Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive articular damage, functional loss and comorbidity. It is apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes responsible for complex inflammatory networks in RA. These molecular and cellular nodes are essential targets in implementing therapeutic interventions. Professor John Isaacs, Director of Therapeutics North East, Newcastle University, United Kingdom, shared his insights on RA treatments beyond conventional therapies, at the International Conference of Chinese Rheumatologists (ICCR) 2019, organized by the Hong Kong Society of Rheumatology.
The advancement of treatment landscape in RA
“The number of treatment options has increased dramatically in recent years,” stated Prof. Isaacs at the beginning of his presentation. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved the clinical outcomes in RA. Better understanding of disease pathogenesis has contributed greatly to the development of new drugs, particularly the mode-of-action studies of specific immune-targeted agents which have revealed immune pathways that drive synovial inflammation and related comorbidities. For example, cytokine inhibitors have been proven effective for elucidating the role of tumor necrosis factor α and interleukin 6 in RA pathogenesis, and also possibly for granulocyte-macrophage colony-stimulating factor.1 More recently, clinical trials with JAKis have shown that cytokines such as interferons, that signal through the JAK/STAT signaling pathways, are important mediators in progressive RA.1 Moreover, the successful use of costimulatory blockade and B-cell depletion has revealed that the adaptive immune response and downstream events initiated by these cells participate directly in synovial inflammation.1
The concept of selectivity of JAKis
JAKs are a family of small molecule non-receptor tyrosine kinases, composed of four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signaling pathway.1 In order to optimize the risk-benefit ratio, selective inhibition of JAK isoforms is likely to be important. Selectivity means that there is a greater potency for one JAK isoform versus others at a given concentration. However, selective inhibition depends on the relative affinity, dose and exposure; as exposure increases, the inhibitory profile may become broader. For example, a selective JAK1 inhibitor, at an optimal therapeutic concentration, inhibits JAK1 effectively with less effects on other JAK molecules. However, if the concentration of this selective JAK 1 inhibitor rises, it will additionally inhibit other JAKs, and potentially non-JAK protein tyrosine kinases at very high concentrations. Thus, during clinical development, the aim is to optimize the dose of JAKis so as to offer maximum efficacy with minimum toxicity.2 Prof. Isaacs explained that JAKis act less like “key into lock”, but more akin to “fingers into gloves”. Tofacitinib is selective for JAK3 and JAK1, while baricitinib is selective for JAK1 and JAK2. In addition, several other JAKis are recently being introduced, such as the JAK1 selective inhibitors upadacitinib and filgotinib.
Proven effectivity of JAKis
Both tofacitinib and baricitinib have been examined in large phase 3 and 4 randomized controlled trials (RCT) among a range of RA patients at different American College of Rheumatology criteria 20/50/70 (ACR20/50/70) responses (Figure 1 & 2).3-11
In methotrexate (MTX) inadequate responders, tofacitinib in ORAL-STANDARD and baricitinib in RA-BEAM, both with background MTX, showed superior ACR responses when compared with placebo (MTX monotherapy).3,4 Tofacitinib showed a similar response to adalimumab while baricitinib in RA-BEAM achieved significantly higher ACR20 and ACR70 responses than adalimumab.4 Similarly, in conventional synthetic disease-modifying antirheumatic drugs (csDMARD) inadequate responders, adding tofacitinib in ORAL-SYNC and baricitinib in RA-BUILD achieved higher ACR responses than placebo.5,6 In biologic inadequate responders, tofacitinib in ORAL-Step and baricitinib in RA-BEACON together with MTX achieved higher ACR responses than placebo.7,8
In ORAL-SCAN, radiographic joint damage was significantly less in patients treated with tofacitinib 10mg bd compared with placebo-treated patients. Baricitinib has also been shown to reduce radiographic joint damage in RA-BUILD, RA BEAM and RA-BEGIN.4,6,9,10 In RA-BUILD, baricitinib in combination with MTX significantly reduced radiographic progression of RA when compared with placebo.6
Upadacitinib, has also shown superiority over placebo and adalimumab for improving signs, symptoms and physical function in RA patients who were receiving background MTX. In addition, radiographic progression of RA was significantly inhibited by upadacitinib as compared to placebo.11 Despite the effective outcomes of current therapies, Prof. Isaacs mentioned that up to a third of patients are refractory to treatment and highlighted, “There are still mechanisms unknown to us that are related to the pathogenesis of RA.”
