Looking for the best target for biologic treatment of spondyloarthritis

Keywords::

• ankylosing spondylitis
• biologic agents
• IL-6
• IL-17
• IL-23
• spondyloarthritis
• therapeutics
• tocilizumab

Anti-TNF agents play a major role in the management of chronic rheumatic diseases, particularly in spondyloarthritis (SpA), a condition in which chemical disease-modifying antirheumatic drugs failed to demonstrate efficacy on axial symptoms. The advancements in the knowledge on immune pathophysiology have allowed the development and use of new alternate targeted biologic therapies with clinical and structural efficacy in rheumatoid arthritis (RA). However, this is not the case in SpA. Under these circumstances, the development of new treatment strategies represents an unmet need in management of SpA

The rationale for anti-TNF therapy was based on the results of elevated levels of TNF in the serum of patients with ankylosing spondylitis (AS), as compared with control subjects, and the presence of TNF mRNA in sacroiliac biopsies obtained from patients with AS. This prompted the use of TNF blockers in this condition, and became known as a major therapeutic advancement in the treatment of AS [1].

IL-6 is another major cytokine involved in the inflammatory processes and therefore a potential target for biologic inhibitors, particularly tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody. This antibody is efficacious and approved for the treatment of RA and juvenile idiopathic arthritis and used off-label in the treatment of several inflammatory conditions with variable results [2].

There is a rationale to target IL-6 in SpA, at least as convincing as the one for anti-TNF agents. Several studies revealed elevated serum IL-6 levels in patients with SpA as compared with controls, which is correlated with disease activity [3,4], and another study demonstrated that IL-6 was expressed in sacroiliac joints of patients with AS, particularly in active, early lesions [5]. Thus, these data support the evaluation of IL-6 as a new target in SpA [6].

Several case reports [7–11] as well as some retrospective series [12–14] have shown conflicting results, but in most of these cases, the patients were refractory to multiple treatments, including one or more TNF blockers.

A randomized controlled trial was needed, since the biologic agent is available and effective in reducing inflammation, as witnessed by reduction in C-reactive protein (CRP) level. This study has been performed [15] in 102 patients (who fulfilled the modified New York criteria for AS, demonstrated inadequate control with NSAIDs and were anti-TNF naive) who were randomized 1:1 to receive either tocilizumab 8 mg/kg or placebo as an intravenous infusion every 4 weeks (BUILDER study). At the pre-planned 12-week interim analysis, the Assessment in Spondyloarthritis International Society (ASAS) 20 response rate was 37.3% in the tocilizumab group and 27.5% in the placebo group, without any statistical difference. No differences were found for ASAS 40 and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) responses, or change in peripheral arthritis or other secondary and exploratory end points. Nevertheless, CRP level was normal in the tocilizumab group (but not in the placebo group), suggesting an adequate IL-6 inhibition.

Similar negative results were reported in another randomized controlled trial on a similar patient profile with sarilumab, a human anti-IL-6R monoclonal antibody [16]. Reported only as an abstract to date, this study (ALIGN study) enrolled 301 patients who were randomized to receive several doses/schedules of subcutaneous injections and placebo. The 12-week interim analysis revealed no improvement compared with placebo in ASAS 20 response, BASDAI evolution or MRI scores, but again a decrease in CRP was observed in the sarilumab groups.

Hence, these two programs were stopped due to the negative results.

What lessons can be learned from these results?

Although the concept is not proven, it illustrates the gap between theoretical targeting and successful treatment.

The disappointing results in the treatment of AS or SpA with other biologics used currently in RA, such as abatacept or rituximab [17,18], also underscore that the impact of a biologic treatment cannot be extrapolated from one inflammatory joint disease to another, even with immunologic arguments for its use.

What will be the next step, the next target?

The IL-23/Th-17 pathway appears to be a promising therapeutic target [19,20]: IL-23R polymorphisms are associated with susceptibility to SpA; elevated production of IL-23 was demonstrated in SpA, particularly in the gut; and the possibility of an unfolded protein response leading to the production of IL-23 may be attributed to the misfolding of HLA-B27 in the endoplasmic reticulum. IL-23 plays a role in the polarization of T cells toward Th-17 and IL-17 production. IL-23 production and IL-23-positive cells were found to occur more frequently in the spinal apophyseal joints of SpA patients than in osteoarthritis patients; and finally, in animal models, systemic exposure to IL-23 in vivo induces a specific and rapidly occurring enthesitis, in favor of a direct effect of IL-23. Moreover, IL-23R+ cells were found in the entheses, aortic arch and gut.

At present, there are many possibilities that interfere with this pathway:

• • Against IL-23: anti-IL-23 antibodies (anti-p40 common with IL-12 = ustekinumab, already used in psoriasis and with positive results in psoriatic arthritis); anti-p19 IL-23 monoclonal antibody; potential anti-IL-23R antibodies.

• • Against IL-17: anti-IL-17A monoclonal antibody: secukinumab, with some preliminary results; brodalumab (anti-IL-17R) with studies on psoriatic arthritis.

We await the results of the ongoing controlled Phase II/III studies for proof that IL-23/Th-17 is a major target for future therapeutic options in SpA.

In the future, other pathways may be targeted using small molecules. For example, JAK kinase inhibitors may be an option, which have already evaluated in psoriasis or Crohn's disease, conditions that are similar to SpA. Apremilast, a small molecule inhibiting phosphodiesterase, has also been evaluated in SpA. Besides inflammatory pathways, interference with bone proliferation may represent another possibility, and inhibition of bone morphogenetic protein demonstrated interesting results in animal models [21].

Until such time, we have to optimize the use of the currently available therapeutic options, namely NSAIDs and TNF blockers.

Financial & competing interests disclosure

D Wendling has received speaking fees and/or consultancy from Abbott, MSD, Pfizer, Roche Chugai, BMS, Amgen, Nordic Pharma and Swedish Orphan Biovitrum. D Wendling has also received grants from Abbott, MSD, Pfizer, Roche Chugai and BMS. In addition, D Wendling is the national co-ordinator of the CAIN 457F2305 (secukinumab in AS, Novartis) study as well as national co-ordinator and investigator of the ALIGN study (sarilumab in AS, Sanofi-Aventis). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.