Autoimmunity Reviews 18 (2019) 583–592 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Review Systemic rheumatic diseases: From biological agents to small molecules T ⁎ Piercarlo Sarzi-Puttinia, , Angela Ceribellia, Daniela Marottob, Alberto Batticciottoc, Fabiola Atzenid a Rheumatology Unit, ASST Fatebenefratelli-Sacco, University of Milan, Italy b Rheumatology Unit, P-Dettori Hospital, Tempio Pausania, Italy c Rheumatology Unit, Internal Medicine Department, ASST Settelaghi, Ospedale Di Circolo - Fondazione Macchi, Varese, Italy d Rheumatology Unit, University of Messina, Messina, Italy ARTICLE INFO ABSTRACT Keywords: The development of biologics and small oral molecules has recently changed the scenario of pharmacologic Biological therapies treatment of systemic rheumatic diseases and it has become a real revolution. These drugs have innovative Biosimilars mechanisms of action, based on the inhibition of specific molecular or cellular targets directly involved in Rheumatoid arthritis disease pathogenesis. Spondyloartropathies This new scenario has lead to a regular update of the management recommendations of several institutions, Psoriatic arthritis such as those for Rheumatoid Arthritis treatment that address the use of conventional and biologic therapies Small molecules Guidelines including TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, ri- Recommendations tuximab, IL-6 inhibitors (tocilizumab and sarilumab), biosimilars and small oral molecules (the JAK inhibitors tofacitinib and baricitinib). Monotherapy, combination therapy, treatment strategies (such as treat-to-target) and the targets of sustained clinical remission or low disease activity are the final goal of the guidelines for rheumatic patients management. In another condition represented by Axial Spondyloarthritis guidelines suggest to start first with non-steroidal anti-inflammatory drugs to improve lifestyle and reduce spine inflammation, but if this is not achieved in 2–4 weeks it is important to consider the use of local therapies (i.e. glucocorticoid injections) or to start biologic therapy such as TNF inhibitors and then eventually switching to another TNF inhibitor or swapping to IL-17 inhibitor. In the case of active Psoriatic Arthritis, guidelines suggest to start with non-steroidal anti-inflammatory drugs and even local glucocorticoid injections especially for oligoarthritis, then to start conventional therapies if lack of efficacy, and finally start biologics or small oral molecules inthe presence of drugs toxicity, unfavorable prognostic factors and still active arthritis. In several cases, active Psoriatic Arthritis patients develop a complex clinical condition with comorbidities such as diabetes, in- flammatory bowel disease and high risk of infections, and for this reason the American College of Rheumatology and the National Psoriasis Foundation have developed specific guidelines for their management. Biologic and new small molecules therapies are very expensive, but the availability of biosimilars offers the opportunity of reducing the treatment cost and significantly decreasing the cost of originators as well. In fact,we live in a period characterized by the need to rationalize costs of these drugs, to allow treating a higher number of patients and to maintain a homogeneous possibility of treatment choice. For these reasons, we need to follow scientific guidelines and patients' clinical conditions to choose the correct treatment, also based on theeconomic burden of therapies. Abbreviations: ANCAs, anti-neutrophil cytoplasmic antibodies; AxSpa, ankylosing spondylitis; BD, Behçet's disease; bDMARDs, biological DMARDs; CCP, cyclic citrullinated peptides; CD, Crohn's disease; cDMARDs, conventional DMARDs; CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; EMA, European Medicines Agency; ESR, erythrocyte sedimentation rate; EULAR, European League against Rheumatism; FDA, Food and Drug Administration; GRAPPA, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; JAK, Janus kinase; JAKin, JAK inhibitors; IBD, inflammatory bowel disease; i.v., intravenous; LFN, leflunomide; mAB, monoclonal antibody; MTX, methotrexate; MTX-IR, incomplete responder to MTX; NPF, National Psoriasis Foundation; NSAIDs,non- steroidal anti-inflammatory drugs; OSM, oral small molecules; PDE4, phosphodiesterase 4; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis;RCT, randomised controlled trial; ReA, reactive arthritis; RF, rheumatoid factor; s.c., subcutaneous; tsDMARDs, targeted synthetic DMARDs; SSZ, sulfasalazine; TNFα, tumour necrosis factor alpha; TNFin, TNF inhibitor; UC, ulcerative colitis; TRAPS, TNF receptor-associated periodic syndrome ⁎ Corresponding author