JAK-STAT inhibitors for the treatment of immunomediated diseases

Med Clin (Barc). 2019;152(9):353–360

www.elsevier.es/medicinaclinica

Review

JAK-STAT inhibitors for the treatment of immunomediated diseases夽 b,∗ ˜ José M. Serra López-Matencio a , Alberto Morell Baladrón a , Santos Castaneda a b

Servicio de Farmacia Hospitalaria, Hospital de La Princesa, Instituto de Investigación (IIS)-Princesa, Madrid, Spain Servicio de Reumatología, Hospital de La Princesa, Instituto de Investigación (IIS)-Princesa, Madrid, Spain

a r t i c l e

i n f o

Article history: Received 11 July 2018 Accepted 19 October 2018 Available online 9 March 2019 Keywords: Janus kinase inhibitors Efficacy Pharmacological interactions Adverse reactions Small molecule drugs

a b s t r a c t The Janus kinase (JAK) pathway is implicated in the pathogenesis of many inflammatory and autoimmune diseases including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. There are a lot of proinflammatory cytokines involved in such diseases using this pathway to transduce intracellular signals. In the last years, JAK inhibitors (jakinibs) have appeared with a great success, showing that these kinds of drugs have a great applicability in clinical practice. Tofacitinib and baricitinib, the first jakinibs approved for the treatment of RA, are being investigated also for treating other autoimmune systemic diseases. Likewise, other jakinibs are in several phases of development. This review analyses the safety and clinical efficacy of the jakinibs, starting with the classics and continuing with next-generation jakinibs. ˜ S.L.U. All rights reserved. © 2018 Elsevier Espana,

˜ Inhibidores de la vía de senalización JAK-STAT en el tratamiento de las enfermedades inmunomediadas r e s u m e n Palabras clave: Inhibidores de las proteínas Janus cinasa Eficacia Interacciones farmacológicas Reacciones adversas ˜ moléculas Pequenas

˜ La ruta de senalización de las proteínas de la familia Janus cinasa (JAK) está implicada en la patogenia de muchas enfermedades inflamatorias y autoinmunitarias, como la artritis reumatoide (AR), la psoriasis y la enfermedad inflamatoria intestinal. Una gran cantidad de citocinas implicadas en el desarrollo de estas ˜ ˜ enfermedades utilizan esta vía de senalización para transducir senales intracelulares. En los últimos ˜ anos, la aparición de los inhibidores de las proteínas JAK (jakinibs) ha demostrado que los fármacos relacionados con esta ruta patogénica pueden tener gran aplicabilidad clínica. Tofacitinib y baricitinib, primeros jakinibs aprobados para el tratamiento de la AR, están en estudio para el tratamiento de otras enfermedades autoinmunitarias. Asimismo, otros jakinibs se encuentran en diferentes fases de desarrollo. En este trabajo se revisan los principales aspectos en cuanto a eficacia, interacciones farmacológicas y seguridad tanto de los jakinibs clásicos como de los de nueva generación. ˜ S.L.U. Todos los derechos reservados. © 2018 Elsevier Espana,

Introduction Janus kinases (JAK) are a group of cytoplasmic enzymes with tyrosine kinase activity that facilitate the transmission of signals from the cell surface to its interior. There are currently four known

夽 Please cite this article as: Serra López-Matencio JM, Morell Baladrón A, Castaneda ˜ ˜ JAK-STAT en el tratamiento de las enferS. Inhibidores de la vía de senalización medades inmunomediadas. Med Clin (Barc). 2019;152:353–360. ∗ Corresponding author. E-mail addresses: [email protected], [email protected] ˜ (S. Castaneda). ˜ S.L.U. All rights reserved. 2387-0206/© 2018 Elsevier Espana,

members of the JAK family in humans (JAK1, JAK2, JAK3 and TYK2); they all have a very similar chemical structure (Fig. 1). JAK1, JAK2 and TYK2 are expressed indiscriminately throughout the body, whereas JAK3 is expressed in the haematopoietic cells.1 Its enormous physiological importance lies in the fact that more than 60 cytokines and hormones use the JAK-STAT3 pathway for intracellular signalling. Thus, JAK1 acts by transmitting the signals of numerous proinflammatory cytokines. In addition, JAK1 collaborates with JAK3 in lymphopoiesis by binding to heterodimeric interleukin (IL) receptors such as IL-2R and IL-7R from class II cytokines (interferons [IFN]), among others. Its inactivation causes death due to a deficit in lymphocyte development and secondary neuronal dysfunction.2

