FormalPara Key Points

New targets for psoriatic arthritis (PsA) treatment have been identified and new molecules approved. Ustekinumab, secukinumab, and apremilast have shown efficacy and safety in PsA patients and represent new treatment options beyond the inhibition of tumor necrosis factor (TNF)-α.

Further clinical trials on other molecules targeting different mechanisms are ongoing, providing possible future new treatment strategies for PsA.

1 Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by the combination of arthritis and psoriasis and by a variety of clinical characteristics and disease courses [1]. Some patients have mild disease that can be responsive to therapeutic intervention, while others have an erosive arthritis that is often refractory to several treatments and potentially associated with functional disability and poor quality of life [1, 2]. With an increasing understanding of the immunologic processes underlying the pathogenesis of disease, PsA therapy has evolved. In this scenario, the goals of treatment include inhibition of the structural damage and improvement of quality of life [3]. The introduction of tumor necrosis factor (TNF)-α inhibitors dramatically changed the outcome for patients with PsA. Data from over 10 years’ experience with randomized controlled trials (RCTs) and observational studies have proven the efficacy of anti-TNFα in all PsA domains (peripheral arthritis, axial involvement, enthesitis, dactylitis, and extra-articular manifestations) [4]. These agents have proven to have significantly better responses than placebo in double-blind placebo-controlled RCTs, with an American College of Rheumatology (ACR)-20 improvement criteria of 51–59 % with anti-TNFα versus 9–24.3 % with placebo over 12–24 weeks of treatment [5]. Etanercept, infliximab, and adalimumab have been compared in a single randomized non-blinded study in 100 patients with peripheral PsA. Clinical and laboratory indices showed similar favorable outcomes for all of these drugs [6]. In two indirect comparison meta-analyses, adalimumab, etanercept, golimumab, and infliximab showed no important differences in effectiveness and safety [7]. Switching to a second-line anti-TNFα therapy proved to be efficacious in non-responders or in patients with PsA experiencing adverse events (AEs) with the first anti-TNFα; however, the probability of retaining a response to a second anti-TNFα was lower than for the first treatment, and some PsA patients tended to not exhibit a good response to second or further anti-TNFα treatments [8]. Moreover, a limitation to anti-TNFα treatment is the appearance of de novo psoriasis-like lesions [9]. TNF-inhibitor biosimilars have recently been approved: infliximab and etanercept biosimilars have been tested in patients with rheumatoid arthritis and approved in Europe for all infliximab and etanercept indications, including PsA, while US FDA approval is pending for an adalimumab biosimilar. The use of biosimilars has possible budgetary implications [10]. Despite improved therapeutic benefits with TNFα inhibitors, disease control in non-responders to traditional disease-modifying anti-rheumatic drugs (DMARDs) and/or anti-TNFα remains unmet. In recent years, a more in-depth understanding of the pathophysiology of psoriasis and PsA has led to the discovery of several cell pathways and cytokines involved in the development of synovitis and in the other clinical manifestations of PsA. T-helper (Th) cells producing interleukin (IL)-17 (Th17 cells, which also produce TNFα, IL-21, and IL-22) seem to play a role in chronic inflammatory conditions and are stimulated by IL-23, which is highly expressed in psoriatic plaques, synovium, and enthesis. The Th17-related cytokines IL-17 and IL-23 are expressed in the joints of PsA patients, and published data support that blocking TNFα and IL-1β, IL-6, IL-18 and IL-23 may be effective in PsA [11, 12]. Other molecules such as phosphodiesterase (PDE)-4, intracellular kinase, and costimulatory proteins likely have a role in the pathogenesis of PsA. The aim of this paper is to review the current potential drugs for the treatment of PsA beyond TNFα inhibition. We searched MEDLINE and Embase for RCTs, longitudinal observational studies (LOS), clinical studies, conference abstracts, case reports, and review articles. The following search terms were used and combined: psoriatic arthritis AND IL-12/23, IL-23p19, IL-17, IL-6, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), janus kinase inhibitors, PDE4 inhibitors, anti-CD20. Inclusion criteria included publication from January 1999 to October 2015; English-language articles or foreign-language articles with English abstract; and human studies.

