Anti cytokine therapy in chronic inflammatory arthritis

Cytokine 86 (2016) 92–99

Contents lists available at ScienceDirect

Cytokine journal homepage: www.journals.elsevier.com/cytokine

Review article

Anti cytokine therapy in chronic inflammatory arthritis Dr Charlotte Thompson MBBCh MRCP(Rheum) a,⇑,1, Dr Ruth Davies MBChB BSc MRCP a,1, Ernest Choy Professor b,1 a

Department of Rheumatology, Institute of Infection and Immunity, Cardiff University School of Medicine, Tenovus Building, Heath Park Campus, Cardiff CF14 4XN, United Kingdom Department of Rheumatology and Translational Research, Institute of Infection and Immunity, Director of Arthritis Research UK CREATE Centre and Welsh Arthritis Research Network (WARN), Cardiff University School of Medicine, Tenovus Building, Heath Park Campus, Cardiff CF14 4XN, United Kingdom b

a r t i c l e

i n f o

Article history: Received 26 August 2015 Received in revised form 21 July 2016 Accepted 22 July 2016

Keywords: Cytokine Inflammatory arthritis TNFa inhibitor Psoriatic Arthritis Rheumatoid Arthritis Ankylosing Spondylitis IL27

a b s t r a c t This is a review looking at anti cytokine therapy in Rheumatoid Arthritis (RA), Psoriatic Arthritis (PSA) and Ankylosing Spondylitis (AS). The review explores the similarities and differences in the clinical features, as well as treatments and cytokines involved in the development and propagation of the disease. Particular attention is paid to TNFa inhibitors IL-1ra, IL-6 and JAK kinase Inhibitors, anti IL23 and IL-12 and the new developments with anti-IL-17. Ó 2016 Elsevier Ltd. All rights reserved.

Contents 1.

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Clinical features of inflammatory arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Spondyloarthropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1. PsA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2. Ankylosing Spondylitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of chronic inflammatory arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of cytokines in the pathogenesis of chronic inflammatory arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. PsA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. AS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. TNFa inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. IL-1ra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. IL-6 inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. JAK kinase inhibitor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. IL23 and IL-12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New developments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Anti-IL-17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. IL17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. IL-27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⇑ Corresponding author. 1

E-mail addresses: [email protected] (C. Thompson), [email protected] (E. Choy). Cardiff University and University Hospital of Wales.

http://dx.doi.org/10.1016/j.cyto.2016.07.015 1043-4666/Ó 2016 Elsevier Ltd. All rights reserved.

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1. Clinical features of inflammatory arthritis According to the World Health Organisations International Classification of Diseases, inflammatory arthritis is one of the major categories of rheumatic diseases (ICD10 classification from M05M14). Three of the most common forms of inflammatory arthritis include Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS) and Psoriatic Arthritis (PSA). Inflammation is part of the body’s immune defence against infection and foreign substances however; it may lead to damage and disease if it is uncontrolled and prolonged. Cytokines are protein messengers within the immune system that enable the immune system to communicate. Consequently, pro-inflammatory cytokines and so consequently are key treatment targets. 1.1. RA RA is the most common chronic inflammatory and destructive arthritis. The pathogenesis is multifactorial and complex, however, rheumatoid factor and ACPA are found in most patients. Synovial inflammation causes joints to be hot, swollen, stiff and painful with the small joints of hands and feet are usually being affected first. Synovial inflammation and hyperplasia are typical pathologic processes that lead to cartilage and bone destruction [1]. If inflammation is inadequately suppressed, it can lead to joint damage and may lead to loss of functional capacity. Once the joint is damaged it cannot be repaired, so treating RA early is the target. Although the articular structures are the primary sites involved by RA, other organs are also affected with extra-articular manifestations including secondary Sjogren’s syndrome, pulmonary fibrosis, renal amyloidosis and cardiovascular disease [2,3]. 1.2. Spondyloarthropathies Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS) are part of the larger group of seronegative spondyloarthropathies (SpA). This is a group of heterogeneous chronic inflammatory arthropathies affecting the spine but can also have peripheral symptoms. Typically patients do not have rheumatoid factor and genetically associated with HLA-B27. 1.2.1. PsA Psoriasis is a common chronic inflammatory disease of the skin. It affects men and women equally. 10–20% of patients with psoriasis have associated Psoriatic Arthritis (PsA). Normally the psoriasis will be present before the arthritis, but arthritis can precede the psoriasis in 15% and occur simultaneously in 20% of patients. Classically the arthritis starts between 30 and 50 years of age. PsA can have multiple joint involvement patterns. This is usually asymmetrical with distal interphalangeal involvement but may be polyarticular or oligoarticular. Patients can develop dactylitis (sausage-shaped digit) and enthesitis (inflammation of ligament insertion into bone). In most patients there is no obvious pattern between the skin and joint involvement and exacerbations and remissions. ‘Arthritis Mutilans’ is a form of PsA, where bone resorption of the distal interphalangeal joints leads to collapse of the soft tissue in the digits. Radiologically PsA is characterised by juxta-articular new bone formation but relative preservation of the joint space and lack of peri-articular osteopenia. The classification criteria for PsA, the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria (Table 1), [4] was developed by an international study group and has a sensitivity of 91% and a specificity of 99%. The patient is considered to have Psoriatic Arthritis if the sum of the points is 3 or more.

