Drugs acting on the immune system

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 diseases (e.g. active vasculitis).

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

Prescribers 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.

Plerixafor is an immunostimulating CXCR4 antagonist and stem cell mobiliser. In use it mobilises haematopoietic stem cells to peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma or multiple myeloma (specialist use only).

Imiquimod is a Toll-like receptor 7 (TLR7) agonist which stimulates innate and acquired immune responses locally at the site of application. Drug action results in destruction of diseased cells. Imiquimod is used to treat actinic keratosis, warts (external genital and perianal) and superficial basal cell carcinoma.

Dimethyl fumarate is a prodrug with neuroprotective and anti-inflammatory effects. Its active metabolite is monomethylfumarate (used to treat psoriasis). Oral dimethyl fumarate is used for the treatment of adults with relapsing-remitting multiple sclerosis.

Fingolimod is used in the treatment of highly active relapsing-remitting multiple sclerosis in patients who have high disease activity despite treatment with at least one disease modifying therapy or in those with rapidly evolving severe relapsing-remitting multiple sclerosis (initiated under specialist supervision). Fimgilimod acts as a cell migration inhibitor, promoting T cell retention in lymphoid tissues thereby reducing autoimmune responses associated with MS.

Other immunostimulants

• Bacillus calmette-guérin (BCG), the live attenuated agent used for immunisation against tuberculosis, isalso used as a nonspecific stimulant of the reticuloendothelial (macrophage) system in the treatment of  high-grade non-muscle invasive bladder cancer (NMIBC) and carcinoma in-situ (CIS). Applied locally, BCG induces an inflammatory response (including infiltration of granulocytes, macrophages and lymphocytes, especially helper T cells) in the vicinity of the tumours (e.g. bladder instillation) and this leads to killing of cancer cells.
• Glatiramer acetate is a MS drug used for treatment of initial symptoms in patients at high risk of developing multiple sclerosis (initiated under specialist supervision). It is also effective for reducing relapse frequency in ambulatory patients with relapsing-remitting multiple sclerosis who have had at least 2 clinical relapses in the past 2 years (again under specialist supervision). Chemically, glatiramer acetate is a mixture of four amino acids found in myelin basic protein so is presumed to limit myelin loss in MS, however its mechanism of action is not fully understood.
• Histamine dihydrochloride is used in maintenance therapy, in combination with aldesleukin (recombinant interleukin-2), in patients with acute myeloid leukaemia in first remission.
• Mifamurtide is a chemotherapy adjunct, used after complete surgical resection in the treatment of high-grade, resectable, non-metastatic osteosarcoma. Chemically mifamurtide is a synthetic analogue of the bacterial cell wall component, muramyl dipeptide (MDP). Mifamurtide mimics MDP's action of stimulating the immune system via activation of microbial pattern recognition receptors such as TLR4 and NOD2.

Mast cell stabilizers are generally cromone derivative type compounds. Mechanistically, they work in part by blocking calcium channels involved in release of preformed chemical mediators such as histamine from intracellular mast cell granules.

• Lodoxamide is used to treat allergic conjunctivitis (see PubChem CID 44564 for chemical structure and further information).
• Nedocromil sodium can be prescribed in the UK to treat seasonal and perennial conjunctivitis, seasonal keratoconjunctivitis and for prophylaxis of asthma. US production was terminated in 2008. Nedocromil's molecular mechanism of action is not completely understood.
• (Di)sodium cromoglicate (cromoglicic acid, cromoglycate, cromolyn) is used for allergic rhinitis, allergic conjunctivitis, seasonal keratoconjunctivitis, as a prophylactic agent in asthma, and food allergy.

In asthma, mast cell stabilisers have largely been replaced by the more convenient leukotriene receptor antagonists as the non-corticosteroid treatment of choice.

T-cell activation inhibitors are immunosuppressants. They find clinical use in autoimmune disease and transplant rejection prevention.

Abatacept is a recombinant protein fusing the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4- required for T cell co-stimulation) with an antibody Fc domain. It acts as a binding protein, effectively removing CTLA-4 from the circulation, thereby suppressing T cell activation. Abatacept is used to treat moderate to severe rheumatoid arthritis and juvenile rheumatoid arthritis.