2 Inhibition of Interleukin (IL)-12/23 and IL-17A in Psoriatic Arthritis (PsA)

IL-12 is a heterodimer comprising a 35-kDa light chain (known as p35) and a 40-kDa heavy chain (known as p40). The two receptor chains for IL-12 (12Rβ1 and IL-12Rβ2) activate the Janus kinase (JAK)–STAT (signal transducer and activator of transcription) pathway of signal transduction. IL-12R is expressed mainly by activated T cells and natural killer (NK) cells but also on other cell types, such as dendritic cells (DCs) and B-cell lines. IL-12R is undetectable on most resting T cells, but it is expressed at a low level by NK cells, which probably explains the ability of these cells, and possibly of certain subsets of T cells, to respond rapidly to IL-12. Similar to other pro-inflammatory cytokines, the production of IL-12 is strictly regulated by positive and negative regulatory mechanisms. Products from microorganisms (including bacteria, intracellular parasites, fungi, double-stranded RNA, bacterial DNA, and CpG-containing oligonucleotides) are strong inducers of IL-12 production by macrophages, monocytes, neutrophils, and DCs; the relative efficiency of the various inducers depends on the differential expression by phagocytes and DCs subsets of the Toll-like receptors that these products engage. IL-12 seems to play an important role in host innate response to bacteria, viruses, and fungi, leading the activation of Th1 response [13]. It was found that IL-12 p40 associates with not only IL-12 p35 but also another molecule, p19, to form the heterodimeric cytokine known as IL-23 [14]. IL-23 binds to a receptor that is formed by IL-12Rβ1 and a new second chain, IL-23R. IL-23 induces the same JAK/STAT signaling molecules as does IL-12 (JAK2, TYK2, STAT1, STAT3, STAT4, and STAT5), but it induces different DNA-binding STAT dimers, possibly explaining the overlapping, but not identical, activities of IL-12 and IL-23 [13]. IL-12 and IL-23 play an important role in the pathogenesis of psoriasis and PsA: mutation in the IL-23 receptor gene and the IL-12 gene have been associated with susceptibility to psoriasis, inflammatory bowel disease (IBD) and PsA [11, 15]. Furthermore, IL-12 and IL-23 are essential for the induction and maintenance of the Th1/Th17 immune response, which are the two major phenotypes present in PsA and psoriasis [16]. IL-23 activates Th17, which produces IL-17, activating DCs to produce IL-12, thereby stimulating Th1. Moreover, IL-23 is essential for the proliferation and terminal differentiation of CD4+ Th17 T cells, maintaining IL-17 production, and ultimately driving the pathogenicity of these cells in multiple autoimmune models [16, 17]. The IL-17 family includes six members (IL-17A-F), and several lines of evidence suggest a role for IL-17 signaling in the pathogenesis of PsA. Polymorphisms associated with susceptibility to PsA are present in genetic loci involved in IL-17 signaling, such as IL-12B and TRAF3IP2. Levels of IL-17 receptor A (IL-17RA) and IL-17-positive T cells are elevated in synovial fluid and psoriatic plaques of patients with PsA. Levels of circulating Th17 cells are higher in patients with spondyloarthritis (PsA and ankylosing spondylitis) than in those with rheumatoid arthritis [18]. IL-17 has also been implicated mechanistically in both inflammation and bone remodeling in a murine model of spondyloarthritis: abundant in synovial fluids, IL-17 stimulated osteoclastogenesis in an osteoblast-dependent manner. Furthermore, IL-17 stimulated bone resorption in combination with TNFα in fetal mouse long bones and induced the expression of the receptor activator of NFκB ligand (RANKL—the osteoclast differentiation factor) in osteoclast-supporting cells [19]. Figure 1 summarizes the pathogenic mechanisms linked to IL-12/23 and IL-17. On this basis, the inhibition of the IL-12/23 and IL-17 axis proved to be effective in both the inflammatory and the bone damage aspects of several auto-immune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and spondyloarthritis. This led to the development of drugs targeting this axis. See Table 1 for a summary of targeting agents other than anti-TNFα.