Table 1 CASPAR scoring. Score Current psoriasis A history of psoriasis (in the absence of current psoriasis) A family history of psoriasis in first or second degree relative (in the absence of current psoriasis and history of psoriasis) Dactylitis Juxta-articular new-bone formation Rheumatoid factor negativity Nail dystrophy

2 1 1 1 1 1 1

1.2.2. Ankylosing Spondylitis Ankylosing Spondylitis (AS) is chronic inflammatory arthritis affecting mainly the spine. Patients commonly present with inflammatory lower back pain and reduced spinal mobility. Radiologically, sacroilitis is a diagnostic feature. It also leads to ossification of the outer annulus fibrosis fibres of intervertebral disc and formation of syndesmophytes between the adjacent vertebral bodies. These give rise to the classic ‘bamboo spine’ appearance on radiograph. AS can also have other extra spinal manifestations such as enthesitis (40–60%), variable involvement of the peripheral joints, lung fibrosis, cardiac involvement and acute anterior uveitis (30– 50%). The main complication of anterior uveitis is the occurrence of synechiae, adhesions between the iris and the lens or cornea. Uveitis that develops with PsA tends to be more chronic and bilateral and often involves posterior elements. Cardiac features are rare but heart block is the most frequent manifestation. Aortic insufficiency secondary to an aseptic endocarditis and aortitis can also be a severe cardiac manifestation of the disease. AS usually starts in early adulthood and although previous thought to predominantly affect men, the number of women affected is increasingly being recognised. The lifetime impact of fatigue, joint stiffness and its effects on social activities can be significant.

2. Treatment of chronic inflammatory arthritis Traditional medications for inflammatory arthritis target the reduction of inflammation thereby improving symptoms and preventing joint damage. There are three main groups of medications: non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs). Several studies into RA [10–12] have provided evidence that early treatment with DMARDs results in superior clinical and radiological outcomes. DMARDs are divided into synthetic DMARDs and biologic DMARDs. Synthetic DMARDS, e.g. Methotrexate, Hydroxychloroquine, Leflunomide and Sulphasalazine are cheaper and are normally used as a first-line. Most synthetic DMARDs were developed initially in RA. For PsA there is modest efficacy been shown for Leflunomide [13] and Sulphasalazine [14] and conflicting evidence for Methotrexate [17]. These are generally used in SpA if there is peripheral joint involvement but they are ineffective for spinal disease. Although synthetic DMARDs improve symptoms and signs in inflammatory arthritis, their efficacy is limited. Few patients achieved adequate control of inflammation to abort joint damage. Biologic DMARDs are used when synthetic DMARDs fail to control RA or in axial SpA after NSAIDs failure. The advent of biologic DMARDs transformed the management and prognosis of inflammatory arthritis. Firstly, ‘‘therapeutic targets” that may be responsible for driving inflammation were identified. Monoclonal antibodies or immunoconstructs can then be developed for these targets. The first successful target was the