at: Rheumatology Unit, ASST Fatebenefratelli-Sacco, University of Milan, Via GB Grassi 74, 20157 Milano, Italy. E-mail address: [email protected] (P. Sarzi-Puttini). https://doi.org/10.1016/j.autrev.2018.12.009 Received 7 December 2018; Accepted 12 December 2018 Available online 05 April 2019 1568-9972/ © 2019 Elsevier B.V. All rights reserved. P. Sarzi-Puttini, et al. Autoimmunity Reviews 18 (2019) 583–592 1. Introduction golimumab can induce the clinical and endoscopic remission of in- flammatory bowel disease (IBD), which is not true for the soluble eta- The development of biological agents and, more recently, oral small nercept [10]. molecules whose innovative mechanisms of action are based on in- It has been demonstrated that TNFin are effective and well tolerated hibiting specific molecular or cellular targets directly involved indis- in a large proportion of patients involved in RCTs, but primary and ease pathogenesis has revolutionised the pharmacological treatment of secondary failures of TNFin strategies affect 30–50% of patients treated systemic rheumatic diseases. The results of randomised clinical trials in clinical practice, particularly those with long-standing diseases [11]. (RCTs) and real-life reports from national registries have clarified many For this reason, a number of other bDMARDs has been developed and of the aspects of biological disease-modifying anti-rheumatic drugs approved for treatment in the case of the failure of anti-TNFα therapy (bDMARDs) in patients with inflammatory rheumatic disorders, in- (Fig. 1), and they will be discussed in the next paragraphs. cluding their mechanisms of action, efficacy and safety, and the pos- sibility of optimising their use in individual patients in order to ensure 1.1.2. Non-anti-TNFα biological agents for the treatment of RA personalised medicine. However, the data concerning Janus kinase In more recent years, additional biologics with different targets and (JAK) inhibitors only come from RCTs, and we still need to discover mechanisms of action have been developed for the treatment of rheu- from registries and real-life experience what their role in future treat- matic diseases (Fig. 1). ment strategies will be. Abatacept, a recombinant fusion protein that selectively modulates The therapeutic models considered in this review are rheumatoid a co-stimulatory signal necessary for T-cell activation, is currently ap- arthritis (RA), ankylosing spondyloarthritis (AxSpA), and psoriatic ar- proved in the EU for use in patients with highly active and progressive thritis (PsA). RA who have not previously received methotrexate (MTX) or who have inadequately responded to previous treatment with at least one con- 1.1. Biological therapies ventional DMARD (cDMARD) including MTX, or TNFin [12,13]. In phase III trials, beneficial effects on RA signs and symptoms, disease 1.1.1. Biological anti-TNFα agents for the treatment of RA activity, structural damage progression and physical function were seen Tumour necrosis factor alpha (TNFα) is an important host defence with both i.v. or s.c. abatacept regimens, in particular in association molecule involved in the acute phase reaction induced by inflammation with methotrexate [14]. Abatacept was also authorised for the treat- and capable of recruiting other pro-inflammatory mediators after its ment of active PsA [15] in the USA (July 2017) and by the EMA (August release [1]. It is the target of five specific inhibitors (TNFin) that have 2017) (Figs. 1 and 2). been approved since 2000 (Fig. 1): intravenously administered (i.v.) Tocilizumab is an IL-6 receptor antagonist that is approved (with infliximab, and subcutaneously administered (s.c.) adalimumab, cer- and without MTX) for the treatment of adults with moderate to severe tolizumab pegol, etanercept and golimumab [2,3]. All these molecules active RA. Extensive clinical experience with both i.v. and s.c. regimens are monoclonal antibodies (mAbs) or fragments of mAbs, while eta- has firmly established their short- and long-term efficacy and safetyin nercept is a fusion protein composed of the 2 extracellular portions of adults with early-stage or established RA [16]. In clinical trials and the the human TNF receptor 2 (p75 TNF receptor) and the Fc portion real world settings, tocilizumab leads to a rapid and sustained im- (hinge, CH2 and CH3 domains) of human IgG1 (Fig. 1)[4]. Anti-TNFα provement in clinical and radiographic outcomes and the health-related agents have proved to be safe when correctly prescribed and monitored quality of life [17]. The safety profile of tocilizumab is comparable to [5–7] and, over the last 20 years, have been approved for the treatment other immunomodulatory