Fig. 1
figure 1

Role of Th1 and Th17 lymphocytes in the pathogenesis of psoriasis and psoriatic arthritis. IL interleukin, Th T-helper cell, TNF tumor necrosis factor

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Table 1 Targeted therapies other than anti-tumor necrosis factor-α agents that are approved or in development for the treatment of psoriatic arthritis (all information from ClinicalTrials.gov)
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2.1 Ustekinumab

Ustekinumab is a fully human immunoglobulin (Ig)-G 1κ monoclonal antibody that binds to the common p40 subunit shared by IL-12 and IL-23, and is the first biologic non-anti-TNFα approved for the treatment of PsA. Ustekinumab therapy rapidly decreased expression of a variety of pro-inflammatory cytokine genes in psoriatic skin lesions, including p19, p40, and IL-17A [20]. Ustekinumab demonstrated efficacy in the treatment of chronic plaque psoriasis [21]. Furthermore, ustekinumab 45 or 90 mg was superior to high-dose etanercept over a 12-week period in patients with psoriasis [22]. In PsA, two phase III studies (PSUMMIT 1 and 2) reported the efficacy and safety of ustekinumab in the treatment of all manifestations of the disease: in PSUMMIT 1, anti-TNFα-naïve patients with active PsA (n = 615) were randomly assigned to placebo, ustekinumab 45 mg, or ustekinumab 90 mg. At week 24, a significantly higher proportion of patients in the ustekinumab groups than in the placebo group achieved an ACR20, ACR50, and ACR70 response. Furthermore, both ustekinumab dosages exhibited efficacy in the treatment of all PsA clinical features (psoriasis, dactylitis, enthesitis, axial involvement) and in the reduction of Health Assessment Questionnaire Disability Index (HAQ) and Short Form (SF)-36 compared with placebo [23]. PSUMMIT 2 also enrolled some patients with PsA previously exposed to TNFα inhibitors. More ustekinumab-treated patients (43.8 % combined) than placebo-treated patients (20.2 %) achieved an ACR20 at week 24. ACR50 (p < 0.05), HAQ improvement (p < 0.001), and Psoriasis Area and Severity Index (PASI) 75 response (p < 0.01) also showed significant treatment differences. All benefits were sustained through week 52. Of note, clinical responses tended to be lower among patients previously exposed to anti-TNFα than among anti-TNFα-naïve patients [24]. The types and numbers of patients who experienced AEs (including serious AEs) were similar across treatment groups in both studies, and no deaths, opportunistic infections, cases of tuberculosis, or malignancies were reported [24]. Ustekinumab treatment was generally safe and well tolerated: the analysis of 2014 PSOLAR (Psoriasis Longitudinal Assessment and Registry) with over 12,000 patients treated with ustekinumab identified no increased risk of malignancy, major adverse cardiovascular events, serious infection, or mortality [25]. Ustekinumab significantly inhibits the radiographic progression of joint damage in patients with active PsA: data from PSUMMIT 1 and 2 showed that, at week 24, significantly higher proportions of ustekinumab-treated (91.7 %) than placebo-treated (83.8 %; p = 0.005) patients demonstrated no radiographic progression, as defined by change in total PsA-modified van der Heijde score from baseline [26]. Clinical and radiographic benefits from ustekinumab treatment were maintained throughout 2-year observation in patients enrolled in PSUMMIT 1 [27].

2.2 Briakinumab

Briakinumab is a monoclonal antibody against the p40 molecule shared by IL-12 and IL-23 that has shown efficacy in psoriasis; however, no data are available in PsA [28]. Of interest, higher numbers of AEs (serious infections, non-melanoma skin cancer, and major cardiovascular events) were observed with briakinumab in a psoriasis trial [28]. Recently, the possibility of selectively inhibiting IL-23, targeting p19, has led to the development of new drugs. In terms of IL-12/23 inhibition through p40 targeting, it is now possible to inhibit the effector cytokines.

Multiple agents targeting IL-17 signaling, including the anti-IL-17A monoclonal antibodies brodalumab, secukinumab, and ixekizumab, have been evaluated for the treatment of PsA, psoriasis, and other inflammatory diseases.