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Fig. 1. JAK family enzymes action pathways and inhibitors of the JAK pathway (jakinibs) mechanism of action. EPO: erythropoietin; GH: growth hormone; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN-AB: interferon alpha-beta; IFN-G: interferon gamma; IL: interleukin; JAK: Janus kinase; TPO: thrombopoietin; TYK2: tyrosine kinase 2. Banerjee et al.59

JAK2 is a major mediator in the transmission of signals of haematopoietic factors (erythropoietin, thrombopoietin, stimulating factor of granulocyte and granulomonocyte colonies). Its inactivation in mouse embryos causes its death due to the absence of erythropoiesis. The main function of JAK3 and TYK2 is to regulate the immune system. In this sense, an inherited form of severe combined immunodeficiency associated with a defect in the functioning of JAK3 has been described,3 while TYK2 mutations have been associated with clinical symptoms of atopic dermatitis with opportunistic infections.4 The importance of the inhibition of the JAK pathway was described in the nineties5 and two decades later, the first JAK inhibitors were approved by the Food and Drug Administration (FDA) for the treatment of some myeloproliferative neoplasms and rheumatoid arthritis (RA). Inhibitors of the JAK pathway are generically called jakinibs. Jakinibs intervene by competitively blocking the adenosine triphosphate binding site in the JH1 joining segment through noncovalent interactions6 (Fig. 2). This is a problem when developing compounds, as they must block this pathway without affecting other tyrosine kinases, whose active domains have great structural analogies 2).6 Another complication is that the JH1 domain and the different existing molecules are very similar, which makes designing jakinibs that block a single JAK selectively very difficult.6 However, despite these limitations, jakinibs have been designed with a good efficacy/safety ratio, although it is not yet clear whether the selective inhibition of a specific JAK would result in a therapeutic specificity.6 This article will review the data on the efficacy, drug interactions and safety of the main first generation jakinibs, while also analyse the data available on those agents that aim to treat systemic autoimmune diseases (SAD) and which are still pending approval. First generation jakinibs Tofacitinib Tofacitinib was the first jakinib approved for the treatment of autoimmune diseases and the drug for which we have most information. Tofacitinib is a JAK1/JAK3 inhibitor that has certain activity on JAK2.6 The majority of its metabolism occurs in cytochrome P450 (CYP) 3A4 and, to a lesser extent, in cytochrome CYP2C19.6 The in vitro inhibition of CYP3A4 with ketoconazole results in the inhibition of its metabolism by more than 70%,6 which supposes an

estimated area under the curve (AUC) increase of in vivo tofacitinib of 103% after administering ketoconazole. Similar effect occurs when it is co-administered with fluconazole. This means that strict recommendations should be given for the dose adjustment of this drug when it is given together with moderate CYP3A4 inhibitors or potent CYP2C19 inhibitors. Similarly, studies with rifampicin, a potent inducer of CYP3A4, led to decreases in the AUC of tofacitinib, although the clinical consequences of this were not so clear. Tofacitinib does not act as a CYP3A4 inhibitor per se, as evidenced by the non-alteration of the pharmacokinetics of midazolam when administered jointly.7 The FDA recently approved a tofacitinib formulation that allows for administration once a day, through a sustained osmotic release system.8 Compared to the immediate release formulation at a dose of 5 mg every 12 h, this sustained release formulation provides a systemic exposure, equivalent Cmax and a minimum plasma concentration. Logically, the half-life and time needed to reach Cmax are greater in the delayed-release formulation. Table 1 shows the most important pharmacokinetic characteristics of the main JAK inhibitors. Results of a phase IIb study showed the efficacy and safety of tofacitinib both in monotherapy and in combination with other disease-modifying antirheumatic drugs (DMARD) in the treatment of RA.9 The doses used in the phase II trials ranged between 1 and 30 mg twice daily. Also, several studies have examined the effect of tofacitinib on structural damage in RA, with very promising results. In a controlled phase II study that compared the effects of tofacitinib monotherapy with methotrexate (MTX) in combination or with MTX monotherapy, both branches of tofacitinib achieved better results in several of the parameters analysed. Similar effects were obtained in a phase III study in which tofacitinib was studied in patients with inadequate response to MTX, obtaining clinically significant improvements.10 The long-term efficacy of tofacitinib in moderate to severe RA was analysed in a study using data from several clinical trials, and which included more than 4100 patients equivalent to 5963 patients-year.11 In this study, consistent data were shown for sustained safety and efficacy of the drug at 48 months.11 Tofacitinib has also shown to be safe and effective in patients who had previously received an anti-TNF agent such as adalimumab.12 In psoriasis, multiple cytokines use the JAK-STAT pathway, such as type I and II IFN, IL-12, IL-22 and IL-23,13 justifying the use of jakinibs in this disease. A phase II study using doses of between 2 and 15 mg every 12 h to treat advanced stages of the disease found

