bDMARDs

Biological disease modifying antirheumatic drugs (bDMARDs)

Recent advances in the development of therapies in the field of rheumatology, particularly through the development of so-called biologics, have now led to a wide range of therapeutic options.

The impressive success of the first biologics that block the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has also initiated the ongoing development of new and targeted therapeutic approaches (hence the frequently used term "targeted therapies").

The most important new therapies currently established in rheumatology are briefly described below. In addition, therapy concepts that are currently still being tested but are expected to be approved in the near future will be described.

TNF-aplha Blocker

TNF-alpha blockers
Three different anti-TNF-alpha drugs - infliximab (Remicade®; a chimeric anti-TNF-alpha antibody), etanercept (Enbrel®; a construct of the TNF receptor 2 and the Fc portion of IgG), adalimumab (Humira®, a human anti-TNF-alpha antibody) are currently approved for the treatment of RA and other rheumatological diseases such as psoriatic arthritis or ankylosing spondylarthropathy (AS). B. psoriatic arthritis or ankylosing spondylarthropathy (AS). The blockade of TNF-alpha is highly effective. A combination of a TNF blocker with the established basic therapeutic agent (disease modifying anti-rheumatic drug; DMARD) methotrexate (MTX) can achieve an approx. 50% improvement in clinical symptoms in approx. 50-70% of treated patients [1, 2].

Two additional anti-TNF antibodies, golimumab and certolizumab, have recently been approved in various countries for the treatment of RA. While neither drug is expected to have a significantly different risk-benefit profile compared to the other TNF blockers, they do offer additional treatment options.

Golimumab (Simponi®) is a human anti-TNF antibody that has been tested for s.c. application at monthly intervals [3, 4]. application at monthly intervals [3, 4]. Certolizumab (Cimzia®) is a pegylated human anti-TNF antibody (polyethylene glycolated Fab' fragment), which consists only of the Fab fragment of the antibody due to pegylation and does not require an Fc component. This should lead to a reduction in Fc-mediated side effects (formation of autoantibodies, antibody-mediated cytotoxicity and cell-mediated cytotoxicity) and also achieve a longer half-life [5-7].

After more than 10 years of clinical experience with TNF blockers, it has been shown that although their efficacy is similar in comparison to each other, patients sometimes react differently to the individual preparations. Patients may therefore benefit from switching to another TNF blocker after failure or an increasing loss of efficacy of a TNF blocker [3]. This fact therefore also justifies the development of new preparations within this substance class to a certain extent.

Blocking of other pro-inflammatory cytokines

TNF-alpha is by no means the only cytokine that plays a role in the pathogenesis of RA. It is currently assumed that a combination of various pro-inflammatory cytokines such as TNF-alpha and IL-6 (but also IL-1), as well as other cytokines such as interleukin (IL)-2, IL-8, IL-12, IL-3, IL-15, IL-17 and IL-23 is responsible for the synovial inflammatory reaction. Based on this, a number of biologics have now been developed that block various pro-inflammatory cytokines.

Anti-IL-1

However, the use of the IL-1 receptor antagonist anakinra (Kineret®) has only shown a moderate effect in the treatment of RA compared to TNF blockers [8]. In contrast, however, anakinra is very effective in the treatment of chronic fever syndromes such as neonatal-onset multisystem inflammatory disease (NOMID) [9] or Still's disease [10]. The relatively unexpected failure of anakinra in the treatment of RA could be due to technical aspects.This could include reaching insufficient concentrations in the joints or insufficient avidity to IL-1, so that newly developed IL-1 blocking preparations could become even more important in the future. These include preparations such as rilonacept (an IL-1 receptor IgG construct) which is being tested in periodic fever syndromes but also in juvenile idiopathic polyarthritis and gout arthropathy; or AMG108, a human antibody against the IL-1 receptor.
 

Anti-IL-6

Tocilizumab (RoActemra®) is a human antibody directed against membrane-bound and soluble IL-6 [11]. In combination with MTX, tocilizumab shows similar efficacy to TNF blockers; in addition, monotherapy with tocilizumab is also able to halt radiological progression in RA patients [12-14]. Tocilizumab is therefore the only biologic to date that is superior to MTX as a monotherapy in terms of its efficacy [12, 15]. Tocilizumab is also an effective therapeutic approach for the treatment of juvenile idiopathic polyarthritis [16] and possibly also chronic inflammatory bowel disease [17].
 A number of other substances that block pro-inflammatory cytokines are or are currently being tested in phase II/III studies. These include, for example, ABX-IL-8 (anti-IL-8), ustekinumab (anti-IL-12/23), IMA-638 (anti-IL-13), AMG 714 (anti-IL-15), LY2439821 (anti-IL-17), r-IL-18 bp (anti-IL-18) and Fontolizumab (anti-IFN-gamma).

