Are there new emerging drugs for ankylosing spondylitis or spondyloarthritis?

Abstract

New emerging drugs in the treatment of ankylosing spondylitis (AS), and spondyloarthritis in general, should be compared to anti-TNF agents, which provided clear evidence of efficacy in these conditions. To date, other biologic agents used in rheumatoid arthritis failed to demonstrate efficacy in AS, even in anti-TNF naïve patients. Some new potential options may target cytokines such as IL-17, or molecules involved in entheseal ossification or signaling pathways, but need confirmatory evaluation.

Keywords::

• ankylosing spondylitis
• anti-TNF agents
• IL-17
• IL-23
• spondyloarthritis
• treatment

1. Introduction

Ankylosing spondylitis, leader of the spondyloarthritides, is a chronic inflammatory rheumatic disease with a potentially heavy burden and socio-economic consequences.

Anti-TNF agents represent a major breakthrough in the treatment of ankylosing spondylitis (AS), and spondyloarthritis (SpA) in general, and the demonstration has been established for years [1], with good efficacy and a number to treat (NNT) around 2 for achieving an ASAS 20 response [2]. Nevertheless, a variable proportion of patients do not develop a clinical response or exhibit side effects or secondary response escape. In this situation, as well reported in the review in this issue of Expert opinion on Emerging Drugs [3], no other therapeutic option was able to demonstrate, to date, a clear clinical benefit. Moreover, no other option of biologic agent could develop sufficient improvement in patients to be considered a valuable alternate option in case of contraindication of TNF blockers [4]. Consequently, there is an urgent unmet need for development of new emerging drugs or treatment strategies for AS and SpA. These may be conventional or biologic drugs licensed in other conditions, mainly rheumatoid arthritis, and used by analogy in another inflammatory arthritis, at one hand, and drugs developed against new targets selected from pathophysiologic concerns at the other hand.

2. Use of conventional therapies

Some new options may be faced in AS beyond anti-TNF agents [5]. These may be developed from extrapolation from other inflammatory diseases, and current available drugs. In this situation, rheumatoid arthritis is often the model supposed to be copied. Systemic administration of corticosteroids had not been well studied until a recent presentation (EULAR 2012 – H. Haibel et al., abstract THU0272) in a randomized controlled trial (RCT) using two dosages and placebo in AS patients over 14 days. In the same way, a randomized study of a bisphosphonate (alendranate) (EULAR 2011 – Coates L. et al., abstract OP0176), did not demonstrate superiority about placebo upon symptoms of disease over a 2-year period. Again, the hope was not transformed into reality with the conventional DMARDs used in RA: sulfasalazin, as well as methotrexate and leflunomide failed to demonstrate clear efficacy upon axial symptoms of AS and SpA [6-8]. Addition of methotrexate to a TNF blocker (infliximab) did not seem to improve pharmacologic parameters of infliximab [9].

3. Non-anti-TNF biologics

The same is true for abatacept [10,11], and in part for rituximab [12], even if in anti-TNF naïve patients, some improvement has been shown in some patients in open or retrospective studies [13]. The same comment may be expressed for IL-1 targeting in AS [14,15]. But only a few patients were assessed. Clearly, better evaluations are needed for these agents before addressing a definitive conclusion.

The story of targeting IL-6 in AS is emblematic of the difficulty to translate immunopathologic findings into practical therapeutic options. A rationale for targeting IL-6 in AS is available [16]: local presence of IL-6 mRNA in sacroiliac joints, elevated serum IL-6 levels in disease, correlated with several other biologic markers or disease features legitimate the use of IL-6 blockade for treating AS. But most of the case reports (mostly in patients with anti-TNF failure) [17], as well as two well-conducted RCTs with two different monoclonal antibodies against IL-6 R in anti-TNF naïve AS patients [18,19], gave disappointing results. These two RCTs and subsequent development in AS were stopped after the results of pre-planned interim analysis at week 12. This illustrates the fact that the quest of emerging drugs, even based on coherent immune or physiopathologic knowledge, may not be successful, and need to be confirmed in clinical trials.

The IL-12/23–IL-17 axis represents currently a light in the dark [20]; the studies are underway, particularly with IL-17 inhibitors (secukinumab) [21]. Interfering with IL-23 may represent another possibility, using monoclonal antibodies directed against the p40 subunit of IL-23 (common with IL-12) (ustekinumab), or directed against the p19 subunit (specific of IL-23). The results of these evaluations are expected with great hope. A pilot trial with ustekinumab is ongoing in Berlin [22].

4. Should we look at other directions?

Another question is what are we looking for? a symptomatic drug, or a disease modifying one? If we consider radiographic structural effect as a treatment goal, the current data about a potential radiographic progression slowing effect of NSAIDs [23], not demonstrated with TNF blockers to date, drives to the classification of the former as a DMARD and the latter as a symptomatic one [24].

Should we focus on other subsets of the disease? The nonradiographic axial SpA and the early stages of the disease may represent suitable situations to test the ability of a treatment to stop the evolution of the disease, in a kind of window of opportunity, and define disease-modifying treatments.

If we aim to stop radiographic disease progression, some new candidates of treatment target may emerge, and animal models may be helpful in that way [25]. There are currently many biologic actors involved in the mechanism of entheseal ossification. Cathepsin K and MMPs at the erosive stage of inflammation, DKK-1, sclerostin, BMPs in the osteoproliferation of the enthesis, may all be targeted and some experimental data are available in animal models (e.g., noggin inhibition of BMP in the DBA-1 mouse model) [26]. But we have to bear in mind that these molecules act locally, and a systemic administered interference may be associated with side effects.

Have signaling pathway inhibitors a potential place in the armament of the treatment of SpA? This question has not been assessed to date, but some studies with JAK inhibitors are underway in inflammatory bowel disease and psoriasis, and this may lead to a future use, or at least evaluation, in SpA.

Other pathways should probably motivate research: intestinal microbiote and dysbiosis, and also the study of the factors linking smoking with disease activity and radiographic progression [27], that may provide some keys for future therapeutic developments.

5. Expert opinion

The current data show that new emerging drugs in AS are scant. New options may emerge from pathophysiologic knowledge of the disease, but, as illustrated by the IL-6 inhibition example, should be confirmed by well-conducted clinical trials. These should also be compared to TNF blockers.

Until this, the currently low available data about new drugs beyond anti-TNF agents represent a plea for the optimization of NSAIDs and TNF inhibitors use in spondyloarthritis [28].

Declaration of interest

Speaking fees, advisory board, grants (< 10,000 Euros each): Abbott Laboratories, Amgen, Bristol-Myers Squibb, MSD, Nordic Pharma, Pfizer, Roche Chugai, SOBI. Investigator in clinical trials: Sanofi Aventis, Novartis, Roche-Chugai.