Resultados

The following section is not meant to cover in details therapeutic strategies for RA. Instead, it focuses on major breakthroughs which provided valuable information on the physiopathology of RA: clinical efficacy in patients being the ultimate proof-of-concept that a particular pathway is important. Understanding pathways implicated in human RA helps to evaluate the relevance of various animal models of arthritis. Clinical guidelines would also take into consideration potential side effects and costs; however both of these criteria provide little insight on the disease itself and are thus not directly relevant to this thesis. The American College of Rheumatology published recently their 2015 guidelines [273].

2.2.6.1 Glucocorticoids

The broad anti-inflammatory action of glucocorticoids is effective to control symptoms of RA and is still considered a valid temporary addition in initial therapy of moderate to severe RA. It can also be used to treat flares. However, it should be used to the lowest possible dose and for the shortest possible duration considering the serious side effects associated to glucocorticoids.

2.2.6.2 Disease-modifying antirheumatic drugs (DMARDs)

As opposed to glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g.

naproxen, indomethacin, diclofenac, ibuprofen) which help to control pain and inflammation rapidly but do not affect RA progression, disease-modifying antirheumatic drugs (DMARDs) usually act slowly but improve the evolution of RA. Hence, their use is crucial for the long term management of RA. DMARDs are now divided in traditional/chemical drugs, and biologic drugs. Despite major advances in biological treatments, traditional DMARDs are still considered a cornerstone of initial therapy of RA. These drugs include methotrexate, sulfasalazine, leflunomide, hydroxychloroquine and gold salts.

A low dose of methotrexate is the most commonly used DMARD therapy. It is an antimetabolite and antifolate drug. It has several effects on the immune system which could explain efficacy in RA, including inhibition of T cells and B cells [274, 275]. Table II presents biologic DMARDs approved for the treatment of RA.

2.2.6.3 TNF-α blockers

The introduction of TNF-α blockers revolutionized treatment of RA almost two decades ago.

These drugs target the pro-inflammatory cytokine TNF-α and have a very good efficacy with a fairly favorable side effects profile. Even nowadays, they are considered the gold standard of RA therapy. Among the list of the top 10 global sales for a drug in 2015, 3 are TNF-α blockers (Humira, Remicade and Enbrel). TNF-α blockers are usually used in patients after unsuccessful initial treatment with traditional DMARD, in particular methotrexate. However, this use as second line therapy is mostly explained by the high cost of biologic drugs such as TNF-α blockers [276]. Hence, this recommendation is mostly based on pharmacoeconomics rather than pharmacotherapy. Upon failure with methotrexate, monotherapy with TNF-α

blockers is considered, or combination with methotrexate in partial responders since there is a demonstrated benefit of the combination [277].

Table II - Biologic drugs in the treatment of RA

Drug Name Brand Description Approval Other indications

Infliximab Remicade Chimeric (mouse/human)

anti-TNF-α 1998 Psoriasis, ulcerative colitis,

Crohn’s disease

Etanercept Enbrel TNF receptor/Fc fusion

protein 1998 Psoriasis

Anakinra Kineret IL-1R antagonist 2001 -

Adalimumab Humira Human IgG1 anti-TNF-α 2002 Psoriasis, ulcerative colitis, Crohn’s disease

Abatacept Orencia CTLA-4/Fc fusion protein 2005 -

Rituximab Rituxan Chimeric (mouse/human)

anti-CD20 2006 -

Certolizumab Cimzia PEGylated Fab’ anti-TNF-α 2008 Psoriatic arthritis, Crohn’s disease

Golimumab Simponi Human IgG1κ anti-TNF-α 2009 Psoriatic arthritis, ulcerative colitis

Tocilizumab Actemra Human IgG1 anti-IL-6 2010 -

Approval: year of approval by the FDA for the treatment of RA

Other indications: other FDA indications in autoimmune diseases relevant for this thesis

The success of TNF-α blockers has obviously generated a large amount of research, both on TNF-α but also other cytokines [278]. Although some patients do not respond to these treatments, others experience total remission. This is due to the unique role of TNF-α in the inflammatory cascade. In fact, TNF-α blockage is useful for several other autoimmune diseases, including psoriasis and Crohn’s disease, demonstrating how central TNF-α is in autoimmunity [181, 279]. Not so surprisingly, an increased risk of severe infections and a potential association to malignancies are the biggest concerns with these treatments [277, 280]. The association to malignancies is however still debated [281, 282].

2.2.6.4 CTLA4-Ig

On T cells, CTLA-4 is an inhibitory receptor binding B7 proteins (CD80 and CD86) of APC.

Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 and the Fc region of IgG1. It acts by binding B7 co-stimulatory molecules on APC, thus preventing interaction between B7 and CD28, and therefore T cells activation [283]. It is indicated for the treatment of RA refractory to TNF-α blockers [284]. Some data suggest favorable comparison to TNF-α blockers, however the large amount of safety information with TNF-α blockers along with extensive clinical experience help them maintain their status as a first choice within biologic DMARDs [285]. It is interesting to note that blockage of CTLA-4 is currently used in cancer immunotherapy to increase T cells response towards malignant cells [97].

2.2.6.5 Anti-IL-6R

Tocilizumab, a monoclonal antibody against IL-6R, is also approved for the treatment of RA in combination with methotrexate [286]. The development of anti-IL-6R therapy originates from the observation that IL-6 is overexpressed in RA [287, 288]. The biological function of IL-6 was fairly difficult to understand since it is produced by a wide variety of cells and also exerts its effects in various cell types [289]. It is now clear that it is associated to the Th17 pathway [290, 291]. Tocilizumab was shown to improve clinical outcome in patients with poor response to TNF-α blockers [289]. Similarly to TNF-α, IL-6 was associated to a variety of autoimmune diseases in animal models, suggesting a central and non-redundant role in chronic inflammation [292, 293].

2.2.6.6 IL-1RA

Anakinra is a recombinant IL-1 receptor antagonist (IL-1RA) approved in RA. It acts by inhibiting the action of IL-1 by preventing its binding to the IL-1R. Secreted by cells of the innate immunity, IL-1 has pro-inflammatory properties [294]. Anakinra improves clinical outcome in patients receiving methotrexate [295]. This treatment generated a lot of interest when it was found to block bone resorption [296, 297]. However, although direct comparison are not available, meta-analyses suggest that Anakinra is less effective than TNF-α blockers, making this treatment less appealing to clinicians [298, 299].

2.2.6.7 Anti-CD20

Rituximab is a monoclonal antibody recognizing CD20, a protein expressed by B cells. It acts by depleting B cells which are responsible for humoral response and are also potent APC.

Rituximab was demonstrated to improve clinical outcome in patients receiving methotrexate, including patients refractory to TNF-α blockers [300, 301]. Although it is officially indicated for the treatment of RA, the main indication of rituximab is in B cell malignancies [302, 303].

B cells depletion has also been investigated for other autoimmune diseases including multiple sclerosis and systemic lupus erythematosus [304-306].