rilonacept is approved to treat
domain of the IL-1 receptor. CAPS is age-dependent. CAPS subtypes:
▪ It binds mainly to IL-1β and binds ▪ In patients 12–17 years of age, 4.4 familial cold autoinflammatory
with lower affinity to IL-1α and IL- mg/kg (maximum of 320 mg) is the syndrome and Muckle-Wells
1RA. loading dose, with a maintenance dose syndrome in patients 12 years or
▪ neutralizes IL-1β and prevents its of 2.2 mg/kg (maximum of 160 mg) older.
attachment to IL-1 receptors. weekly. ▪ Rilonacept is also used to treat
▪ Those 18 years and older receive 320 gout
mg as a loading dose and 160 mg
weekly thereafter.
▪ The steady-state plasma concentration
is reached after 6 weeks.
Indications Adverse effects:
▪ Corticosteroids have been used in 60–70% of RA patients. ▪ Some of the symptoms of RA, especially morning stiffness ▪ Prolonged use of corticosteroids leads to serious
▪ Their effects are prompt and dramatic, and they are capable of and joint pain, follow a circadian rhythm, probably due to and disabling toxic effects
slowing the appearance of new bone erosions. an increase in proinflammatory cytokines in the early ▪ Many of these adverse effects occur at doses
▪ Corticosteroids may be administered for certain serious extra- morning. below 7.5 mg prednisone equivalent daily
articular manifestations of RA such as pericarditis or eye ▪ A recent approach uses delayed-release prednisone for ▪ Even 3–5 mg/d can cause adverse effects in
involvement or during periods of exacerbation. the treatment of early morning stiffness and pain in RA. susceptible individuals when this class of drugs is
▪ When prednisone is required for long-term therapy, the dosage ▪ The tablet contains an inactive outer layer and a core of used over prolonged periods.
should not exceed 7.5 mg daily, and gradual reduction of the dose the active drug.
should be encouraged. ▪ The outer layer dissolves over 4–6 hours, releasing the
▪ Alternate-day corticosteroid therapy is usually unsuccessful in RA. prednisone.
▪ Other rheumatic diseases in which the corticosteroids’ potent ▪ Taking the drug at 9–10 pm results in a small pulse of
anti-inflammatory effects may be useful include vasculitis, SLE, prednisone at 2–4 am, decreasing the circadian
Wegener’s granulomatosis, PA, giant cell arteritis, sarcoidosis, inflammatory cytokines.
and gout. ▪ At low doses of 3–5 mg prednisone, the adrenal-pituitary
▪ Intra-articular corticosteroids are often helpful to alleviate painful axis does not seem to be impacted.
symptoms and, when successful, are preferable to increasing the
dosage of systemic medication.

Acetaminophen ▪ Acetaminophen is administered ▪ Phenacetin, a prodrug that is ▪ Although said to be equivalent to