J.M. Serra López-Matencio et al. / Med Clin (Barc). 2019;152(9):353–360 JH7

FERM domain

JH6

JH5

JH4

JH3

SH2 domain

JH2

355 JH1

Pseudokinase domain Kinase domain

Fig. 2. Linear structure of Janus kinase (JAK) showing the different domains it presents. JAKs have four functional domains: kinase domain, pseudo kinase, protein domain 4.1, ezrin and radixin–moesin (FERM), and two homologous domains (SH2). The kinase domain is where the catalytic activity resides and the inhibition carried out by the jakinibs occurs. The FERM domain and the pseudo kinase interact with the kinase and have mainly regulatory functions. A type of additional nomenclature, based on the final amino acid sequence of the domains, classifies them into seven homologous Janus domains (JH).

clinically significant improvements compared to placebo. Its extension study also compared doses of 5 and 10 mg every 12 h with weekly etanercept, and obtained better results with tofacitinib at a dose of 10 mg but not at 5 mg.14 It has recently been approved for use in Europe for the treatment of psoriatic arthritis. Likewise, the use of topical tofacitinib for the treatment of moderate/severe psoriasis has also been studied.15 Regarding its efficacy for the treatment of ulcerative colitis (UC),16 tofacitinib has shown to be usefulness in one recently published phase II study17 and two phase III trials in patients with moderate-severe UC.18,19 Furthermore, the beneficial effect of tofacitinib in UC is observed almost immediately, after only a few days of administering.20 In terms of duration, the OCTAVE trial, which examined the efficacy of tofacitinib as maintenance therapy in UC, and its long-term extension study, provided even more clarifying data.21 For all these reasons, tofacitinib has recently been approved for the treatment of UC. The data are less consistent for the treatment of Crohn’s disease (CD). A phase II study including 139 patients with moderate to severe CD receiving 1 mg, 5 mg, or 15 mg of tofacitinib or placebo, every 12 h for four weeks, showed no clinical efficacy. However, a dose of 15 mg did result in a significant reduction in C-reactive protein (CRP) and faecal calprotectin levels, both markers of disease activity.22 These contradictory findings for CD have also been confirmed by other authors.23

Ruxolitinib Ruxolitinib is an inhibitor of JAK1 and JAK2 with moderate activity against TYK2.24 This drug was approved by the FDA before tofacitinib and originally developed for the treatment of polycythemia vera and myelofibrosis. It has a pharmacokinetics similar to that of tofacitinib (Table 1). However, it has more active metabolites and lower renal elimination. Generally speaking, ruxolitinib is metabolised by CYP3A4 and to a lesser extent by CYP2C19. Recently, several pharmacokinetic and pharmacodynamic studies have been conducted using ketoconazole and erythromycin, both inhibitors of CYP3A4, with rifampicin as an inducer, to evaluate their metabolism.24 Thus, coadministration with ketoconazole resulted in an increased drug exposure of 90% and an increase of its half-life by approximately 2 h. Its administration with rifampicin resulted in a Cmax reduction of 52% and a half-life reduction of 50%. These results were supported by a study – whose results were clinically and statistically significant – into its impact on the inhibition of STAT3 phosphorylation, decreasing pharmacodynamic activity by 13% when administered with rifampicin. However, it was generally considered that this had no clinical relevance and dose adjustment is not recommended.24 Its use in SAD is promising. A phase II study into RA achieved good results compared to placebo.25 Additionally, there are several cases in which different SAD have been treated successfully when administering ruxolitinib.26 Similarly, satisfactory results

