Abstract
Abstract
The treatment of rheumatoid arthritis has changed dramatically over the last two decades since the development of biological disease-modifying anti-rheumatic drugs (bDMARDs). Moreover, Janus kinase (JAK) inhibitors became available in 2013. JAK inhibitors are low-molecular-weight compounds, which exert anti-rheumatic effects by suppressing the action of JAK, an intracellular tyrosine kinase. Of note, biologics bind to extracellular proteins and block their activity. The availability of JAK inhibitors that are as effective as bDMARDs, despite the completely different route of administration and mode of action, has enabled the treatment of rheumatoid arthritis to enter a new stage. JAK inhibitors are useful in a variety of cases, including patients who inadequately responded to treatment with methotrexate and/or bDMARDs. Oral administration is convenient for patients. Nevertheless, the drugs should be carefully prescribed as they are metabolized in the liver and kidneys. Attention should also be paid to adverse events, such as infections including herpes zoster. It is necessary to understand the characteristics of JAK inhibitors and use these agents judiciously.
1. Introduction
With the advent of biological disease-modifying anti-rheumatic drugs (bDMARDs), the treatment of rheumatoid arthritis (RA) has changed dramatically in the last 20 years [1,2]. At the end of the twentieth century, the tumor necrosis factor α (TNFα) inhibitors etanercept and infliximab were approved by the US Food and Drug Administration, followed by the launch of three other TNFα inhibitors. In addition, an interleukin-6 (IL-6) receptor antibody inhibitor and a CD80/86 inhibitor, termed cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig), are also commercially available. In 2013, tofacitinib, a Janus kinase (JAK) inhibitor, was launched in Japan. Thereafter, baricitinib, peficitinib, and upadacitinib were approved in 2017, 2019, and 2020, respectively. Another agent, filgotinib, is currently in the process of approval. JAK inhibitors are the sole member of targeted synthetic DMARDs, are low-molecular-weight compounds, and can be administered orally. bDMARDs bind to extracellular proteins and suppress their activity, whereas JAK inhibitors suppress the action of intracellular kinase JAK. The availability of JAK inhibitors has enabled the treatment of rheumatoid arthritis to enter a new stage. This article describes the basic knowledge regarding JAK and JAK inhibitors, as well as their clinical usefulness and characteristics.
2. Mechanism of action of JAK inhibitors
2.1. Cytokines and JAK
Cytokines are classified according to their structure. Cytokines such as interleukin (IL-2), IL-6, interferon α (IFNα), IL-12/23, erythropoietin, and granulocyte macrophage colony-stimulating factor (GM-CSF) are classified into class I/II. TNFα, IL-17, and IL-1 belong to different groups, and are involved in signaling through a pathway independent of JAK. Of note, JAK is a molecule specifically involved in the signaling of class I/II cytokines.
There are four types of JAKs, namely JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). As shown in Table 1, the combination of JAKs binding to each cytokine receptor is fixed [3]. For example, JAK3 is always paired with JAK1. This combination uses the common γ chain as a receptor and is important for lymphocyte survival and differentiation. Cytokines, such as erythropoietin and IL-3, bind to homodimeric receptors and use two JAK2 molecules. This group of cytokines is involved in the differentiation and maintenance of hematopoietic stem cells. Many cytokines involved in immune and inflammatory responses use a combination of JAK1, JAK2, and TYK2. For example, IL-6 and IL-10, which are potent pro- and anti-inflammatory cytokines, respectively, use JAK1, JAK2, and TYK2. IFNγ, a T helper 1 (Th1) cytokine, use JAK1 and JAK2. IFNα, which exerts an important antiviral effect, uses JAK1 and TYK2. IL-12/23, which is involved in the Th17 immune response, uses the JAK2 and TYK2 combination.
Table 1. Cytokines and JAK usage.
2.2. Mode of action of JAK inhibitors
A JAK inhibitor competitively binds to the adenosine triphosphate-binding site of JAK and suppresses the enzyme activity of JAK, thereby suppressing cytokine signal transduction and cytokine action. As described above, signaling pathways such as TNFα and IL-17 do not use JAK. Thus, JAK inhibitors do not suppress the effects of such cytokines. bDMARDs are monoclonal antibody agents, therefore, suppressing only one specific cytokine. In contrast, JAK inhibitors simultaneously suppress the action of multiple cytokines belonging to class I/II. On the other hand, when a bDMARD is administered in a sufficient amount, the activity of the specific cytokine may be completely blocked. However, at clinical doses, a JAK inhibitor only partially blocks the JAK-STAT pathway. In other words, JAK inhibitors involve a completely different mechanism from bDMARDs, and target a different range of cytokines.
