NSAIDs, by virtue of their action, primarily provide symptomatic relief of arthritis.  They do not actually slow the progression of the disease.  As the disease does progress and the degree of inflammation increases, they will often appear to loose their effectiveness.  Drugs that do at least in part impede the disease process are those that decrease the immune response either with or without subsequent anti-inflammatory activity.  For this reason, IMMUNOSUPPRESSANTS may be used late in the disease.  Note that these agents are not a first line of treatment, primarily because of their high incidence of adverse reactions.  These agents do not show an immediate response and may require from six weeks to six months to exert measurable efficacy.

Cytotoxic Immunosuppressants -- Anti-neoplastics

Methotrexate -- this anti-metabolite (specifically a folate antagonist) inhibits the enzyme dihydrofolate reductase, thereby inhibiting thymidylate synthase and subsequent thymidine synthesis.  It also inhibits aminoimidazolecarboxamide ribonucleotide (ACIR) transformylase.  These actions decrease the replication of immune cells and thus decrease the immune response.  The typical dose for methotrexate is 5 mg three times weekly (up to 25 mg weekly).  The major side effects include nausea and GI upset, gastric mucosal ulcers, and hepatoxicity.  Potential methotrexate overdose and undue toxicity may be avoided by the administration of Leucovorin or by folate supplementation.  (This aspect of methotrexate therapy will be covered later in the semester, with the anti-neoplastics.)

Azathioprine -- this purine antagonist also decreases nucleic acid synthesis to decrease lymphocyte proliferation.  The major adverse effects of azathioprine include bone marrow suppression with leukopenia, anaemia, thrombocytopenia; rash, fever, nausea/vomiting/diarrhoea, and hepatotoxicity.

Other cytotoxic immunosuppressants that have been used in arthritis include meclorethamine, cyclophosphamide, and chlorambucil.  The actions and effects of these agents will be covered in the anti-neoplastic portion of the course.  The immunosuppressant cyclosporine and the immunomodulator levamisole have also been employed in the treatment of late-stage arthritis.  These agents will also be examined more in-depth later in the course.

ETANERCEPT -- Etanercept (Enbrel®)is a recombinant human form of the receptor for a cytokine that is specifically identified as tumour necrosis factor (TNF) alpha.  Endogenous TNF-alpha is produced by macrophages and activated T-cells and acts to stimulate the inflammatory response.  Actions that result from TNF-alpha receptor activation include increased production of interleukins, granulocyte-macrophage stimulating factors, and other cytokines that ultimately contribute to the inflammatory process.  Etanercept, as the receptor for TNF-alpha, binds to TNF-alpha thus preventing its binding to the endogenous receptor.  The drug has the capability of binding to TWO TNF-alphas.  This essentially inhibits the actions of both molecules of  TNF-alpha and the pain, swelling, and other signs of inflammation that may result from the cytokine.  Etanercept is intended as a second line therapeutic agent for the treatment of rheumatoid arthritis (it is also being investigated for use in congestive heart failure).  It may be administered alone or in combination with other immunomodulators such as methotrexate.  Subacute studies (6 months in duration) have shown relatively few side effects (redness at sight of injection, upper respiratory tract irritation).  Chronic effects have yet to be released, however, there is concern over immunosuppression sufficient to cause infection with prolonged administration.  Etanercept is administered subcutaneously (in the thigh, arm, or abdomen) twice weekly at a dose of 10 mg (approximately 16 mg/m²).

ANTI-MALARIALS -- Chloroquine and Hydroxychloroquine have been used for some 40 years in the treatment of advanced rheumatoid arthritis.  Their exact mechanism of action is not known.  They do, however, decrease rheumatoid factor titre, decrease inflammation, decrease leukocyte chemotaxis, stabilise lysosomal membranes, and decrease T lymphocyte responsiveness.  It is presumed that their efficacy is mediated by either inhibition of DNA/RNA synthesis or complexation with DNA, preventing replication and/or RNA transcription, thus inhibiting lymphocyte proliferation.  They do NOT totally inhibit progressive bone lesion formation.  Side effects most often exhibited include gastrointestinal actions (N/V/D), headache, pruritus (especially among patients of African ancestry), anorexia, malaise, blood dyscrasias, and uncommonly, alopecia and bleaching of hair. More rare but potentially life-threatening or irreversible are retinopathy, ototoxicity, myopathy, and altered ECGs.  The time to clinically measurable improvement may be as long as 12 to 24 weeks.