2.3 Secukinumab

The anti-IL-17 drug secukinumab has been tested in two phase III double-blind, placebo-controlled studies. In the FUTURE 2 study, adults aged ≥ 18 years with active PsA were randomly allocated in a 1:1:1:1 ratio to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54 %] patients; odds ratio [OR] vs. placebo 6.81, 95 % confidence interval [CI] 3.42–13.56; p < 0.0001), secukinumab 150 mg (51 [51 %] patients; OR 6.52, 95 % CI 3.25–13.08; p < 0.0001), and secukinumab 75 mg (29 [29 %] patients; OR 2.32, 95 % CI 1.14–4.73; p = 0.0399) versus placebo (15 [15 %] patients). Up to week 16, the most common AEs were upper respiratory tract infections (four [4 %], eight [8 %], ten [10 %], and seven [7 %] with secukinumab 300, 150, 75 mg, and placebo, respectively) and nasopharyngitis (six [6 %], four [4 %], six [6 %], and eight [8 %], respectively). Serious AEs were reported by five (5 %), one (1 %), and four (4 %) patients in the secukinumab 300, 150, and 75 mg groups, respectively, compared with two (2 %) in the placebo group. No deaths were reported [29]. The authors reported that subcutaneous secukinumab 300 and 150 mg improved the signs and symptoms of PsA, suggesting that secukinumab is a potential future treatment option for patients with this disease [29]. However, despite its efficacy in the treatment of PsA features, the authors of the FUTURE 1 study reported that four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95 % CI 0.2–1.5) and two had a myocardial infarction (0.3 per 100 patient-years; 95 % CI 0.0–1.0) as compared with no patients in the placebo group [30].

Ustekinumab and secukinumab have been approved for the treatment of PsA, and have therefore been included in recent European League Against Rheumatism (EULAR) update 2015 [31] and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2015 [32] recommendations as playing an important role in the treatment of predominant enthesitis and dactylitis, as well as in the treatment of disease with predominant joint involvement.

2.4 Brodalumab

Brodalumab, a human anti-IL-17A receptor monoclonal antibody, inhibits the activity of interleukin-17A, interleukin-17F, interleukin-17A/F, and interleukin-17E [33]. In a phase II, placebo-controlled, dose-ranging trial involving patients with moderate-to-severe psoriasis, 77 and 82 % of patients in the brodalumab 140 and 210 mg groups, respectively, had at least 75 % improvement in the PASI score at week 12 as compared with no patients in the placebo group [33]. In a phase II, randomized, double-blind, placebo-controlled study involving patients with PsA, 168 patients were randomized (57 in the brodalumab 140 mg group, 56 in the brodalumab 280 mg group, and 55 in the placebo group). At week 12, the brodalumab 140 mg and 280 mg groups had higher rates of ACR20 than the placebo group (37 % [p = 0.03] and 39 % [p = 0.02], respectively, vs. 18 %); they also had higher rates of ACR50 (14 % [p = 0.05] and 14 % [p = 0.05] vs. 4 %). Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR20 response rates in the brodalumab 140 and 280 mg groups were 51 and 64 %, respectively, as compared with 44 % among patients who switched from placebo to open-label brodalumab [34]. At week 12, serious AEs had occurred in 3 % of patients in the brodalumab groups and in 2 % of those in the placebo group [34]. Brodalumab has recently been submitted to regulatory authorities for approval in psoriasis.

2.5 Ixekizumab

Another IL-17 inhibitor, ixekizumab, has shown promising results in the treatment of plaque psoriasis and IBD [35] and is in pre-registration for use in psoriasis. SPIRIT-P1 and SPIRIT-P2 are current phase III multicenter, randomized, double-blind, active and placebo-controlled studies on the efficacy and safety of ixekizumab in patients with active PsA (ClinicalTrials.gov Identifier: NCT01695239 and NCT02349295).