The administration of anti-cytokine antibodies in patients with RA revealed a role of some of type I/II cytokines in the pathophysiology of RA. IL-6 is one of the cytokines playing a major role in RA, as demonstrated by the clinical success of anti-IL-6 receptor antibodies. GM-CSF is also an important cytokine; an anti-GM-CSF receptor α antibody (mavrilimumab) has shown similar efficacy to that of a TNF inhibitor [4,5]. Treatment with anti-IFNγ antibody has been performed in a small number of patients, demonstrating limited efficacy [6]. In contrast, anti-IL-12/23 p40 and anti-IL-23 antibodies have failed to show efficacy. IL-15 blockade appeared effective at the early stages of disease; however, it was ineffective at late stages. The results of IL-21 inhibition have not been released. Moreover, treatment against IL-20 or IL-22 did not show a difference [7]. These results indicated that IL-6 and GM-CSF signaling is a main target of JAK inhibitors, although blockade of other cytokines may play a role in suppressing RA.
2.3. Types of JAK inhibitors
Thus far, four JAK inhibitors have been approved in Japan, while another (filgotinib) is currently in the process of approval. Tofacitinib, baricitinib, and peficitinib were launched, while upadacitinib was approved in 2020 (not yet released as of February 2020).
There are four JAKs, and two JAKs usually bind to cytokine receptors to transmit signals. The five aforementioned JAK inhibitors differ slightly in their selectivity for JAKs. As different cytokines are suppressed depending on which of the four JAKs is targeted, different results may be obtained. Theoretically, the efficacy and side effects observed in the clinic may be different among the five JAK inhibitors. However, the association between the difference in JAK inhibitory activity and the clinical effect is not as strong as expected [8].
3. Clinical characteristics of JAK inhibitors
3.1. Clinical efficacy
The results of representative clinical trials of each JAK inhibitor are shown in Figures 1 and 2. All trials were phase III randomized controlled trial (RCT), and the primary endpoints differed slightly depending on the trials. The figures show American College of Rheumatology (ACR) response criteria (ACR20/50/70) with the dose approved in Japan at the time of the primary endpoint of each trial. All inhibitors showed good efficacy; however, the efficacies of these inhibitors should not be numerically compared because they were determined separately.
Published online:
05 June 2020Figure 1. Efficacy of JAK inhibitors on RA patients with inadequate response to MTX, csDMARDs, and bDMARDs. ACR20/50/70 responses to JAK inhibitors at the dose approved in Japan at the time of the primary endpoint of each trial. Results for patients with inadequate response to MTX (upper), csDMARD (middle), and bDMARD (lower). JAK: Janus kinase; RA: rheumatoid arthritis; MTX: methotrexate; csDMARD: conventional synthetic disease-modifying anti-rheumatic drug; bDMARD: biological disease-modifying anti-rheumatic drug; ACR: American College of Rheumatology; IR: inadequate response; TNFi: tumor necrosis factor inhibitor.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/timm20/2020/timm20.v043.i04/25785826.2020.1770948/20201208/images/medium/timm_a_1770948_f0001_b.jpg"})
Figure 1. Efficacy of JAK inhibitors on RA patients with inadequate response to MTX, csDMARDs, and bDMARDs. ACR20/50/70 responses to JAK inhibitors at the dose approved in Japan at the time of the primary endpoint of each trial. Results for patients with inadequate response to MTX (upper), csDMARD (middle), and bDMARD (lower). JAK: Janus kinase; RA: rheumatoid arthritis; MTX: methotrexate; csDMARD: conventional synthetic disease-modifying anti-rheumatic drug; bDMARD: biological disease-modifying anti-rheumatic drug; ACR: American College of Rheumatology; IR: inadequate response; TNFi: tumor necrosis factor inhibitor.