Novel targets in the effective management of RA
1.Therapeutic immune tolerance induction
Immune tolerance can be induced by several specific and nonspecific ways, including manipulation of costimulatory signals, induction of regulatory T cells and tolerization to heat shock proteins. Whereas, dendritic cells (DCs) are also recognized for their antigen presenting functions in driving immune responses against pathogens and tumor cells
A study conducted by Prof. Isaacs, assessed the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee.12 IA tolDC therapy appears to be safe, feasible and acceptable by most of the patients. Knee symptoms were stabilized in two patients who received 10×106 of tolDC, without systemic clinical or immunomodulatory effects.12
2.Prevention or early treatment of RA
Developing primary and secondary preventive strategies in RA would represent a significant paradigm shift from treatment to prevention and would have major implications for patients as well as the society. “This is a new paradigm,” remarked Prof. Isaacs and questioned, “Can we interfere with RA earlier, in order to switch it off completely?”. Finding asymptomatic patients with preclinical RA is a desirable goal, but there are many obstacles to overcome for the primary and secondary prevention, and there may be potential negative consequences related to overscreening, overdiagnosis and overtreatment.13 Moreover, despite successful tertiary preventive strategies in controlling the disease progression, there remains a considerable unmet need in reducing the burden of RA globally.
There has been a shift from an era of biological therapies to small molecule targeted inhibitors in RA. In order to optimally prescribe these drugs, it is important to understand the concept of therapeutic selectivity. Selectivity is influenced by the drug concentration, and particularly, the pharmacokinetics. Additionally, prevention and immune tolerance induction are focusing on the pre-RA disease stage. With both proven current and novel therapies available, RA will soon be memorized as the “yesterday’s disease”.
In an interview with Omnihealth Practice, Prof. Isaacs responded on how to select JAKis in the clinical practice, “Currently, the JAK selectivity is determined by reductionist assays in the laboratories, for clinical decisions, we need to look more closer at the data from clinical trials and in the clinic”. He further pointed out, “If JAK2 is targeted, there is a higher possibility to demonstrate anemia or neutropenia, if these side effects and other effects, like thrombocytopenia, are experienced, it is likely that the JAK selectivity is not optimal.” Prof. Isaacs also mentioned that in the reactivation of herpes zoster, it is not clear which JAK pathways are triggered, although inhibition of interferons is likely. The patient reported outcomes are higher with JAKis, including quality of life. JAKis might also have effects on other mechanisms, probably in the pain pathway, that have been de-activated and that could bring additional benefits. In the prevention of RA, Prof. Isaacs stated, “With the current treatments, more sero-positive patients tend to have responses than sero-negative individuals.” If patients are selected prior to the appearance of symptoms for treatment, it is important to consider the safety, and the way to determine efficacy – which biomarkers should be tested? As a message to the rheumatologists in Hong Kong, he emphasized, “There is still a long way to go to achieve effective treatment for RA and we are not there yet. As there are still a significant number of patients who are refractory to treatment, it is important to pay focus on new therapies, especially those focusing on the immune or non-immune targets rather than the inflammation only. Furthermore, effective prevention of RA is also an important aspect that needs much more attention.”
2. Kremer JM et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis & Rheumatology (Hoboken, NJ). 2016;68(12):2867-2877.
3. van Vollenhoven RF et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-519.
4. Taylor PC et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017;376(7):652-662.
5. Kremer J et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159(4):253-261.
6. Dougados M et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(1):88-95.
7. Burmester GR et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451-460.
8. Genovese MC et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374(13):1243-1252.
9. van der Heijde D et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559-570.
10. Fleischmann R et al. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis & Rheumatology (Hoboken, NJ). 2017;69(3):506-517.
11. Fleischmann R et al. Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis & Rheumatology (Hoboken, NJ). 2019;71(11):1788-1800.
12. Bell GM et al. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Annals of the Rheumatic Diseases. 2017;76(1):227-234.
13. Isaacs JD. The changing face of rheumatoid arthritis: sustained remission for all? Nat Rev Immunol. 2010;10(8):605-611.