▪ Adverse Effects:
orally. metabolized to acetaminophen, is aspirin as an analgesic and ▪ In therapeutic doses, a mild reversible
▪ Peak blood concentrations are more toxic and should not be antipyretic agent, acetaminophen increase in hepatic enzymes may
usually reached in 30–60 minutes. used. lacks antiinflammatoryn properties.
occasionally occur.
▪ Acetaminophen is poorly bound to ▪ Acetaminophen is the active ▪ does not affect uric acid levels▪ With larger doses, dizziness, excitement,
plasma proteins metabolite of phenacetin and is ▪ lacks platelet-inhibiting effects and disorientation may occur.
▪ Partially metabolized by hepatic responsible for its analgesic effect. ▪ drug is useful in mild to moderate
▪ Ingestion of 15 g of acetaminophen may
microsomal enzymes to the inactive ▪ It is a weak COX-1 and COX-2 ▪ pain such as headache, myalgia, be fatal, death being caused by severe
sulfate and glucuronide inhibitor in peripheral tissues and postpartum pain, and other hepatotoxicity with centrilobular
▪ Less than 5% is excreted unchanged. possesses no significant anti- ▪ circumstances in which aspirin is an
necrosis, sometimes associated with
▪ A minor but highly reactive inflammatory effects. effective analgesic. acute renal tubular necrosis
metabolite ▪ Acetaminophen alone is inadequate
▪ Even 4 g acetaminophen is associated
▪ (N-acetyl-p-benzoquinone) is therapy for inflammatory conditions
with increased liver function test
important in large doses because it such as RA. abnormalities.
is toxic to both liver and kidney ▪ For mild analgesia, acetaminophen
▪ Doses greater than 4 g/d are not usually
▪ The half-life of acetaminophen is 2– is the preferred drug in patients recommended
3 hours ▪ history of alcoholism contraindicates
allergic to aspirin, when salicylates
▪ relatively unaffected by renal are poorly tolerated. even this dose.
function. With toxic doses or liver ▪ It is preferable to aspirin in patients
▪ Early symptoms of hepatic damage
disease, the half-life may be with hemophilia, in those with a include nausea, vomiting, diarrhea, and
increased twofold or more. history of peptic ulcer, and in those
abdominal pain.
in whom bronchospasm ▪ Cases of renal damage without hepatic
is
precipitated by aspirin. damage have occurred, even after usual
▪ Unlike aspirin, acetaminophen doesdoses of acetaminophen.
not antagonize the effects of ▪ Therapy for overdose is much less
uricosuric agents. satisfactory than that for aspirin
overdose.
▪ In addition to supportive therapy, one
should provide sulfhydryl groups in the
form of acetylcysteine to neutralize the
toxic metabolites
▪ Hemolytic anemia and
methemoglobinemia are very rare.
▪ Interstitial nephritis and papillary
necrosis— serious complications of
phenacetin—have not occurred, and GI
bleeding also has not occurred. Caution
is necessary in patients with any type of
liver disease.
▪ Dosage: Acute pain and fever may be
effectively treated with 325–500 mg
four times daily and proportionately less
for children.
▪ Dosing in adults s is now recommended
not to exceed 4 g/d, in most cases.
Ketorolac ▪ Ketorolac is an NSAID promoted for systemic use mainly as a short-term analgesic (not longer than 1 week), not as an anti-inflammatory drug (although it has
typical NSAID properties).
▪ The drug is an effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain.
▪ It is most often given intramuscularly or intravenously, but an oral formulation is available.
▪ When used with an opioid, it may decrease the opioid requirement by 25–50%.
▪ Toxicities are similar to those of other NSAIDs, although renal toxicity is more common with chronic use.

Tramadol ▪ Tramadol is a centrally acting synthetic analgesic, structurally related to opioids.

▪ Since naloxone, an opioid receptor blocker, only inhibits 30% of the analgesic effect of tramadol, the mechanism of action of this drug must involve both
nonopioid and opioid receptors.
▪ Tramadol does not have significant anti-inflammatory effects.
▪ The drug may exert part of its analgesic effect by enhancing 5-hydroxytryptamine (5-HT) release and inhibiting the reuptake of norepinephrine and 5-HT.
 ✓ Gout is a metabolic disease characterized by recurrent episodes of acute ✓ Attracted by these chemotactic mediators, polymorphonuclear leukocytes migrate into the joint
arthritis due to deposits of monosodium urate in joints and cartilage. space and amplify the ongoing inflammatory process. In the later phases of the attack, increased
✓ Uric acid renal calculi, tophi, and interstitial nephritis may also occur. numbers of mononuclear phagocytes (macrophages) appear, ingest the urate crystals, and release
✓ Gout is usually associated with a high serum uric acid level (hyperuricemia), a more inflammatory mediators.
poorly soluble substance that is the major end product of purine metabolism. ✓ Before starting chronic urate-lowering therapy for gout, patients in whom hyperuricemia is
✓ In most mammals, uricase converts uric acid to the more soluble allantoin; this associated with gout and urate lithiasis must be clearly distinguished from individuals with only
enzyme is absent in humans. hyperuricemia.
✓ While clinical gouty episodes are associated with hyperuricemia, most ✓ The efficacy of long-term drug treatment in an asymptomatic hyperuricemic person is unproved.
individuals with hyperuricemia may never develop a clinical event from urate ✓ Although there are data suggesting a clear relationship between the degree of uric acid elevation
crystal deposition. and the likelihood of clinical gout, in some individuals, uric acid levels may be elevated up to 2
✓ The treatment of gout aims to relieve acute gouty attacks and prevent standard deviations above the mean for a lifetime without adverse consequences.
recurrent gouty episodes and urate lithiasis. ✓ Many different agents have been used for the treatment of acute and chronic gout. However, non-
✓ Clinical gout is dependent on a macromolecular complex of proteins, called adherence to these drugs is exceedingly common; adherence has been documented to be 18%–
NLRP3, which regulates the activation of IL-1. 26% in younger patients.
✓ Urate crystals activate NLRP3, resulting in release of prostaglandins and
lysosomal enzymes by synoviocytes.