GOLD -- Gold sodium thiomalate, Aurothioglucose, Auranofin
Gold salts may prove effective in many patients with advanced rheumatoid arthritis.  However, side effects and/or toxicity may limit its usefulness in some patients.  In those patients who are responsive to gold (usually around 70% of patients taking gold will respond), it does decrease symptoms and limits disease progression.  The first two (2) products listed are aqueous solutions for intramuscular injection.  The third is administered orally (NOTE, bioavailability of auranofin is only about 25%). There does not appear to be a correlation between blood levels of gold and therapeutic efficacy.   Again, for these agents, the exact mechanism of action is not known.  They do alter macrophage function, stabilise lysosomes, decrease histamine release from mast cells, decrease complement activity, decrease phagocytosis by leukocytes, and decrease release of PGE₂, LTB₄, and LTC₄, all of which would decrease the immune response.  Gold may accumulate in the body, especially the skin and renal tubules, for which it has a relatively high affinity.  In fact, one month following the final dose of gold, 25% may be left in the body.  The most common side effects include diarrhoea and pruritic dermatitis (15-20%) and blood dyscrasias.  Other adverse effects include nephrotic syndrome, stomatitis, metallic taste, skin pigmentation, peripheral neuropathy, and corneal gold deposition.  Gold sodium thiomalate may also induce a nitroid-type reaction of flushing, sweating, faintness, and headache, due to its vehicle.  NOTE that many patients may first exhibit a worsening of symptoms (pain, difficulty in movement) early in therapy.  ALSO, patients in whom the drug is withdrawn may show a relapse, in which the arthritic symptoms worsen more quickly that would be expected.

D-PENICILLAMINE
This agent, a metabolite of penicillin, is more commonly used as a metal chelator, as in copper chelation in Wilson's disease. (NOTE gold products and D-penicillamine should not be co-administered for this reason -- the penicillamine will chelate the gold, decreasing the efficacy of both drugs.)  Penicillamine is usually used if the patient does not respond to gold therapy.  Again, its mechanism of action is not know, but it does interfere with receptors on lymphocytes and decrease DNA synthesis.  The latency for effect usually ranges from 3 to 4 months.  Adverse effects of penicillamine include slow wound healing, proteinuria (in about 20% of patients, 4% of whom progress to nephritis), blood dyscrasias, metallic taste, anorexia, nausea, vomiting, and rash.  In a very few individuals, penicillamine may actually precipitate other autoimmune diseases such as myasthenia gravis, Goodpasture's disease, lupus erythematosus, haemolytic anaemia, and thyroiditis.  As with gold therapy, withdrawal of penicillamine may cause a relapse of the arthritis.  Additionally, if penicillamine precipitates any of the autoimmune diseases, it should never be restarted in that patient.

GLUCOCORTICOIDS
Glucocorticoids, or corticosteroids, are effective anti-inflammatory and immunosuppressive agents.  In arthritis, they provide both symptomatic relief and also slow the progression of the disease.

By virtue of their broad mechanisms of action, they are also effective in treating the inflammation and immune response in allergic reactions and asthma.  Mechanistically they inhibit the enzyme phospholipase A₂ (PLA₂) which inhibits the production of arachidonic acid thereby inhibiting the production of all eicosanoid mediators of inflammation (PG, LT, TX).  Additionally, they inhibit the expression of COX II, which also contributes to their efficacy by inhibiting inflammation-induced PG synthesis.  As a result of these mechanisms (and perhaps independent from them) GCs will decrease the migration of lymphocytes, monocytes, eosinophils, and basophils to an inflammed area.  They also decrease the functional response of these elements of inflammation as well as macrophages.  Additionally, these drugs act as lympholytic agents, actually lysing lymphocytes that may contribute to the inflammatory process.  NOTE that these agents have numerous other effects.  These, and the mechanisms of adverse actions of the glucocorticoids, will be covered more in-depth in the endocrine portion of the course.

Short-term side effects of corticosteroids include gastrointestinal upset for the PO agents and throat irritation, hoarseness, dysphonia, coughing, and dry mouth for inhalational agents.

Long-term consequences of corticosteroids include infection, cataracts, fluid/electrolyte imbalance, peptic ulceration, behavioural changes (most often psychosis), bone fractures, adrenal suppression and subsequent decreased stress response, and in those patients pre-disposed, complications of diabetes and the cardiovascular system (atherosclerotic disease and hypertension).

Commonly used agents in the treatment of arthritis include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, and rarely, betamethasone and triamcinolone.  These agents may be administered PO chronically for management of the disease or injected intra-articularly for the management of acute arthritic exacerbation.

Corticosteroids more commonly used as inhalational products for the treatment of asthma or allergies include beclomethasone, dexamethasone, triamcinolone, and flunisolide.