Belatacept is similar in structure and function to abatacept, but is instead approved for prophylaxis of organ rejection after kidney transplant.

TNF-α binding proteins can be monoclonal antibody in nature or can be recombinant proteins which act as circulating TNF-α receptors. To date their immunosuppressive activity is utilised in the treatment of autoimmune conditions.

Anti-TNF-α monoclonal antibodies

Adalimumab was the first fully human monoclonal approved by the FDA. It induces immunosuppression by selectively binding to TNF-α. It is approved for the treatment of auto-immune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease, hidradenitis suppurativa, and in the US non-infectious intermediate, posterior and panuveitis.

Infliximab binds soluble and membrane-anchored TNF-α, bringing about immunosuppression. Infliximab is approved for the treatment of auto-immune diseases including rheumatoid arthritis (in combination with methotrexate), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis.

Golimumab is used in adults to treat moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis and moderate to severe ulcerative colitis.

Certolizumab pegol is a antibody derivative, comprising only the antigen-binding Fab' fragment of an anti-TNF-α monoclonal. It is conjugated with polyethylene glycol to increase its circulating half-life as Fab' fragments are normally rapidly degraded in vivo. Used to treat rheumatoid arthritis and Crohn's disease.

TNF-α receptor agent

Etanercept is a dimeric recombinant protein fusing the TNF receptor 2 to the Fc region of the human IgG1 antibody, so it effectively immuno-neutralises circulating TNF-α.  It is used to treat severe active rheumatoid arthritis in adults, severe juvenile idiopathic arthritis, ankylosing spondylitis, and severe plaque psoriasis.

The anti-lymphocyte monoclonal antibodies suppress lymphocyte activity. All such agents must be administered under the supervision of an experienced specialist, in a setting with immediate access to full resuscitation facilities.

Alemtuzumab is a CAMPATH-1 (CD52) antigen inhibitor. It is primarily used for the treatment of relapsing-remitting multiple sclerosis. Alemtuzumab can also be used in B-cell chronic lymphocytic leukemia (CLL) therapy and in transplant indications, but access for these indications is controlled through a patient access programme.

Basiliximab acts as a functional IL-2 receptor antagonist, inhibiting IL-2-mediated activation of T lymphocytes. It is for prophylaxis of acute rejection in allogeneic renal transplantation. It is used alongside cyclosporin and corticosteroid-containing immunosuppression regimens.

Belimumab suppresses B-cell mediated immunity and the autoimmune response by binding to circulating soluble TNFSF13B (BLyS). IN the UK belimumab can be prescribed as adjunctive therapy for patients with active, autoantibody-positive systemic lupus erythematosus (SLE), in particular for those patienst whose disease is unresponsive to standard therapy.

Natalizumab binds to the α₄-subunit of α₄β₁ and α₄β₇ integrins on leukocyte cell surfaces. This action inhibits leukocyte adhesion to the counter-receptor vascular cell adhesion molecule-1 (VCAM-1), thereby inhibiting leukocyte migration to inflamed tissue and reducing active inflammation. IN the UK natalizumab is licensed to treat relapsing-remitting multiple sclerosis despite treatment with interferon beta or glatiramer acetate, or rapidly evolving severe relapsing-remitting multiple sclerosis. In the US it may also be used to treat moderate to severe treatment-resistant Crohn's disease in adults.

Obinutuzumab is an anti-CD20 monoclonal approved for the treatment of chronic lymphocytic leukemia (CLL) and rituximab-relapsed follicular lymphoma (FL) (in the US, in combination with bendamustine, followed by obinutuzumab monotherapy).

Ofatumumab is another anti-CD20 monoclonal approved for certain cases of CLL e.g. CLL refractory to fludarabine and alemtuzumab, or treatment-naive patients who are not eligible for fludarabine based therapy.

Rituximab also targets CD20 on B-cells. It is used to treat CD20-positive non-Hodgkins lymphoma, chronic lymphocytic leukemia, and DMARDTHF inhibitor-resistant sever active rheumatoid arthritis.

Vedolizumab binds specifically to the α₄β₇ integrin, expressed on gut homing T helper lymphocytes. This action reduces gastrointestinal inflammation. Used to treat adult patients with moderate to severe ulcerative colitis or moderate to severe Crohn‘s disease.