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cytokine, Tumour Necrosis Factor alpha (TNFa). Sir Marc Feldmann and Sir Ravinder Maini formulated their hypothesis implicating TNFa in the pathogenesis of RA in the 1980s [18]. Subsequent clinical trials using Infliximab, a chimeric anti-TNFa monoclonal antibody, and the immunoconstruct Etanercept, confirmed the importance of TNFa in driving inflammation and joint damage. After the impressive benefit of TNFa inhibitors in RA, clinical trials in AS and axial PsA followed that demonstrated their efficacy also in these conditions. Several TNFa inhibitors are now licensed for the treatment of RA, PsA and AS. 3. The role of cytokines in the pathogenesis of chronic inflammatory arthritis 3.1. RA Both the innate and adaptive immune responses are involved in the inflammatory and destructive rheumatoid processes. T and B cells, antigen presenting cells, monocytes and cytokines have all been implicated. It is thought that CD4+ T helper cells may initiate the disease process in RA. These cells produce IL-2 and interferon gamma when activated by an antigen presenting cells. IL-2 and interferon gamma may go on to activate lymphocytes, macrophages and other cell populations, including synovial fibroblasts. Macrophages and synovial fibroblasts are the main producers of TNFa, interleukin (IL)-6 and IL-1. Aberrant production and regulation of both pro-inflammatory and anti-inflammatory cytokines and cytokine pathways are found in RA. Experimental models suggest that synovial macrophages and fibroblasts may become autonomous in the presence of a pro-inflammatory cytokine network leading to chronic inflammation. TNFa is known to be responsible for endothelial cell activation, the induction of metalloproteinases and adhesion molecules, angiogenesis, regulation of inflammatory cytokines, bone erosion and fibroblast, keratinocyte and enterocyte activation. Reduced expression of adhesion molecules and cellularity in RA synovium after TNFa inhibition may support that the anti-inflammatory effects could be partly explained by down regulation of cytokineinducible vascular adhesion molecules in synovium, with a consequent reduction of cell traffic into joints [19]. In addition to angiogenesis being significantly reduced and lymphangiogenesis increased, circulating levels of IL-1 and IL-6 are also decreased after anti TNFa treatment. Interleukin (IL)-6 is secreted by T-cells and macrophages to stimulate an immune response. It is a pro-inflammatory cytokine involved in immunologic responses during host infection, inflammatory disease, haematopoiesis and oncogenesis. RA patients have been found to have high IL-6 in synovial tissues, so it is implicated in up-regulation of endothelial adhesion molecule expression, in osteoclast maturation and bone erosion. IL-1 is expressed in the epithelial cells, synovial fibroblasts and articular chondrocytes, indicating its main role is in immune defence and inflammation. IL-1 is mainly secreted by macrophages and induces the production of IL-2 by T cells. TNFa is a powerful inducer of IL-1 in animal studies. TNFa and IL-1 can act synergistically to cause further damage to the joint in patients with RA [5]. IL-1 also seems to recruit activated leucocytes and activation synovial cells and the dysregulation of IL-1 receptor antagonist production and failure to modulate the effects of IL-1beta in RA [20] could indicate another key role in the disease pathogenesis. B cells are also important in the pathologic process and may serve as antigen-presenting cells. B cells also produce numerous autoantibodies (e.g. RF) and secrete cytokines. Antibodies form immune complex can activate complement cascade causing tissue damage.