Published online:
05 June 2020Figure 2. Efficacy of JAK inhibitors in patients with RA under various conditions. ACR20/50/70 responses to JAK inhibitors at the dose approved in Japan at the time of the primary endpoint of each trial. Results for MTX-naive patients (upper), in comparison with adalimumab (middle), and in the presence or absence of MTX (lower). JAK: Janus kinase; RA: rheumatoid arthritis; ACR: American College of Rheumatology; MTX: methotrexate; csDMARD: conventional synthetic disease-modifying anti-rheumatic drug; ADA: adalimumab.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/timm20/2020/timm20.v043.i04/25785826.2020.1770948/20201208/images/medium/timm_a_1770948_f0002_b.jpg"})
Figure 2. Efficacy of JAK inhibitors in patients with RA under various conditions. ACR20/50/70 responses to JAK inhibitors at the dose approved in Japan at the time of the primary endpoint of each trial. Results for MTX-naive patients (upper), in comparison with adalimumab (middle), and in the presence or absence of MTX (lower). JAK: Janus kinase; RA: rheumatoid arthritis; ACR: American College of Rheumatology; MTX: methotrexate; csDMARD: conventional synthetic disease-modifying anti-rheumatic drug; ADA: adalimumab.
The effectiveness of all five JAK inhibitors (i.e., tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib) on patients with inadequate response (IR) to methotrexate (MTX) has been confirmed by RCT. Based on evidence from the Oral Standard [9], RA-BEAM [10], RAJ4 [11], SELECT COMPARE [12], and FINCH1 [13] studies, additional administration of a JAK inhibitor alongside MTX in those patients proved effective.
The efficacy of JAK inhibitors (tofacitinib, baricitinib, peficitinib, and upadacitinib) in patients with IR to conventional synthetic DMARDs has been assessed in RCTs. The ORAL SYNC [14], RA BUILD [15], RAJ3 [16], and SELECT NEXT [17] studies demonstrated the efficacy of JAK inhibitors.
RCTs investigating tofacitinib, baricitinib, upadacitinib, and filgotinib in patients with IR to TNF inhibitors or non-TNF bDMARDs have been performed. The ORAL STEP [18], RA-BEACON [19], SELECT BEYOND [20], and FINCH2 [21] studies proved that switching to JAK inhibitors is effective in those patients.
Comparison between JAK inhibitor monotherapy and MTX monotherapy in MTX-naïve patients has been performed for four JAK inhibitors. The efficacy of JAK inhibitor monotherapy was demonstrated in the ORAL START [22], RA BEGIN [23], SELECT EARLY [24], and FINCH3 [25] studies.
Studies comparing the efficacy of adalimumab and a JAK inhibitor in combination with MTX in patients with IR to MTX have been conducted. In the ORAL STANDARD [9], RA BEAM [10], and SELECT COMPARE [12] studies, the inhibitors were non-inferior or superior to adalimumab in terms of efficacy.
Studies examining the efficacy of JAK inhibitor monotherapy and combination of a JAK inhibitor plus MTX have been performed, including the ORAL STRATEGY [26], RA BEGIN [23], and FINCH3 [25] studies. The results showed that JAK inhibitor monotherapy was equivalent to the combination therapy (JAK inhibitor plus MTX), whereas one study did not reach the conclusion [26].
As described above, the efficacy of JAK inhibitors has been demonstrated in various patients (e.g., MTX-IR, bDMARD-IR, and MTX-naïve) and situations (e.g., patients intolerant to MTX). The figures do not offer a comparison among JAK inhibitors, but show the type of trials conducted for each drug.
3.2. Patient-reported outcomes (PRO)
One of the notable features of JAK inhibitors is their effect on PRO. In the RA-BEAM [10] (baricitinib) and SELECT COMPARE [12] (upadacitinib) trials, comparison with adalimumab was performed in combination with MTX. JAK inhibitors outperformed adalimumab at week 12 ACR20 and week 12 ACR50 in the former and latter study, respectively. When compared using each ACR component, JAK inhibitor improved patient pain visual analog scale (VAS) and C-reactive protein levels versus adalimumab in both trials. Therefore, the better improvement in ACR response rate observed with baricitinib and upadacitinib is attributed to the improvement in VAS. In both studies, the improvement in the health assessment questionnaire disability index (HAQ-DI) as a result of treatment with JAK inhibitors was superior to that observed with adalimumab, implying that the improvement of pain VAS resulted in the improvement of HAQ. On the other hand, the effects of JAK inhibitors on joint destruction were equivalent to that noted with adalimumab. In the RA-BEAM [10] (baricitinib) and SELECT COMPARE [12] (upadacitinib) trials, there seems numerically no difference in the number of swollen joints or modified total Sharp score between JAK inhibitors and adalimumab although direct comparison was not done.