have been obtained when treating cases of psoriasis and alopecia topically.27

Baricitinib Baricitinib is a selective inhibitor of JAK1/JAK2 that intracellularly inhibits the proinflammatory signal of several cytokines, such as IL-6, IL-12, IL-23 and IFN-gamma.28 Its main route of elimination is the renal route, which is why it is not expected to have significant interactions in the metabolic pathway mediated by cytochrome P450.28 However, a significant increase in their half-life is expected in patients with renal dysfunction28 (Table 1). A phase II study has shown drug efficacy in RA patients at doses of 4 and 8 mg compared to MTX during periods spanning 24 weeks.28 Similarly, several phase III studies have been carried out, unequivocally showing their effectiveness in RA. Thus, a direct comparison study between baricitinib and adalimumab (RA-BEAM study), showed that baricitinib was clearly superior to adalimumab and/or placebo in questionnaires answered by the patient after 52 weeks of treatment.29 Interestingly, the RA-BUILD30 study found a rapid improvement in the ACR (response measure by the American College of Rheumatology) in only one week, while no response in the first four weeks was a predictor of long-term failure. This information can be used to avoid unnecessary exposure to the drug. In addition, this study showed improvements in patients’ functional capacity and pain.30 The purpose of the RA-BEYOND study currently being carried out is to investigate the long-term safety of baricitinib in patients who have previously completed a study with the drug for RA (NCT01885078; http://www.clinicaltrials.gov). Baricitinib has been available and approved for use in RA in Spain since 2017 (www.ema.europa.eu/documents/productinformation/olumiant-epar-product-information en.pdf). Regarding its use in other immunomediated diseases other than RA, the drug has been shown to be effective in patients with moderate to severe psoriasis,31 atypical neutrophilic dermatosis with lipodystrophy32 and systemic lupus erythematosus (SLE).33

Oclacitinib This pan-JAK is approved for canine eczema and atopic dermatitis. This fact indicates that this drug can be effective in allergic diseases in humans, although results are currently somewhat preliminary.

New generation jakinibs In order to minimise adverse reactions to these types of drugs while maintaining their therapeutic efficacy, we are currently working on the development of new generation jakinibs with selective inhibitory activity for a specific JAK.

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30% renal excretion

Same for immediate form Insignificant

>66% renal excretion

Approximately 3

Approximately 5.9

Approximately 8

Approximately 3

Excretion Elimination half-life, h

Decernotinib Decernotinib is a new-generation jakinib whose in vitro studies have shown a five-fold greater kinase activity on JAK3 than on JAK1, JAK2 and TYK2 (Fig. 1). It is currently being studied in patients with RA. Regarding its metabolism and pharmacokinetics, decernotinib has a major metabolite, M3, which acts as a potent inhibitor of CYP3A4. That is why this active principle is very likely to present pharmacological interactions with other drugs.34 The main adverse effects include elevation of lipid parameters. Preliminary results of the drug in RA have been promising. Phase II trials have demonstrated efficacy at a daily dose of 50–150 mg, with improved ACR and DAS28 compared with placebo; the main adverse effects reported are those similar to first generation jakinibs (infections, hyperlipidaemia or increase of transaminases). However, no anaemia was found, consistent with its selectivity for JAK3 over JAK2. Surprisingly, severe neutropenia has been detected, which shows pharmacological effects unrelated to its mechanism of action.35 Finally, a recent study has shown an improvement in synovitis and osteitis in patients with RA, refractory to synthetic DMARDs and treated with decernotinib, compared with placebo.36

– 1.5 postdose Baricitinib

CYP: cytochrome; Tmax: maximum time. Modified from Banerjee et al.59

2

Tofacitinib (sustained release) Ruxolitinib

4

CYP3A4 CYP2C19 CYP3A4 CYP2C9 –

1/10 capacity for JAK1 and JAK3 with regard to the original molecule Same as immediate release form Yes CYP2C19

CYP3A4 1

Minimal <10% related to activity

Metabolism Absorption (Tmax), h

Tofacitinib (immediate release)

Jakinib

Table 1 Pharmacokinetics of the main Janus kinase inhibitors.