These different classes and targets for biologic DMARDs have been shown to significantly decrease not only the inflammatory activity of RA, but also the radiographic progression. 3.2. PsA Both innate and acquired immunity are currently considered to be responsible for PSA. Previously it has been thought that PsA and psoriasis were mainly Th-1 cell mediated, due to the high levels of IFN-gamma producing cells in psoriasis [21]. As in AS, recent studies have suggested that T helper 17 (Th17) cells play a more central role in the disease process of PsA and psoriasis. Th17 cells induce acquired immune responses against microbes and produce interleukins IL-17A, IL17-F, IL-21 and IL-22. TNF-alpha, IFNgamma, IFN-alpha, IL-6 and IL-1-beta induce the secretion of IL-12 and IL-23, which then cause the differentiation TH-1 and TH-17 cells respectively [22]. IL-23 stimulates Th17 differentiation and then Th17 cells produce IL-17. IL-17 and IL23 have been found at higher levels within the Psoriatic Arthritis synovium and therefore thought to be involved in the osteoclastogenesis and bone erosion process in PsA [23–25]. Elevated frequencies of CD4+ IL-17+ cells were seen in PsA synovial fluid compared to peripheral blood [26]. 3.3. AS AS appears to have a significant genetic link in its pathogenesis. The predominant genetic association is with HLA B27. However, a 2011 study in genome association showed that HLA B27 was linked with AS susceptibility in only 23.3% [27]. Having the gene does not mean you get the disease and more than 10% of patients with the disease do not have the gene [28], so consequently there looks to be other factors responsible for the pathogenesis of AS. The strongest genetic association with HLA B27 and AS is with the MHC region. Several lines of evidence suggest that HLA B27 may not behave like other class 1 molecules: HLA B27 heavy chains can form homodimers that do not contain the b2-microglobulin light chain (a phenomenon also called HLA B27 misfolding). Such homodimers could mediate, or be the target for, a proinflammatory response. This function of HLA-B27 as a MHC class I molecule, could present an ’arthritogenic peptide’ to CD8+ T cells, thus propagating a pathogenic inflammatory response. Despite numerous studies, however, such a peptide has not yet been discovered. The genes outside the MHC region that have also been implicated in AS hereditability are those that are involved in the cytokine production, specifically genes in the IL-17-IL-23 axis, the NFkB and the type 2 T helper pathway (IL4, IL13) [29]. A study in 2011 [8] showed that the number of IL-17+ T cells in facet joints of AS patients was significantly higher than OA patients and a 2010 study demonstrated the potentially pathogenic role of IL-23 [30] in AS: the number of IL-23-positive cells in bone marrow of facet joints of AS patients was significantly higher in comparison to osteoarthritis and no spinal disease. Synovial fluid and peripheral blood of SpA patients however, did not differ in comparison to RA/OA patients or healthy controls. IL-23 has also been found to be increased in comparison to OA patients in the subchondral bone marrow and in fibrous tissue replacing bone marrow in facet joints in AS [9]. These studies add to growing conviction for IL-17/23 being an important therapeutic target. TNF-alpha is accepted as being a potent proinflammatory molecule and has shown to have increased expression in the sacroiliac joints [31], synovium and serum of AS patients. The important role of TNF in these diseases has been proven by their successful treatment with anti-TNF drugs [7]. Despite the success of anti TNF therapy on regression of disease activity [32], to date the evidence of radiographic progression in AS with anti TNF agents treatment, has been that progression was unaltered [33]. However, emerging

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evidence in a more recent study has shown that early initiation and longer duration appears to reduce progression [34]. Regarding radiographic progression in AS, TNFa, lead to an up regulation of Dickkopf-1. This is an inhibitor of osteophyte regulators and increase in which causes increased new bone formation, which is the radiographic hallmark of AS. Inhibition of TNFa and Dickkopf-1, by TNFa blockers, may result to a blockade on syndesmophyte formation after sufficient suppression. Other mRNA and protein expression of cytokines that that have also been found to be higher in AS include IFN-c [35], transforming growth factor beta-1, vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor IL-6 and soluble IL-2 receptor. The latter was shown to have a positive association with fatigue and pain scores and with the Bath AS Functional and Metrology Indices. Other cytokines associated with worse function and higher disease activity in established AS patients, have increased levels of HGF and CXCL8 cytokines [36]. 3.4. TNFa inhibitors Infliximab was the first agent to be licensed. It is a chimeric (one-quarter murine and three-quarters human) monoclonal IgG1 antibody. This was closely followed by Etanercept, the second biological agent licensed for RA in 1998, which is a soluble p75 TNFa receptor IgG1 fusion protein that is made up of two TNFa receptors. These are bound to the Fc portion of IgG, therefore bivalent binding two TNFa molecules per Etanercept molecule. Adalimumab and Golimumab are two fully human anti-TNFa monoclonal antibodies and then Certolizumab, a polyethyleneglycolated Fab’ fragment with anti-TNFa reactivity. The above five TNFa inhibition agents have been shown to be effective for the treatment of RA, PsA and AS, which have all been approved for this indication both in the European Community and the USA. Of the TNFa inhibition agents, Infliximab and Adalimumab are preferred for rapid control of skin psoriasis by the British Association of Dermatology (BAD) [37]. 3.5. IL-1ra Following anti-TNFa blockade, alternative cytokines were targeted for the development of new treatments. Anakinra, an IL-1 receptor antagonist, was licensed for the treatment of RA in 2006. However it has been shown to be less potent than the TNFa inhibitors in most patients [38,39] and as a result, is used less frequently now. At present, Anakinra does not seem to have a role in the treatment of SpA. 3.6. IL-6 inhibitor Tocilizumab is a widely used humanised anti-IL-6 receptor monoclonal antibody, which has been licensed for the treatment of RA [40]. In clinical trials, Tocilizumab reduced disease activity and radiographic joint damage. Sarilumab is the first fully-human monoclonal antibody directed against the IL-6 receptor (IL-6R). It is subcutaneously delivered and has completed its phase 3 trial in RA patients who were inadequate responders to methotrexate therapy. It met the ACR70 for at least 24 consecutive weeks and showed sustained improvement in signs and symptoms of RA after 52 weeks [41]. Sarilimumab is in phase III trials currently being compared directly to Etanercept in the RA-COMPARE study as a second line biologic agent. Olokizumab, another humanised anti-IL6 monoclonal antibody, presented its phase IIb trial data in moderate-to-severe RA who had previously failed TNF inhibitor therapy. 221 randomised patients showed that Olokizumab produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12,

