Abstract
Spondyloarthritis represents a heterogeneous group of articular inflammatory diseases that share common genetic, clinical and radiological features. The therapy target of spondyloarthritis relies mainly in improving patients’ quality of life, controlling articular inflammation, preventing the structural joints damage and preserving the functional abilities, autonomy and social participation of patients. Among these, traditional disease-modifying antirheumatic drugs have been demonstrated to be effective in the management of peripheral arthritis; moreover, in the last decade, biological therapies have improved the approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor α inhibitors are currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs has failed. The aim of this review is to summarize the current experience and evidence about the pharmacological approach in spondyloarthritis patients.
Introduction
Spondyloarthritis (SpA) represents a heterogeneous group of articular inflammatory diseases involving spine, sacroiliac and, less frequently, peripheral joints (asymmetric mono-arthritis or oligo-arthritis), which prototype is represented by ankylosing spondylitis (AS) [Raychaudhuri and Deodhar, 2014]. The clinical spectrum of SpA can be found in patients affected by psoriasis or having familiarity for psoriasis [psoriatic arthritis (PsA)] [Scarpa et al. 2007; Peluso et al. 2015], by inflammatory bowel disease [IBD; enteropathic spondyloarthritis (EASpA)] [Peluso et al. 2013a], or by infectious triggering diseases [reactive arthritis (ReA)] [Selmi and Gershwin, 2014]; it can also be separate from any of these forms, remaining uncharacterized [undifferentiated spondyloarthropathy (USpA)] [Olivieri et al. 2012]. The SpA genetic background provides frequent positivity for major histocompatibility complex molecules, mainly represented by the HLA-B27 antigen, but several predisposing and susceptibility factors can be associated [Chatzikyriakidou et al. 2011].
The main goal of the SpA management is to reduce disease activity and control joint damage, improving the quality of life and preserving the functional abilities of patients as well as autonomy and social participation. The successful management of extra-articular clinical findings of SpA, such as psoriasis, uveitis, and IBD, requires active cooperation between the rheumatologist and other specialists, in collaboration with the primary care physician. Further, information and education of patients represent key factors for improving SpA outcome, as well as rehabilitation represented by home exercises [Olivieri et al. 2014].
In parallel with progress in the understanding of various pathogenetic and clinical aspects of SpA [Atzeni et al. 2014; Scarpa et al. 2008], advances in diagnostics (adoption of new criteria and the use of magnetic resonance [Tillett et al. 2012; Wendling et al. 2012b; Peluso et al. 2012; Pedersen et al. 2012; Soscia et al. 2009]) has given the opportunity to identify early and nonradiographic phases in SpA, which can be useful to prevent and monitor structural damage [Scarpa et al. 2011; Fiocco et al. 2013].
It has been demonstrated that traditional disease-modifying antirheumatic drugs (tDMARDs) are ineffective in the treatment of patients with axial involvement. Specifically, efficacy of methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LFN), and cyclosporine A (CsA) in inhibiting radiologic joint damage still needs to be clarified [Favalli et al. 2014; Wendling et al. 2014].
Meanwhile, therapy has evolved thanks to the growing understanding of the pathogenetic mechanisms of the disease, involving dysfunction and over-secretion of multiple pro-inflammatory molecules, such as tumor necrosis factor (TNF)-α [Fiocco et al. 2014; Chimenti et al. 2013]. As a consequence, the recent introduction of TNF-α inhibitors has offered new perspectives for SpA patients, with impressive improvements of their clinical outcome [Olivieri et al. 2012; Novelli et al. 2014]. Currently, five biological agents that target TNF-α are available [with US Food and Drug Administration (FDA) approval] for the therapy of SpA, namely infliximab (IFX), adalimumab (ADA), etanercept (ETN), golimumab (GOL), and certolizumab pegol (CTZ). These drugs are reasonably safe in SpA, in particular in association with close and careful monitoring.
The aim of this review is to summarize the current experience and evidence about the pharmacological approach in SpA.
From nonsteroidal anti-inflammatory drugs to traditional disease-modifying antirheumatic drugs
According to the recommendations of the Assessment of Spondyloarthritis International Society (ASAS) and the European League Against Rheumatism (EULAR), the first-line therapy of SpA is represented by nonsteroidal anti-inflammatory drugs (NSAIDs) and nonpharmacological treatment [Wendling et al. 2014; Braun et al. 2011]. NSAID therapy effectively controls joint symptoms and signs of axial involvement [Escalas et al. 2010; Benhamou et al. 2010], giving no significant effects on laboratory markers of inflammation [Escalas et al. 2010]; moreover, some studies suggest NSAIDs have beneficial effect on axial structural damage [Wendling, 2013]. When they are contraindicated (i.e. cardiovascular and/or gastrointestinal and/or renal diseases), physical therapy and/or treatment with analgesics should be evaluated as first-line treatment, because they can control articular manifestations in SpA patients.
