Immunopharmacology

Immunopharmacology

Immunopharmacology, as its name suggests, is the branch of pharmacology that applies to the immune system. In general immunopharmacology describes the manipulation of the immune system and immune responses by pharmacological modulators, for the benefit of the host. This is an immense, and continually expanding field. Immunopharmacological therapeutics range from small molecule antihistamines, disease-modifying antirheumatics, and non-steroidal antiinflammatories to the more recently developed monoclonal antibodies and fusion proteins that can be used to treat autoimmune and chronic inflammatory diseases, as well as infection and cancer.

For a refresher on immunology and the immune system users can refer to sections on the Immunopaedia website, including The Basics of the Immune System, Advanced Immunology, and the Innate Immune System. Immunopaedia produces free online courses (free registration required), for example providing Core Immunology Modules, so you can test your own knowledge.

 

Disease-modifying anti-rheumatic drugs (DMARDs)

Different types of arthritis (rheumatic disease) are treated with different drugs. The aim of the clinician is to prescribe drugs which improve symptoms and, where possible, slow or halt progress of the condition. As their name suggests, disease-modifying anti-rheumatic drugs (DMARDs) offer benefit via the latter mechanism. Full therapeutic response to DMARDs may take several months to become evident. Early intervention with DMARD therapy is recommended to control the signs and symptoms of rheumatic disease and to limit joint damage.

There are two main categories: conventional DMARDs and biological therapies. This topic covers conventional DMARDs, biological therapies are described in the Biological DMARDs topic.

Conventional DMARDs include:

Methotrexate is an oral medication prescribed for moderate to severe RA.

Gold (as sodium aurothiomalate) is given by deep intramuscular injection for active progressive RA. This is a long-term treatment, requiring regular dosing up to 5 years post-complete remission. Second courses of gold are not usually effective if the patients suffers a complete relapse.

Penicillamine has a similar action to gold. Penicillamine should be discontinued if there is no improvement within 1 year.

Sulfasalazine is prescribed for active RA on expert advice.

Hydroxychloroquine is prescribed for active RA on expert advice. 

 

Because of their toxicity, these next immunosuppressants are only used for RA when patients have not responded to other DMARDs:

Ciclosporin, a calcineurin inhibitor: only prescribed for severe active RA when conventional second-line therapy is inappropriate or ineffective.

Leflunomide is a pyrimidine synthesis inhibitor which regulates autoimmune lymphocytes. Used by specialist practitioners for treating moderate to   severe active RA and active psoriatic arthritis.

Cyclophosphamide: can be prescribed for RA with severe systemic manifestations and other connective tissue diesases (e.g. active vasculitis).

Azathioprine can be prescribed for RA that has not responded to other DMARDS.

Prescibers should consider co-morbidity and patient preference when choosing which DMARD (or combination of DMARDs) to prescribe. Whilst providing similar efficacy as intramuscular gold and penicillamine, methotrexate or sulfasalazine are often better tolerated. Gold and penicillamine can be effective in palindromic rheumatism. Methotrexate is generally prescribed alongside at least one other DMARD, and often short-term corticosteroid treatment for newly diagnosed RA.

Tofacitinib is an immunomodulating agent and DMARD with a novel mechanism of action. It selectively inhibits the activity of Janus kinase 3 (JAK3), a hematopoietic cell-restricted mediator of cytokine, growth factor, and interferon signalling via the JAK-STAT pathway. Inhibition of JAK3 appears to disrupt development and function of T, B, and NK cells. The FDA has approved tofacitinib for use in the management of moderate to severe active RA in patients who have shown an inadequate response or intolerance to methotrexate. Tofacitinib can be used alone or in combination with methotrexate or other nonbiologic DMARDs, although concomitant use with biologic DMARDs (e.g. adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, anakinra or rituximab), selective costimulation modulators (abatacept), and the anti-interleukin-6-receptor monoclonal antibody tocilizumab, is not recommended. Concomitant use with other immunosuppressive agents  (e.g. azathioprine or cyclosporine) is also not recommended. Serious, sometimes fatal infections (including cryptococcosis, pneumocystosis, tuberculosis and other mycobacterial infections, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infection) have been reported. Tofacitinib treatment should not be initiated in patients with active infections.