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compared to placebo. It demonstrated similar efficacy to Tocilizumab across multiple endpoints and no new safety signals were identified [42]. Sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active Rheumatoid Arthritis (RA) despite methotrexate therapy. The primary endpoint (ACR50 at week 12) was achieved with sirukumab 100 mg [43]. Safety results through 38 weeks were consistent with other IL-6 inhibitors. Promising findings in a phase IIb study using Clazakizumab, a humanised anti-IL-6 monoclonal antibody, for RA patients have also been reported [44]. The combination of MTX and Clazakizumab (80, 160 and 320 mg intravenously at day 1 and week 8) was associated with rapid and significant improvements in disease activity as measured by ACR20 and DAS28 in 127 RA patients with MTX inadequate responders within 12/16 weeks after treatment. Overall the safety profiles were similar between the five anti IL6 mAbs. The ACR20 response rates achieved with tocilizumab, olokizumab, sarilumab and sirukumab were significantly higher than with placebo. The pathological relevance of the difference between the three serum IL-6 and the two soluble/membrane IL-6R remains unclear [45]. Anti-IL-6R mAbs indiscriminately affect both the membrane form and the soluble form of the receptor, but results suggest that anti-IL-6 mAbs could inhibit IL-6 from binding to soluble receptor or membrane receptor, which results in a similar efficacy profile.

3.7. JAK kinase inhibitor The JAK kinases are cytoplasmic protein tyrosine kinases that are essential for signal transduction from the plasma membrane receptors. Cytoplasmic domain of type I and II cytokine receptors binds to members of a specific kinase family, known as the Janus kinases (Jaks) which include Tyk2, Jak1, Jak2 and Jak3. These cytokine receptors then signal to different Jaks, which are activated on cytokine binding. Jaks then catalyse the transfer of phosphate from ATP to various substrates such as cytokine receptors. Important JAK substrates are the STAT DNA binding proteins [46]. Phosphorylation of STATs promotes their nuclear accumulation and regulation of gene expression. Tofacitinib is an orally administered Janus kinase (JAK kinase) inhibitor that decreases a number of cytokine signalling. Tofacitinib inhibits Jak3 and Jak1 and to a lesser extent Jak2 (IL-3, IL-5 and GM-CSF as well as erythropoietin and IFN-c). It has little effect on Tyk2 [47]. Jak3 inhibition blocks IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines and Jak 1 inhibits of the gp130 family including IL-6 and IL-11, as well as the type II cytokine receptor family such as interferon (IFN)-a/b, IFN-c and IL-10 [48]. Blocking of JAK1/2 interferes with the differentiation of IFN-c producing Th1 cells and blocks the generation of pathogenic Th17 cells dependent on IL23 [47,49]. Tofacitinib oral monotherapy results showed significant reduction in signs and symptoms of active RA after three months of treatment compared with placebo (ACR20 of 60 versus 27%) [50] in a randomized trial of 611 patients with an inadequate response to one or more synthetic or biologic DMARD. It has also shown benefit in combination with Methotrexate in patients who have not had an adequate response to Methotrexate as a monotherapy, and was comparably effective to an anti TNFa in this setting [51]. Tofacitinib reduced disease activity in RA in a series of phase II/III trials, including patients with inadequate responses to Methotrexate, other traditional synthetic DMARDs and TNFa inhibitors [50,52–55]. The potent inhibition of JAK signaling can lead to some important side effects such as severe infections. However, severe infection rates were comparable to those seen with other biologic

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Table 2 Comparison of main pathogenesis and involvement between RA, PSA and AS.