Active metabolites

Filgotinib This drug inhibits both JAK1 and JAK2 (Fig. 1). However, it has a 30-fold higher selectivity for JAK1. In addition, it has dosedependent inhibitory activity on Th1, Th2 and, to a lesser extent, on differentiation to Th17 cells.37 In terms of metabolism and pharmacokinetics, in vitro studies show that neither filgotinib nor its metabolites have activity over CYP – as neither inhibitors nor as potentiators.37 The same has been confirmed in a study, using healthy individuals, into the clearance of midazolam when administered concomitantly with filgotinib, in which no modifications were found.37 Currently, this drug is being studied for the treatment of RA.38 Phase II studies in patients with active RA and inadequate response to MTX showed efficacy of monotherapy filgotinib over placebo at a dose of 30 mg/day. This has been confirmed in two phase IIb trials: DARWIN1 and DARWIN2. In the DARWIN2 study, filgotinib was superior to placebo in controlling the activity of the disease by ACR 20/50, DAS28-PCR, simple and clinical index of disease activity.38 Filgotinib is also being researched in moderate to severe CD, specifically in the FITZROY study.39 Preliminary data from this trial showed a higher percentage of referrals evaluated by means of a clinical activity index and a quality of life questionnaire, comparing filgotinib versus placebo.39 Its safety profile has been favourable in all the mentioned studies; additionally, the FITZROY study found that it has a favourable lipid profile as it increases HDL cholesterol without producing changes in LDL cholesterol.39 Furthermore, an increase in the haemoglobin value was observed without producing variation in the neutrophil count. There were also no changes in liver function.40 Upadacitinib Upadacitinib is a new generation jakinib that is 74 times more selective on JAK1 than on JAK2, based on its ability to block the JAK1 receptor by binding to JH1 at different sites, in addition to the adenosine triphosphate binding site. Because these unions are produced with a less conserved domain, it is considered specific for JAK1. It is worth highlighting that, because both the JAK2 and JAK3 signals remain intact, upadacitinib does not affect the erythropoietin signalling cascade or the peripheral NK count at the therapeutic