COLCHICINE
– Although NSAIDs, corticosteroids, or colchicine are first-line drugs for acute gout, colchicine was the primary treatment for many years.
– Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale.
Pharmacokinetics Pharmacodynamics Indications Adverse Effects: Dosage
▪ absorbed readily after oral ▪ relieves the pain and inflammation ▪ for gout ▪ diarrhea and may occasionally ▪ Prophylaxis : 0.6 mg one to three
▪ administration of gouty arthritis in 12–24 hours ▪ used between attacks (the cause nausea, vomiting, and times daily.
▪ reaches peak plasma levels without altering the metabolism or “intercritical period”) for abdominal pain ▪ For terminating a gouty attack:
within 2 hours excretion of urates and without prolonged prophylaxis (at low ▪ Hepatic necrosis, acute renal 1.2 mg followed by a single 0.6
▪ eliminated with a serum half- other analgesic effects. doses) failure, disseminated intravascular mg oral dose was as effective as
life of 9 hours ▪ produces its anti inflammatory ▪ prevents attacks of acute coagulation, and seizures have also higher dose regimens and
▪ Metabolites are excreted in effects by binding to the intracellular Mediterranean fever been observed. adverse events were less with
the intestinal tract and urine. protein tubulin, thereby preventing ▪ mild beneficial effect in sarcoid ▪ may rarely cause hair loss and bone this lower dose regimen.
its polymerization into microtubules arthritis and in hepatic cirrhosis marrow depression, as well as ▪ Intravenous preparations
and leading to the inhibition of ▪ treat and prevent pericarditis, peripheral neuritis, myopathy, and, containing colchicine
leukocyte migration and pleurisy, and coronary artery in some cases, death. discontinued because of their
phagocytosis. disease, probably due to its anti- ▪ more severe adverse events have potential life-threatening adverse
▪ It also inhibits the formation of inflammatory effect. been associated with the effects.
leukotriene B4 and IL-1β. ▪ Although it has been given intravenous administration of
▪ Several of colchicine’s adverse intravenously, this route is no colchicine
effects are produced by its inhibition longer approved by
of tubulin polymerization and cell ▪ the FDA (2009).
mitosis
NSAIDS FOR GOUT
– In addition to inhibiting prostaglandin synthase, NSAIDs inhibit urate crystal phagocytosis.
– Aspirin is not used because it causes renal retention of uric acid at low doses (≤ 2.6 g/d). It is uricosuric at doses greater than 3.6 g/d.
– Indomethacin is commonly used in the initial treatment of gout as a replacement for colchicine.
– For acute gout, 50 mg is given three times daily; when a response occurs, the dosage is reduced to 25 mg three times daily for 5–7 days.
– All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes.
– Oxaprozin, which lowers serum uric acid, is theoretically a good choice.
– These agents appear to be as effective and safe as the older drugs.

URICOSURIC AGENTS
 Probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent
gouty attacks.
 In a patient who excretes large amounts of uric acid, the uricosuric agents should not be used.
 Lesinurad (RDEA594) is a promising new uricosuric agent that is currently in phase 3 trials.

Pharmacokinetics Pharmacodynamics Indications Adverse Effects: Dosage

▪ Uricosuric drugs are organic ▪ Uricosuric drugs—probenecid, ▪ Uricosuric therapy should be ▪ Both of these organic acids cause ▪ Probenecid is usually started at a
acids sulfinpyrazone, fenofibrate, and initiated in gouty patients with equivalent GI irritation, but dosage of 0.5 g orally daily in
▪ act at the anion transport losartan—inhibit active transport underexcretion of uric acid when sulfinpyrazone is more active in this divided doses, progressing to 1 g
sites of the renal tubule sites for reabsorption and secretion allopurinol or febuxostat is regard. daily after 1 week.
▪ Probinecid completely in the proximal renal tubule so that contraindicated or when tophi ▪ A rash may appear after the use of ▪ Sulfinpyrazone is started at a
reabsorbed by the renal net reabsorption of uric acid in the are present. either compound. dosage of 200 mg orally daily,
tubules and metabolized proximal tubule is decreased. ▪ Therapy should not be started ▪ Nephrotic syndrome has occurred progressing to 400–800 mg daily.
slowly with a terminal serum ▪ Because aspirin in doses of less than until 2–3 weeks after an acute after the use of probenecid. It should be given in divided
half-life of 5–8 hours. 2.6 g daily causes net retention of attack. ▪ Both sulfinpyrazone and probenecid doses with food to reduce
▪ Sulfinpyrazone or its active uric acid by inhibiting the secretory may rarely cause aplastic anemia. adverse GI effects.
hydroxylated derivative is transporter, it should not be used Contraindications and Cautions:
excreted by the kidneys. for analgesia in patients with gout. ▪ It is essential to maintain a large
▪ The duration of its effect ▪ The secretion of other weak acids urine volume to minimize the
after oral administration is (eg, penicillin) is also reduced by possibility of stone formation.
almost as long as that of uricosuric agents.
probenecid, which is given ▪ As the urinary excretion of uric acid
once or twice daily. increases, the size of the urate pool
decreases, although the plasma
concentration may not be greatly
reduced. In patients who respond
favorably, tophaceous deposits of
urate are reabsorbed, with relief of
arthritis and remineralization of
bone.
 ▪ With the ensuing increase in uric
acid excretion, a predisposition to
the formation of renal stones is
augmented rather than decreased;
therefore, the urine volume should
be maintained at a high level, and at
least early in treatment, the urine
pH should be kept above 6.0 by the
administration of alkali.