Inflammation involves several symptoms, such as pain, swelling, redness, and fever. The reason responsible for the marked improvement in pain by JAK inhibitors remains unknown. However, recent progress indicates that JAK-STAT pathway plays important roles in both peripheral and central pain processing mechanism including nociceptive pain and neuropathic pain [26].
On the other hand, in the ORAL STRATEGY trial [27], there was no difference in the ACR improvement rate between tofacitinib + MTX and adalimumab + MTX. Moreover, the improvement in patient pain VAS and HAQ-DI in the sub-analysis was exactly equal. The discrepancies observed among JAK inhibitors also remain unexplained. Further studies are needed to explore the action of JAK inhibitors in pain, especially from the point of clinical dose and JAK selectivity. Overall, the PRO-improving effects of JAK inhibitors are clinically significant as these agents are at least as effective as TNF inhibitors.
Fatigue is one of the dominant symptoms in patients with rheumatoid arthritis, affecting 80% of this population. The 36-item Short Form Vitality Domain (SF-36 VT) and Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F) are the most commonly used outcome measures for fatigue. SF-36 consists of eight domains. Thus far, the effects of tofacitinib and baricitinib have been reported. Tofacitinib and baricitinib reduced fatigue in five and three clinical trials, respectively [28]. The mechanism of fatigue is not fully understood, because it is affected by various factors including RA-specific factors such as inflammation and pain, and non-RA-specific factors such as sleep disturbance and depression [29–31].
We conducted the survey to evaluate the subjective well-being (SWB), which is synonymous with happiness, of RA patients. Although we found many non RA-specific factors such as financial status, self-assessment of health, psychological stress, and social network are important determinants for the SWB, we also found that achieving the therapeutic target can result in better SWB in RA patients, indicating that better efficacy of the treatments may result in the better SWB of the patients irrespective of the socio-economic backgrounds [32]. Thus, I assume that JAK inhibitors may improve fatigue of RA patients by reducing inflammation and pain.
3.3. Adverse events
Significant adverse events include neutropenia/lymphopenia/anemia, serious infection, herpes zoster, malignancy, major adverse cardiovascular events (MACE) and venous thromboembolism (VTE).
Neutropenia was observed with all JAK inhibitors and may be a consequence of JAK inhibition. Thrombocytopenia is also observed with all JAK inhibitors, except for baricitinib, and is thought to be associated with a reduction in inflammation. Anemia usually improves as inflammation subsides. However, baricitinib and upadacitinib may cause a decrease in hemoglobin due to bone marrow suppression. Elevated levels of creatine kinase, total cholesterol, and serum creatinine are common side effects of JAK inhibitors [33–35].
The incidence of serious infections is comparable to that observed with bDMARDs. The use of pneumococcal and influenza vaccines is recommended. The incidence of shingles with JAK inhibitors is higher than that recorded with bDMARDs [31]. This frequency is particularly high for Japanese and Korean patients. In Japan, the frequency is estimated to be seven for every 100 person-years. Elderly individuals and patients receiving treatment with steroids are at risk. In addition, those receiving treatment with baricitinib are at obvious risk [36]. However, as described above, there is a difference in the incidence depending on race and age; hence, it is necessary to take this into consideration when comparing JAK inhibitors.
Malignancy is one of the major concerns of JAK inhibitor. A recently published article performed meta-analysis to estimate the incidence rates of AE including malignancy in patients with RA, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis and received JAK inhibitors [37]. They found incidence of malignancy was not increased in patients receiving JAK inhibitors in RCT. Long-term follow-up data of tofacitinib also showed no increased risk of malignancy [38]. However, further watching is important to confirm safety of JAK inhibitors.
Recently the impact of JAK inhibitors on the risks of cardiovascular events (CVE), MACE, and VTE has been investigated by meta-analysis of RCTs with tofacitinib, baricitinib, upadacitinib, peficitinib, and decernotinib [39]. There was no statistically significant difference between JAK inhibitors and placebo regarding all CVE, MACE and VTE. Dose-dependent impact was not observed with tofacitinib and uoadacitinib, but baricitinib 2 mg was found safer than 4 mg in all CVE events. Although there is no evident signal of JAK inhibitor for CVE events including VTE, more post-marketing data are needed since the prevalence of VTE is very low (0.2%).
4. Characteristics of the five JAK inhibitors
The relative efficacy and safety among JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib) and adalimumab have been compared using Bayesian network meta-analysis [40]. The result suggests that baricitinib and upadacitinib may have higher efficacy as well as lower safety in terms of serious infection and herpes zoster. Whether the different specificity of JAK inhibitors result in different clinical efficacy and safety remains elusive.