Blocking of T cell costimulation

The activation of autoreactive T cells by antigen presenting cells (APC) is the initial event in the triggering of various autoimmune diseases. Blocking the activation of autoreactive T cells could therefore have a decisive influence on the course of the disease and is the aim of the following therapeutic approaches.

Abatacept (Orencia®, a construct from the extracellular domain of CTLA-4 bound to a modified Fc part of IgG) blocks by its binding to CD80/CD86 on APCs their binding to CD28 on the T cell, and thus the (co)stimulus for T cell activation, which is co-responsible as signal 2. The efficacy and safety profile of Abatacept was tested in clinical trials, in which Abatacept also proved effective in patients after failure of TNF blockers [18, 19].

Belatacept, also a CTLA-4Ig fusion protein, differs from Abatacept in its structure in only 2 amino acids, but has a higher binding affinity to CD80/CD86 compared to Abatacept. Clinical phase I/II studies in patients with RA have already been conducted.

Alternative therapeutic approaches for blocking costimulation are antibodies such as RhuDex or galiximab, which directly target the costimulatory molecule CD80 on APCs.

Anti-B Cell Therapies

B cells play an important role in the development of various rheumatological diseases due to their ability to produce autoantibodies, but also in their function as APCs or as producers of pro-inflammatory cytokines.

These considerations have led to the development of preparations for B cell depletion, of which rituximab (MabThera®, a chimeric anti-CD20 antibody) is currently authorised for the treatment of RA in combination with MTX. Rituximab leads to an approx. 50% clinical improvement in approx. 30% of RA patients [20, 21] and is also effective in patients who have failed a TNF blocker [22]. Rituximab is preferentially effective in rheumatoid factor-positive patients, although the exact mechanism of action is not fully understood. Rituximab depletes precursor B cells and mature B cells, but not plasma cells, for up to 6 months. A renewed increase in disease activity usually goes hand in hand with the reappearance of B cells, but can also occur without B cells [23].

A number of other preparations for B cell depletion are currently undergoing clinical trials. Some of these are further developed antibodies against CD20 (ofatumumab, ocrelizumab, tositumumab) or against other B cell surface molecules such as CD22 (epratuzumab) or CD19+CD22 (DT2219).Another part blocks factors that are important for the vitality of B cells, such as BAFF (belimumab, atacicept) or attacks the cells directly via the B cell receptor (abetimus).

Blocking of adhesion molecules

In addition to signal 1 (MHC class II molecules and T cell receptor) and signal 2 (see above), various adhesion molecules are also involved in the interaction of T cells with APCs, which contribute to the stabilisation of cell-cell interaction. In addition, they are important for the functional properties (growth, differentiation and migration) of cells such as monocytes/macrophages, osteoclasts and endothelial cells, among other things through interaction with extracellular matrix molecules.  Individual preparations such as efalizumab (Raptiva®, an anti-CD11a antibody) have already been withdrawn from the market due to side effects, while clinical trials with another preparation (natalizumab, Tysabri®, an anti-VLA-4 antibody) were discontinued in RA patients due to insufficient efficacy. With another preparation, Alefacept (Amevive®, a fusion protein from the extracellular portion of LFA-3 with an Fc portion of IgG), at least a 20% clinical improvement was achieved in 54% of cases in combination with MTX in patients with psoriatic arthritis (PsoA) [24]. Other preparations such as MEDI-522 (Vitaxin, a human antibody against a5b3 integrins) have been tested in RA patients in phase II studies to date.

Blocking of osteoclasts

Osteoclasts are cells that are ultimately responsible for the active destruction of bone substance in RA [26, 27]. Denosumab is a human antibody and binds to the ligand (L) of RANK (Receptor Activator of Nuclear factor-kB). It thus blocks the interaction between RANK and RANKL, which is crucial for the differentiation and activation of osteoclasts. In a clinical phase II study in RA patients, it was shown that denosumab in combination with MTX can effectively block the progression of bone erosions [28].

The need to develop new therapeutic approaches in the direction of targeted therapy

In general, biologics have led to a revolution in the treatment options for rheumatic diseases. Nevertheless, even with the use of biologics, a cure for diseases such as rheumatoid arthritis (RA) is still not in sight, and complete remission according to strict clinical criteria is only achieved in around 20% of patients [29].

These facts underline the need for new therapeutic approaches for the treatment of rheumatological diseases.

However, it will be at least as important to achieve a better understanding of the individual steps in the pathogenesis of rheumatological diseases by intensifying efforts in the field of basic research. This should also enable the development of reliable biomarkers with the help of which it might be possible to make statements about the chances of success of a particular therapy at a particular point in time, even in the early stages of the disease. This stratification is not only important for the individual patient in order to avoid ineffective therapy attempts at an early stage, but also from a socio-economic point of view in order to be able to use optimal forms of therapy in a cost-effective manner.

References

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