ALLOPURINOL
✓ preferred and standard-of-care therapy for gout during the period between acute episodes
✓ reduces total uric acid body burden by inhibiting xanthine oxidase

▪ Isomer of hypoxanthine ▪ Dietary purines are not an ▪ Allopurinol is often the first-line ▪ In addition to precipitating gout ▪ The initial dosage of allopurinol is
▪ Allopurinol is approximately important source of uric acid. agent for the treatment of (the reason to use concomitant 50–100 mg/d.
80% absorbed after oral ▪ Quantitatively important amounts chronic gout in the period colchicine or NSAID), GI intolerance ▪ It should be titrated upward until
admin. of purine are formed from amino between attacks and it tends to (including nausea, vomiting, and serum uric acid is below 6 mg/dL;
▪ terminal serum half-life of 1– acids, formate, and carbon dioxide prolong the intercritical period. diarrhea), peripheral neuritis and ▪ this level is commonly achieved
2 hours in the body. ▪ As with uricosuric agents, the necrotizing vasculitis, bone marrow at 300–400 mg/d but is not
▪ Like uric acid, allopurinol is ▪ Those purine ribonucleotides not therapy is begun with the suppression, and aplastic anemia restricted to this dose; doses as
metabolized by xanthine incorporated into nucleic acids and expectation that it will be may rarely occur. high as 800 mg/d may be
oxidase, but the resulting derived from nucleic acid continued for years if not for ▪ Hepatic toxicity and interstitial needed.
compound, alloxanthine, degradation are converted to life. nephritis have been reported. ▪ As noted above, colchicine or an
retains the capacity to inhibit xanthine or hypoxanthine and ▪ When initiating allopurinol, ▪ An allergic skin reaction NSAID should be given during the
xanthine oxidase and has a oxidized to uric acid colchicine or NSAID should be characterized by pruritic first months of allopurinol
long enough duration of ▪ Allopurinol inhibits this last step, used until steady-state serum maculopapular lesions occurs in 3% therapy to prevent the gouty
action so that allopurinol is resulting in a fall in the plasma uric acid is normalized or of patients. arthritis episodes that sometimes
given only once a day. urate level and a decrease in the decreased to less than 6 mg/dL ▪ Isolated cases of exfoliative occur.
overall urate burden. and they should be continued dermatitis have been reported.
▪ The more soluble xanthine and for 6 months or longer. ▪ In very rare cases, allopurinol has
hypoxanthine are increased ▪ Thereafter, colchicine or the become bound to the lens, resulting
NSAID can be cautiously stopped in cataracts.
while continuing allopurinol
therapy.
Interactions and Cautions:
▪ When chemotherapeutic purines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%.
▪ Allopurinol may also increase the effect of cyclophosphamide.
▪ Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration.
▪ Safety in children and during pregnancy has not been established.