Pathogenesis Stereotypical joints affected Extra articular involvement

Major Cytokines Involved Therapy

RA

PSA

AS

RF and ACPA Metacarpophalangeal joints

HLA-B27. Th17 cells, Th1 cells Proximal and distal interphalangeal joints

HLA-B27 Spine and sacroiliac joints

Lung fibrosis, pleural effusions, pleuritis, atherosclerosis, pericarditis, lymph node and spleen enlargement, nerve entrapment, skin, scleritis, sicca symptoms, osteoporosis TNF, IL-6, IL-1 [5], IL-2 and IFN gamma

Enthesitis, skin, iritis

Uveitis, pulmonary fibrosis, pleuritis, aortic incompetence, cardiomegaly, conduction defects, osteoporosis

TNF, IFN gamma, IL-17 [6], IL-23, IL-12, IL-21

Steroids, NSAIDs, Synthetic DMARDs [10–12], Anti TNF, Abatacept, Tocilizumab, Rituximab

NSAIDs, Synthetic DMARDS [13,14], Anti TNF, Ustekinumab [15]

TNF [7], IL-17 [8], IL-23 [9], IFN gamma, TGF beta-1, VEGF, IL-6 NSAIDs, Synthetic DMARDs if peripheral involvement, Anti TNF [16].

22.8% of the placebo group achieved ACR20 at week 24 (p < 0.0001). This study included only biologic naïve patients, but PSUMMIT-2 enrolled patients biologic naïve (n = 132) as well as TNF failure patients (n = 180). 35.6% patients previously treated with anti-TNF achieved ACR20 in comparison to 14.5% of the placebo arm. The studies were combined to show that Ustekinumab also inhibited radiographic progression of joint damage, assessed via PsA-modified van der Heijde-Sharp (vdH-S) scores, in patients with significant PsA [60]. Ustekinumab is approved for treating moderate to severe psoriasis and PsA, as established in large phase three trials [15]. Ustekinumab was associated with a reduction of signs and symptoms in active AS and was well tolerated [61]. Please see Table 3 for a summary of cytokine therapies and outcomes. Apremilast, an oral inhibitor of phosphodiesterase 4 (PDE4) for cyclic adenosine monophosphate (cAMP) results in a decreased induction of TNFa, IL-23 and an increase in IL-10 [62]. Although not superior to anti-TNF biologic, Apremilast is now an option for treating active Psoriatic Arthritis following failure of a synthetic DMARD (Table 2).

DMARDs [56] although reactivation of zoster infection appeared more common. A number of oral JAK inhibitors with different specificity for JAK isoforms are currently being developed. These include promising investigation into the testing of Baricitinib, Lestaurtinib, INCB039110, GSK2586184, VX501 and GLPG063. Clinical trials of these agents will reveal whether more selective inhibition of JAK isoforms confers additional benefit or risk. 3.8. IL23 and IL-12 IL-12 and IL-23 are heterodimeric cytokines. Both cytokines have a 40-kDa heavy chain (p40) but having different light chains: p35 in IL-12 and p19 in IL-23. Their respective receptors also share one subunit (IL-12Rb1). Despite structural similarity, IL-12 and IL-23 have discrete roles in the regulation of T-cell immunity. IL-23 is critical for maintaining T helper (Th)-17 cells phenotype and to acquire the full effector function [57]. Th-17 cells play a role in inflammation and tissue damage and appear to be implicated in the immunopathophysiology of PsA [58] and AS. IL-12 is an important factor for the differentiation of naïve T-cells into IFNc-producing Th1-cells. Ustekinumab is a human immunoglobulin G1j monoclonal antibody that binds to the common p40-subunit shared by IL-12 and IL23. In PSUMMIT-1 study of 615 patients, Ustekinumab treatment significantly improved active PsA compared to placebo [59]. 49.5% in the higher dose 90 mg Ustekinumab group in comparison to

4. New developments 4.1. Anti-IL-17 4.1.1. IL17 IL-17 is produced by Th17, mast cells, Tcells and some dendritic cells (reference). It has two isoforms A and F and binds to IL-17R.