3 Inhibition of Phosphodiesterase (PDE)-4

Phosphodiesterases (PDEs) are the enzymes that hydrolyze and degrade cyclic adenosine monophosphate (cAMP) [36]. PDE4 is a cAMP phosphodiesterase widely expressed in hematopoietic cells (e.g., myeloid, lymphoid), non-hematopoietic cells (e.g., smooth muscle, keratinocyte, endothelial), and sensory/memory neurons [37]. PDE4 genes (A, B, C, and D) exhibit distinct target and regulatory properties, and each of these genes can produce multiple protein products due to messenger RNA (mRNA) splice variants: gene expression resulting in approximately 19 different type of PDE4 proteins that fall into either short or long isoform categories. The major PDE4 isoforms expressed in leukocytes are PDE4 B2 (short isoform) and PDE4 D3 and D5 (long isoforms) [38]. PDE4 regulates leukocyte responses, which includes the pro-inflammatory actions of leukocytes (e.g., monocytes, T cells, neutrophils), airway/vascular smooth muscle constriction, and neurotransmitter signaling through adenylyl cyclase-linked G-protein. Evidence of a role for PDE4 in inflammatory responses derives from different observations, mostly based on the use of non-selective and selective inhibitors: it has been demonstrated that lipopolysaccharides (LPSs) selectively induce PDE4B2 mRNA expression in human circulating monocytes, and PDE4A4 and PDE4B2 were detected at higher levels in peripheral blood monocytes of smokers than in non-smokers [39]. Monocytes and macrophages are the main producers of the pro-inflammatory cytokine TNFα, the levels of which decrease upon inhibition of PDE4 [40]. The production of TNFα, IL-2, IL-4, and IL-5, and the proliferation of T lymphocytes, are all dependent upon PDE4 activity. It has been shown that inhibition of protein kinase A (PKA) increases T-cell receptor-induced immune responses, and that inhibition of PDE4 blunts T-cell cytokine production. Moreover, overexpression of PDE4 results in augmented T-cell receptor/CD28-stimulated cytokine production. PDE4 is recruited to the cell surface upon cross-ligation of CD28 and T-cell receptors, where it can reduce local cAMP levels, which finally leads to cytokine production by T cells [41]. Production of IL-12 in macrophages, which is important for the differentiation of Th 1 cells, is also regulated by PDE4 [42]. This indicates that PDE4 is a key enzyme in the production of cytokine and pro-inflammatory mediators. Given this, PDE4 inhibitors have been tested in some immune-mediated diseases.

3.1 Apremilast

Apremilast is a selective inhibitor of PDE4. It binds to the catalytic site of the PDE4 enzyme, thereby blocking cAMP degradation. The compound did not demonstrate any marked PDE4 subfamily selectivity, thus does not represent a PDE4-subtype-selective inhibitor [41]. With respect to human T lymphocytes, apremilast inhibits the synthesis of T-cell-derived cytokines in vitro. This includes the expression of IL-2 and interferon (IFN)-γ [43]. With respect to neutrophils, apremilast inhibits the production of IL-8, which is a chemokine required for neutrophil chemotaxis to inflamed tissues, and TNFα production from ultraviolet (UV)-treated keratinocytes, which is important for inflammatory skin diseases such as psoriasis. In contrast, apremilast did not have any significant effect on normal keratinocyte proliferation or viability, suggesting that it would not have an unwanted thinning effect on skin [41]. The efficacy and safety of apremilast in the treatment of moderate-to-severe plaque psoriasis were evaluated in two multicenter, randomized, double-blind, placebo-controlled, phase III trials of comparable design: ESTEEM 1 (N = 844) and ESTEEM 2 (N = 413). Patients were randomized 2:1 to receive apremilast 30 mg twice daily or placebo for 16 weeks. At 16 weeks, all patients were treated with apremilast through week 32, followed by a randomized withdrawal phase through week 52 and an optional 4-year, open-label extension phase to assess safety. The approval of apremilast was based on the data at 16 weeks [44, 45]. At week 16, the proportion of patients achieving a PASI75 response was significantly greater (p < 0.0001) in the apremilast-treated group than in the placebo group in both studies (ESTEEM 1: 33 vs. 5 %, respectively; ESTEEM 2: 29 vs. 6 %, respectively). Compared with placebo, significantly more apremilast-treated patients achieved a score of 0 or 1 on the patient global assessment (ESTEEM 1: 4 vs. 22 %, respectively; p < 0.0001; ESTEEM 2: 4 vs. 20 %; p < 0.0001) [44, 45]. Significant results were also noted in favor of apremilast in the percent change from baseline in affected body surface area (BSA) and PASI score and in the percentage of patients achieving a PASI50. Three trials have evaluated the efficacy and safety of apremilast in PsA. The PALACE 1 trial was an international, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of apremilast in patients with active PsA despite previous use of DMARDs and/or biologic therapy [46]. In this trial, 504 patients were randomized to placebo (n = 168), apremilast 20 mg twice daily (n = 168), or apremilast 30 mg twice daily (n = 168). At week 24, placebo-treated patients were re-randomized to either the apremilast 20-mg arm or the apremilast 30-mg arm. Prior use of a biologic was reported by 24 % of the 504 randomized patients. The primary efficacy endpoint was the proportion of patients achieving an ACR20 at week 16: significantly more patients achieved this endpoint in the apremilast 20-mg group (31 %, p = 0.0140) and in the apremilast 30-mg group (40 %, p = 0.0001) than in the placebo group (19 %) [46]. Significant improvements in additional secondary efficacy measures at week 24 were also noted with apremilast therapy (e.g., ACR20, ACR50, ACR70, and physical functioning). Study discontinuation because of AEs was comparable among groups (6 % for apremilast 20 mg, 7 % for apremilast 30 mg, and 5 % for placebo) [46]. The most frequently reported AEs with apremilast were largely mild to moderate in severity and dose dependent. These included diarrhea (11 and 19 % with apremilast 20 and 30 mg, respectively, vs. 2 % for placebo) and nausea (10 and 19 % with apremilast 20 and 30 mg, respectively, vs. 7 % for placebo). These AEs presented early and were self-limiting, accounting for few study discontinuations. The 52-week results of the PALACE 1 trial demonstrated that treatment efficacy was maintained in patients who continued treatment with apremilast; ACR20 responses of 63 and 55 % were reported with apremilast 20 and 30 mg, respectively [47]. Furthermore, both doses of apremilast were efficacious in reducing the Maastrict enthesitis score (MASES), while none of the two doses significantly reduced C-reactive protein levels and dactylitis score compared with placebo at week 24. No information was available regarding the efficacy of apremilast in axial disease or about the possibility of achieving disease remission. PALACE 2 and 3 studies are ongoing. Given this information, apremilast has been approved for the treatment of psoriasis and PsA.