JAK selectivity is defined by the results of an enzymatic assay. The results of the enzymatic assays are shown in Figure 3 as radar charts. The upper part shows balances of 1 of half maximal inhibitory concentration (IC50), which indicate suppressing activity, while the lower parts show non-suppressing activity. IC50 values were obtained from the literature [41,42]. Peficitinib is unique because it dominantly inhibits JAK3, while others mostly inhibit JAK1. Tofacitinib, peficitinib, and upadacitinib do not affect TYK2, while baricitinib and filgotinib do not suppress JAK3. Baricitinib suppresses JAK2, while others do not. Of note, slightly different IC50 values were reported depending on the nature of the studies [41–44]. Moreover, these profiles may be insufficient to determine the function of each JAK inhibitors because JAKs act as pairs.
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05 June 2020Figure 3. JAK selectivity according to the results of the enzymatic assay. The results of the enzymatic assays are shown as radar charts. Upper: 1/IC50 for JAK1, JAK2, JAK3, and TYK2. Bottom: IC50 of each JAK inhibitor for JAK1, JAK2, JAK3, and TYK2. JAK: Janus kinase; IC50: half maximal inhibitory concentration; TYK2: tyrosine kinase 2.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/timm20/2020/timm20.v043.i04/25785826.2020.1770948/20201208/images/medium/timm_a_1770948_f0003_b.jpg"})
Figure 3. JAK selectivity according to the results of the enzymatic assay. The results of the enzymatic assays are shown as radar charts. Upper: 1/IC50 for JAK1, JAK2, JAK3, and TYK2. Bottom: IC50 of each JAK inhibitor for JAK1, JAK2, JAK3, and TYK2. JAK: Janus kinase; IC50: half maximal inhibitory concentration; TYK2: tyrosine kinase 2.
Two recently published studies have extensively examined the effects of different JAK inhibitors on the inhibition of STAT using various human cells and cytokines [41,45]. Tofacitinib and upadacitinib were potent suppressor of JAK1/3-dependent cytokines (IL-2, IL-4, IL-15, IL-21), although tofacitinib is expected to be most potent. Baricitinib, upadacitinib, and tofacitinib suppressed JAK1/2-dependent (IL-6, IFNγ), JAK2/2-dependent (IL-3, granulocyte-CSF), and JAK2/TYK2-dependent (IL-10, IFNα) cytokines, although baricitinib is expected to be a potent suppressor of JAK2/2. Furthermore, when a clinically efficacious dose was considered, JAK inhibition of cytokine signaling appeared similar with small differences [43]. Thus, the in vivo action of distinctive JAK inhibitors should be interpreted based on the in vitro enzymatic assay, cell-based signal inhibition assay, as well as the kinetics and drug metabolism of each individual. In addition, data on peficitinib are currently lacking. Further experience is warranted to determine the appropriate use of distinctive JAK inhibitors.
5. Conclusion
The present review explains the basic and clinical aspects of JAK inhibitors. The proper use of the five JAK inhibitors is a future clinical challenge. The indications of JAK inhibitors are expected to expand in clinical trials for other diseases. The usage of these agents is expected to increase in the future; thus, further clinical information on the long-term results and side effects is expected to be accumulated for the safe use of JAK inhibitors.
| Cytokine | JAK usage | Cytokine function |
|---|---|---|
| IL-2, L-4, IL-7, IL-9, IL-15, IL-21 | JAK1, JAK3 | Lymphocyte homeostasis and function |
| IFNα, IFNβ | JAK1, TYK2 | Viral infection |
| IL-6, IL-11, LIF, OSM, IL-13, IL-10, IL-19, IL-20, IL-22 | JAK1, JAK2, TYK2 | Immune responses, inflammation |
| IFNγ | JAK1, JAK2 | Th1 cells |
| IL-12, IL-23 | JAK2, TYK2 | Th1, Th17 differentiation |
| IL-3, IL-5, GM-CSF, EPO, TPO, G-CSF, GH, leptin | JAK2 | Hematopoietic cell differentiation |
IL: interleukin; JAK: Janus kinase; IFN: interferon; TYK2: tyrosine kinase 2; LIF: leukemia inhibitory factor; OSM: oncostatin M; Th: T helper; GM-CSF: granulocyte macrophage colony-stimulating factor; EPO: erythropoietin; TPO: thrombopoietin; G-CSF: granulocyte colony-stimulating factor; GH: growth hormone.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
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