Table 3 Cytokine therapies and their targets. Cytokine therapy

Medication

Disease

Outcome

Anti TNF

Infliximab Adalimumab Golimumab Etanercept Certolizumab

RA/PSA/AS

Infliximab and Adalimumab preferred for skin psoriasis by BAD [63]

Anti IL-1

Anakinra [39]

RA

Less potent that anti-TNF treatment [64]

IL-6 Inhibition

Tocilizumab [40] Sarilimumab [41] Olokizumab [45] Sirukumab [43] Clazakizumab [44]

RA

Tocilizumab reduces disease activity and radiographic progression

Jak Kinase Inhibition

Tofacitinib Baricitinib Lestaurtinib

RA

ACR 20 achieved in comparison to placebo [50]

IL-12/23

Ustekinumab

PSA

Significant improvement in active PSA and inhibited radiographic progression [59]

IL-17

Secukinumab Ixekizumab Brodalumab [65]

AS

Secukinumab reduced activity of AS [66] Ixekizumab EULAR response criteria met in 73% [67]

C. Thompson et al. / Cytokine 86 (2016) 92–99

IL-17 induces the production of cytokines including IL-6, TNFa, TNFb, G-CSF, GM-CSF, chemokines and prostaglandins (reference). IL-17 is thought to play an important role in joint degradation, demonstrated in the collagen-induced arthritis (CIA) model in mice, IL-17A overexpression accelerated development of joint degradation and enhanced the severity of synovial inflammation and bone erosion [68]. A second study with human rheumatoid synovial and bone explants showed that IL-17A enhanced bone resorption and collagen degradation, and blocked collagen synthesis and bone formation [69]. IL17 pathway has been implicated in mediating AS disease activity [70]. Despite IL-17A producing cells being increased in the synovial fluid of patients with PSA [71,72], ongoing clinical trial have yielded modest responses in PsA using Secukinumab. Secukinumab is a high-affinity fully human monoclonal anti-human interleukin-17A (IL-17A) antibody of the IgG1/kappa isotype. It rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial [66]. Secukinumab was compared with placebo and Etanercept in RA patients and unfortunately failed to meet its primary endpoint of 20% reduction in symptoms by ACR20 rate at week 16, in a phase II trial reported in 2010 [73]. This raised doubts about IL-17 as a target for RA, however, further trials are ongoing into AS, results due in September 2015. Another, anti-IL-17A monoclonal antibody, Ixekizumab, indicated that it was better than placebo in phase II trial. EULAR response criteria at week 12 was 73% in the 80 mg Ixekizumab group compared to 44% of placebo-treated patients (P < 0.05) [67]. Furthermore, it was effective in patients who had previously failed on TNFa inhibitors. The safety profile was similar to other biological agents. Brodalumab is a fully humanised anti-IL-17 receptor monoclonal antibody, which showed equivocal results. The primary endpoint was ACR50 at week 12, which was achieved by 10–16% of patients in the Brodalumab groups compared with 13% of those in the placebo group. Mean changes from baseline in DAS28 also did not differ significantly between Brodalumab and placebo groups [65]. 4.1.2. IL-27 IL-27 is emerging a new potential target in RA. Previously thought to enhance inflammation [74], there is increasing evidence the IL-27 has both pro- and anti-inflammatory roles. Increased levels of IL-27 have been measured in the synovial fluid of RA patients as compared to controls [75]. However, studies using the collagen-induced arthritis murine model have highlighted the therapeutic potential of IL-27, where both local and systemic IL-27 delivery ameliorates arthritis severity [76,77]. Here, serum and joint levels of IL-17 and IL-6 were reduced by IL-27 treatment, resulting in decreased IL-17-mediated monocyte recruitment and angiogenesis. These observations reflect the ability of IL-27 to inhibit the generation of pro-inflammatory IL-17-producing T helper (Th17) cells [78]. Interestingly, through evaluation of RA synovial tissues it was recently shown that local IL-27 expression decreases the incidence of ectopic lymphoid structures via effects on Th17 cells and genes associated with their development and activity [79]. Such observations advocate the development of IL-27-based biologics for the treatment of RA. 5. Summary With ever emerging evidence that different cytokines appear to play key roles in different inflammatory conditions, there is not yet

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