As with drugs targeting the IL-12/23 and Il-17 axis, there are no direct head-to-head comparisons of targeted agents in PsA; however, in Table 2 we summarize the common outcome measures for anti-TNFα and novel agents from RCTs in patients with PsA. In this context, a recent meta-analysis stated that the likelihood of achieving an ACR20 response in patients with an inadequate response to a TNFα inhibitor is not significantly different between non-TNFα biologic agents (ustekinumab, secukinumab, apremilast, and abatacept) tested in PsA [48].

Table 2 Summary of key clinical outcomes from randomized controlled trials of targeted agents for psoriatic arthritisa
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4 Anti-CD20 Target Therapy

This target therapy has never been formally investigated for PsA or psoriasis. Few data are available from case series or case reports. In fact, Mease [49] showed that B-cell lymphoid aggregates were present in PsA synovial tissue, and the partial remission of psoriasis was reported in patients receiving the anti-CD20 therapy with rituximab for non-Hodgkin lymphoma. Furthermore, Cohen [50] described a case in which rituximab led to a dramatic clinical improvement and possible structural effects in a patient with severe PsA. Only a few reports have investigated the effect of B-lymphocyte-depleting therapy in PsA. Overall, small cohorts of patients with PsA receiving rituximab with the same regimen as used in rheumatoid arthritis (two intravenous injections of rituximab 1000 mg separated by an interval of 2 weeks) showed only a slight improvement in joint counts and a low impact on skin lesions [51].

5 Inhibition of IL-6 in PsA

IL-6 is a key pro-inflammatory cytokine involved in the pathogenesis of many autoimmune diseases, including PsA: IL-6 promotes synovitis by inducing neovascularization, infiltration of inflammatory cells, and synovial hyperplasia. IL-6 also causes bone resorption by inducing osteoclast formation via the induction of RANKL in synovial cells and cartilage degeneration by inducing the production of matrix metalloproteinases in synovial cells and chondrocytes. Moreover, IL-6 is involved in autoimmunity by altering the balance of Th17 cells by inducing the differentiation of Th17 cells from naıve CD4+ T cells [52]. Two monoclonal antibodies are described in the present review.

5.1 Clazakizumab

Clazakizumab is an anti-IL-6 antibody currently in phase IIb clinical trials in PsA. It was effective in controlling clinical features of PsA, such as arthritis, enthesitis, and dactylitis, with modest skin benefits [53].