FEBUXOSTAT
 non-purine xanthine oxidase inhibitor that was approved by the FDA in 2009.
Pharmacokinetics Pharmacodynamics Indications Adverse Effects: Dosage
▪ more than 80% absorbed ▪ Febuxostat is a potent and selective ▪ Febuxostat is approved at doses ▪ As with allopurinol, prophylactic ▪ Recommended starting dose of
following oral administration. inhibitor of xanthine oxidase, of 40 or 80 mg for the treatment treatment with colchicine or NSAIDs febuxostat is 40 mg daily.
▪ With maximum thereby reducing the formation of of chronic hyperuricemia in gout should be started at the beginning ▪ Because there was concern for
concentration achieved in xanthine and uric acid without patients. of therapy to avoid gout flares. cardiovascular events in the
approximately 1 hour and a affecting other enzymes in the ▪ Although it appeared to be more ▪ The most frequent treatment original phase 3 trials, the FDA
half-life of 4–18 hours, once- purine or pyrimidine metabolic effective then allopurinol as related adverse events are liver approved only 40 mg and 80 mg
daily dosing is effective. pathway. urate-lowering therapy, the function abnormalities, diarrhea, dosing.
▪ extensively metabolized in ▪ In clinical trials, Febuxostat at daily allopurinol dosing was limited to headache, and nausea. ▪ No dose adjustment is necessary
the liver. dosing of 80 mg or 120 mg was 300 mg/d, thus not reflecting ▪ Febuxostat is well tolerated in for patients with renal
▪ All of the drug and its more the actual dosing regimens used patients with a history of allopurinol impairment since it is highly
inactive metabolites appear ▪ effective in lowering serum urate in clinical practice. intolerance. metabolized into an inactive
in the urine, although less levels than allopurinol at a standard ▪ At this time, the dose ▪ There does not appear to be an metabolite by the liver.
than 5% appears as 300 mg daily dose. equivalence of allopurinol and increased risk of cardiovascular
unchanged drug. ▪ The urate-lowering effect was febuxostat is unknown. events.
comparable regardless of the
pathogenic cause of
hyperuricemia— overproduction or
underexcretion.

PEGLOTICASE
 newest urate-lowering therapy to be approved for the treatment of refractory chronic gout.
Chemistry Pharmacokinetics Pharmacodynamics and Dosage Adverse Effects:
▪ Pegloticase is a recombinant ▪ Recommended dose: 8 mg every 2 ▪ Urate oxidase enzyme, absent in ▪ Gout flare can occur during treatment with pegloticase, especially during
mammalian uricase that is weeks administered as an humans and some higher the first 3–6 months of treatment, requiring prophylaxis with NSAIDs or
covalently attached to intravenous infusion. primates, converts uric acid to colchicine.
methoxy polyethylene glycol ▪ rapidly acting drug, achieving a allantoin. ▪ Large numbers of patients show immune responses to pegloticase.
(mPEG) to prolong the peak decline in uric acid level within ▪ highly soluble ▪ The presence of antipegloticase antibodies is associated with shortened
circulating half-life and 24–72 hours. ▪ easily eliminated by the kidney circulating half-life, loss of response leading to a rise in plasma urate levels,
diminish immunogenic ▪ Serum halflife ranges from 6 to 14 ▪ maintain low urate levels for up and a higher rate of infusion reactions and anaphylaxis.
response. days. to 21 days after a single dose at ▪ Anaphylaxis occurs in more than 6–15% of patients receiving pegloticase.
▪ Several studies have shown earlier doses of 4–12 mg, allowing for ▪ Monitoring of plasma uric acid level, with rising level as an indicator of
clearance of PEG-uricase (mean of IV dosing every 2 weeks. antibody production, allows for safer administration and monitoring of
11 days) due to antibody response ▪ should not be used for efficacy.
when compared to PEG-uricase asymptomatic hyperuricemia. ▪ In addition, other oral urate-lowering agents should be avoided in order
antibody-negative subjects (mean not to mask the loss of pegloticase efficacy.
of 16.1 days).
 ▪ Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea
may occur.
▪ Other less frequent side effects noted include upper respiratory tract
infection, peripheral edema, urinary tract infection, and diarrhea.
▪ There is some concern for hemolytic anemia in patients with glucose-6-
phosphate dehydrogenase deficiency because of the formation of
hydrogen peroxide by uricase; therefore, pegloticase should be avoided in
these patients.
GLUCOCORTICOIDS
✓ Corticosteroids are sometimes used in the treatment of severe symptomatic gout, by intra-articular, systemic, or subcutaneous routes, depending on the degree of pain and
inflammation.
✓ The most commonly used oral corticosteroid is prednisone.
✓ Recommended oral dose: 30–50 mg/d for 1–2 days, tapered over 7–10 days.
✓ Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcinolone acetonide can be given if the patient is unable to take oral medications.

INTERLEUKIN-1 INHIBITORS
✓ Drugs targeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept, are used for the treatment of gout.
✓ Although the data are limited, these agents may provide a promising treatment option for acute gout in patients with contraindications to, or who are refractory to, traditional
therapies like NSAIDs or colchicine.
✓ Canakinumab,
 fully human anti- IL-1β monoclonal antibody
 provide rapid and sustained pain relief at a dose of 150 mg subcutaneously.
✓ These medications are also being evaluated as therapies for prevention of gout flares while initiating urate-lowering therapy.

Source: Katzung, 13th Edition