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dose tested.41,42 The pharmacokinetics of upadacitinib have a biexponential behaviour proportional to the dose administered.42 Two phase II multicentre, randomised, double-blind, placebocontrolled studies (BALANCE 1 and 2) were carried out in patients with moderate to severe RA who were non-responders to either anti-TNF therapy (BALANCE I) or MTX (BALANCE II).43,44 Both studies showed a rapid improvement in terms of ACR 20/50/70 and DAS28-PCR with upadacitinib compared to placebo. These results were registered quickly, within two weeks of initiating treatment.43,44 Peficitinib Peficitinib is a new generation jakinib that inhibits the enzymatic activities of JAK1, JAK2, JAK3 and TYK2, showing moderate selectivity for JAK3 (Fig. 1). Furthermore, it only relatively moderates JAK2 inhibition, which gives it an acceptable safety profile and a certain advantage over traditional jakinibs.45 Peficitinib is rapidly absorbed orally and does not have a single metabolic pathway.45 This makes it very interesting from a drug interaction perspective, since in principle it is not susceptible to presenting too many. In a phase IIb trial in patients with RA, the drug showed a significant ACR20 response compared to placebo using a drug dose scale of 25, 50, 100 and 150 mg/day.46 In a phase II trial in patients with plaque psoriasis, dose-dependent efficacy was demonstrated in the Psoriasis Area and Severity Index (PASI) and the Body Surface Area (BSA). None of these studies reported any serious adverse effects.47 Solcitinib Solcitinib is a selective inhibitor of JAK1 that has recently been evaluated for the treatment of moderate to severe plaque psoriasis. In a 12-week placebo-controlled clinical trial, the drug showed significant improvement in PASI75 (75% cutaneous improvement).48 Because JAK1 causes a decrease in IFN synthesis and patients with SLE present aberrant signalling of this pathway, the drug was studied in a phase II placebo-controlled study in patients with moderate to severe SLE. However, on two occasions, adverse reactions in the form of eosinophilia appeared, with a marked, albeit reversible, increase in several hepatic parameters. This forced the study to end prematurely.49 Itacitinib Itacitinib is another selective JAK inhibitor (Fig. 1). Specifically, itacitinib is 20 times more selective for JAK1 than for JAK2 and 200 times more than for JAK3. Preclinical studies have shown their efficacy in models with mice with induced arthritis, at doses that do not inhibit erythropoietic activity. In addition, itacitinib has been shown to inhibit inflammatory pathways related to the pathogenesis of psoriasis.50 A phase II trial in patients with active RA showed significant improvement in both 20/50/70 and ACR DAS28-CRP compared to placebo, at dose intervals of 100 mg/12 h and 600 mg daily. Another phase II trial, this time in patients with psoriasis, also obtained promising results both in improvements of PASI 50/75% and in BSA.51 The most frequent adverse effects were the same as those described with non-selective jakinibs, such as nasopharyngitis, elevated transaminases or hypertriglyceridemia.51 Safety of first generation jakinibs The fact that first-generation jakinibs block and transform the signalling of important proinflammatory cytokines means that

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their mechanism of action is related to the possible appearance of adverse effects. These can affect the patient’s haematopoiesis and immune status. One of the main fears of these drugs is a risk of secondary infections, especially serious infections. In clinical trials performed with different jakinibs, there is an increase in both banal infections (nasopharyngitis, upper respiratory tract infections, bronchitis or gastroenteritis) and opportunistic infections related to varicella zoster virus (VZV), tuberculosis, cellulitis, panniculitis, septic shock and osteomyelitis.52,53 The rate of adverse effects is similar to that of other DMARDs; there is not sufficient current evidence to conclude that their overall toxicity is lower than that of biological DMARDs.52,53 However, it has been shown that the risk of VZV reactivation is greater with tofacitinib and baricitinib, and possibly with the other jakinibs, than with conventional DMARDs.53 This fact may be due to the importance of the cytokines dependent on the JAK3 pathway in the development of NK lymphocyte activity, very important in the control of viral infections such as varicella zoster. In addition, opportunistic infections due to the BK polyomavirus with associated nephropathy have been detected in patients treated with tofacitinib associated with mycophenolate mofetil. This has also been seen in patients treated with concomitant cyclosporine.54 One patient with myelofibrosis treated with ruxolitinib presented with progressive multifocal leukoencephalopathy.55 Another major concern regarding its long-term use is the possible development of tumours, since both IFN I and II play an important role in the immune system’s antitumour response. In transplant patients treated with tofacitinib, the risk of presenting lymphoproliferative syndromes increased, although these patients also received concomitant immunosuppressive treatment. However, in studies into SAD patients being treated with tofacitinib, the risk of experiencing lymphoma or melanoma was not higher than that observed when using biological agents.54 Therefore, more studies are needed to confirm whether the inhibition of the JAKSTAT pathway is related or not to the appearance of tumours. The appearance of haematological disorders (cytopenias) could be frequent because of the inhibition of colony stimulating factors or erythropoietin by the JAK2 pathway; all this would lead to a decrease in haemoglobin values and the lymphocyte count, NK cells, platelets and neutrophils. However, although cases of neutropenia and anaemia have been reported sporadically, only the highest doses of tofacitinib have produced serious adverse effects.52 Likewise, an increase in LDL and HDL cholesterol values and cardiovascular events (CV) such as atrioventricular block, congestive heart failure or acute myocardial infarction has been observed in patients treated with different jakinibs. However, there has not been an increase in long-term CV episodes.56 In the same vein, data from a study in phase III showed that lipid levels stabilised after three months of treatment with tofacitinib and that the number of CV episodes were no higher to those in the placebo group.56 It seems that the effect of tofacitinib on lipid levels is similar to that observed with tocilizumab and that it is due to blocking of the signal mediated by IL-6. In 2017, and because of the appearance of thromboembolic effects in the trials carried out with baricitinib, an alert recommended a special control in patients with high thromboembolic risk.57 It seems that this effect is largely due to the total absence of CV episodes at the start of the study in the placebo group. In fact, to date, studies have not shown the appearance of more serious CV events in patients treated with tofacitinib compared to placebo.56 Other analytical alterations include sporadic elevations of transaminases and creatinine, although no cases of severe hepatic or renal failure have been reported. In a phase I study, creatinine serum and glomerular filtration rate (GFR) changes were analysed