5.2 Tocilizumab

Tocilizumab is a recombinant humanized monoclonal antibody that inhibits the signal transduction of IL-6 by preventing it from interacting with the membrane-expressed receptor [54]. It has been approved for the treatment of moderate and severe rheumatoid arthritis in adults who have inadequately responded to or been intolerant of previous DMARD or anti-TNFα therapy (in Europe in January 2009 and the USA in 2010). Treatment with tocilizumab has also been reported to be efficient in treating Castleman’s disease, adult-onset Still’s disease, Crohn’s disease, Takayasu arteritis, and juvenile inflammatory arthritis [55, 56]. A recent case study of two patients treated with tocilizumab for 6 months did not show a significant improvement in arthritis or skin lesions, although it did lead to a decrease in serum C-reactive protein in both patients [57]. Although there is a theoretical rationale for the potential efficacy for tocilizumab in PsA, evidence in this disease and in spondyloarthritis is lacking. Sieper et al. [58] recently reported on a phase II study of tocilizumab for ankylosing spondylitis. They enrolled 102 patients with ankylosing spondylitis, and 51 patients were treated with tocilizumab for 12 weeks. Although a decline in C-reactive protein levels was observed, symptoms did not improve [58]. Other data in spondyloarthritis has shown similar results [59].

6 Cytotoxic T-Lymphocyte-Associated Protein-4 (CTLA-4) Inhibition

Abatacept, a fusion protein that resembles the extracellular domain of CTLA-4 linked to a modified Fc portion of human immunoglobulin IgG1, inhibits T-cell activation. Abatacept was tested in PsA because the inhibition of T-cell co-stimulation should lead to the suppression of Th1 and Th17 functions with a decrease in cytokine release as in rheumatoid arthritis [60]. Abatacept has demonstrated efficacy in rheumatoid arthritis [61]. In PsA, abatacept was tested in a phase II multicenter, randomized, double-blind, placebo-controlled trial [62]. The percentage of patients achieving ACR20 response was slightly higher for abatacept 10 and 30/10 mg/kg (two initial doses of 30 mg/kg, followed by 10 mg/kg) than for placebo [62]. However, the efficacy of the molecule on skin, entheseal, and extra-articular manifestations appeared low.

7 Inhibition of the JAK-STAT Pathway

JAKs are intracellular tyrosine kinases that participate in the cytokine-signaling pathway (including IL-2, IL-12, IL-6, and many others) by associating with specific cytokine receptors and facilitating activation of STAT proteins [63]. JAKs consist of four members: tyrosine protein kinase 2, JAK1, JAK2, and JAK3. Abnormalities in the expression/activity of different transcription factors involved in the JAK/ STAT signaling pathway have been hypothesized to play a role in the pathogenesis of psoriasis. STAT1 expression and activation is increased in psoriatic skin. In the synovial fluid of clinically active joints of patients with PsA, activation of JAK1/STAT3/STAT1 and protein kinase Cδ phosphoproteins that may drive the local inflammation is enhanced, and Th17 showed expansion [64, 65]. Tofacitinib is an oral inhibitor of JAK3 and JAK1, and—to a lesser degree—JAK2. It blocks cytokines such as IL-2, IL-4, IL-15, and IL-21 by blocking JAK3 and also inhibits signaling of IFNγ, IL-6, and—to a lesser extent—IL-12 and IL-23 by blocking JAK1 and JAK2. Many of these key cytokines use the JAK/STAT pathway to exert their effects rendering them amenable to therapeutic blockade with JAK inhibitors (jakinibs). Given the apparent pathogenic role of a variety of cytokines such as IL-6, IL-12, IL-23, IFNs, and granulocyte macrophage colony-stimulating factor (GM-CSF) in rheumatoid arthritis, psoriasis, IBD, ankylosing spondylitis, and other autoimmune diseases, the ability of jakinibs to block such cytokines is likely a major aspect of their mechanism of action [66]. Tofacitinib showed efficacy in rheumatoid arthritis and has been approved for the treatment of this disease [67]. Tofacitinib is now in pre-registration for psoriasis, and phase III studies are ongoing for PsA.

8 Conclusion

Anti-TNFα agents have exhibited efficacy for more than 10 years; remission or low disease activity are achievable targets in spondyloarthritis [68, 69] and PsA [70, 71]. However, approximately 40 % of patients do not respond to anti-TNFα agents and the possibility of inhibiting the radiographic progression of the disease is as yet out of reach. Fortunately, PsA treatment is evolving rapidly: novel therapies that target new molecules are emerging. Understanding of the role of Th17 cells and that of cytokine production together with the pathways involved in immune system activation, have made possible the development of new drugs effective in treating PsA. Some of these agents are now available, and their effectiveness on the various components of the disease could be indirectly compared with anti-TNFα agents. Other mechanisms that have shown efficacy in other conditions such as rheumatoid arthritis have not shown similar efficacy and/or safety when tested as targets for treating spondyloarthritis and PsA.