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Table 2 JAK-STAT inhibitors approved by the European Medicines Agency. Medication

Approved indication

Dose

Future applications

Tofacitinib

Moderate to severe active rheumatoid arthritis and psoriatic arthritis

5 mg/12 h

Ankylosing spondylitis Kidney transplant Crohn’s disease Vitiligo Atopic dermatitis Psoriasis Multiple myeloma Haematopoietic neoplasia Alopecia areata Thalassemia

Ruxolitinib

Baricitinib

Ulcerative colitis Splenomegaly, primary myelofibrosis, myelofibrosis secondary to polycythemia vera or essential thrombocythemia Moderate to severe active rheumatoid arthritis

in patients with RA treated with tofacitinib and were found to be higher than those from the placebo group: results showed a 5% increase in creatinine levels and a decrease in GFR of 8%, which disappeared when the drug was discontinued.58 The safety data of new generation jakinibs are less known.

10 mg/12 h (8 weeks) 5 mg/12 h (maintenance) 15 mg/12 h (platelet count between 100,000 and 200,000/mm3 ) 20 mg/12 h (if platelets count >200,000/mm3 ) 4 mg/24 h

Atopic dermatitis Giant cell arteritis Systemic lupus erythematosus Graft-versus-host disease

JAK-dependent cytokines to different degrees and in certain patient phenotypes. From all the above we could conclude that, as occurred with biological agents, jakinibs may result in a revolution in the treatment of SAD in the coming years. Conflict of interest

Future of JAK-STAT pathway inhibitors Given the high number of proinflammatory cytokines involved in the JAK-STAT pathway, it is not surprising that jakinibs have become the first kinase inhibitors to be successfully used in the treatment of immunomediated diseases. At present, tofacitinib and baricitinib are the only ones approved for the treatment of SAD. However, due to the large number of clinical trials that are currently being carried out in diseases such as RA or psoriasis, it is expected that other jakinibs will be successfully used in the near future.59 Table 2 shows the main clinical indications, current or future, of the jakinibs currently approved by the European Medicines Agency. Similarly, various diseases characterised by an elevation of serum cytokines related to this signalling pathway should respond to these drugs. This would include diseases in which IFN I plays a determining role, such as SLE, polymyositis, scleroderma or Sjögren’s syndrome, as well as in IL-6-dependent diseases, such as relapsing polychondritis or vasculitis. In fact, several studies have evaluated the effectiveness of jakinibs in the treatment of diseases with IFN involvement, based on preclinical data or the observation that baricitinib is effective for the treatment of certain ‘monogenic interferonopathies’ such as chronic atypical neutrophilic dermatosis.32 The successes obtained in preliminary studies in the treatment of alopecia and other skin diseases such as vitiligo and alopecia areata60 are also very encouraging, considering the lack of really effective treatments in these diseases. The optimisation of the doses of these drugs is also a challenge that will have to be answered in the coming years, since approved regimens are currently based on single doses both for induction of remission and for maintenance, which does not seem to be very appropriate; a better option may be to start with a high dose to induce remission and continue with a lower dose to maintain. Research into non-oral formulations of jakinibs in diseases such as psoriasis, allergic dermatitis or eye diseases is in a preliminary phase. The development of biomarkers to identify different patient profiles that may benefit from these molecules – targeted agents – is also of interest, since autoimmune diseases may be promoted by

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