Recent studies confirm the beneficial effects of physical therapy and self-rehabilitation programs on disease activity and functional status (BASDAI and BASFI) [Eppeland et al. 2013; Staalesen Strumse et al. 2011]. A recent study has shown significantly greater improvements in the BASDAI, motion ranges, and BASFI, with a persistent effect for many months later [Masiero et al. 2011]. On the other hand, analgesic agents can be used in patients with residual pain despite NSAIDs therapy, and in patients with contraindications or intolerance to NSAIDs [Ramiro et al. 2011].
Intra-articular steroid injections into the affected joints can be used mainly for treatment of peripheral manifestations (arthritis, enthesitis, dactylitis) and in the treatment of active sacroiliitis (CT-guided injections) in axial subset [Braun et al. 1996]: they provide rapid but only temporary relief. A recent study has compared locally injected betamethasone to locally injected ETN in patients with refractory enthesitis; the results have shown significant improvements in both groups of patients with no significant differences after 12 weeks [Huang et al. 2011].
Systemic steroids are usually not recommended in the treatment of axial involvement of SpA, because they have adverse effects and there is little data in the literature to confirm their validity. However, these drugs may deserve attention when the peripheral joint manifestations are not well controlled, in the absence of effective or possible treatment options (i.e. in patients with contraindications to TNF-α inhibitors). In these cases, short-term treatment in severe forms (intravenous pulse therapy for 2 weeks) with the lowest possible dosage of systemic steroids have been suggested [Haibel et al. 2012; Peters and Ejstrup, 1992].
The tDMARDs, such as MTX, SSZ, and LFN, are generally not effective in the management of axial and/or entheseal involvement in SpA patients [Braun et al. 2006; Haibel et al. 2005a, 2007]. They can be considered in patients with peripheral involvement who do not respond to NSAIDs and/or local glucocorticoid injections [Kingsley et al. 2012; Dougados et al. 2012]. However, tDMARDs should be selected according to the patient’s clinical profile (i.e. MTX should be given in patients with SpA and cutaneous psoriasis). Some tDMARDs, such as SSZ and MTX, may also improve extra-articular manifestations, such as uveitis and bowel disease in patients with SpA. Moreover, the experts agree that tDMARDs are not indicated in patients with isolated entheseal involvement [van den Berg et al. 2012; Gossec et al. 2012; Ash et al. 2012].
Biological therapies
Since the beginning of 2000, TNF-α-inhibitors are used for the management of SpA. TNF-α inhibitors, usually administrated after the failure of tDMARDs, have the same efficacy in PsA [Atteno et al. 2010; Ritchlin et al. 2009] and in axial involvement of SpA [Baraliakos et al. 2012; Migliore et al. 2012]. It is not well known whether MTX gives an additive or synergistic benefit when used in combination with TNF-α-inhibitors in PsA. Nevertheless, a recent study [Fagerli et al. 2014] revealed that MTX has a role in the retention rate of biological therapy but not in response rate; the results showed it is useful only in association with IFX for its potential value to suppress antibody formation against biological therapies [Atzeni et al. 2013; Bruner et al. 2014]. In the RAPID-ax-SpA study, CTZ was demonstrated to be effective in reducing signs and symptoms of axial involvement in patients with SpA, AS and nonradiographic axial SpA (nr-axSpA) [Landewé et al. 2014]. Moreover, CTZ, in the RAPID–PsA study, showed inhibition of radiographic progression in patients with PsA after 24 weeks of therapy [Landewé et al. 2014]. Although only ADA has been approved for nr-axSpA, [Sieper et al. 2013], ETN [Song et al. 2013], CTZ [Landewé et al. 2014; Song and Rudwaleit, 2013], and IFX [Sieper et al. 2014a, 2014b] have been demonstrated to be effective and safe for patients with this SpA subtype. In arthritis related to IBD, TNF-α inhibitors, with the exclusion of ETN [Sandborn et al. 2001; Song et al. 2008], are used to treat bowel disease and joint involvement [Denmark and Mayer, 2013].
Recently, some studies showed the efficacy of therapy with TNF-α inhibitors in the treatment of extra-articular manifestation of SpA, such as uveitis [Levy-Clarke and Nussenblatt, 2006; van der Horst-Bruinsma and Nurmohamed, 2012]. TNF-α inhibitors significantly reduce the incidence of uveitis flares in patients with AS [Braun et al. 2005]. However, more recently, Guignard and colleagues demonstrated that the incidence of uveitis remained unchanged with ETN treatment, whereas it was dramatically reduced after treatment with IFX and ADA [Guignard et al. 2006]. In a prospective study, a significant decrease in recurrence rate of uveitis during ADA treatment was observed [van Denderen et al. 2014]. There has been a recent observational report showing the utility of GOL in SpA associated with refractory uveitis [Miserocchi et al. 2014]. Although TNF-α inhibitors are effective in the treatment of skin and nail lesions of psoriasis, about 5% of patients may develop an onset or exacerbation of psoriasis during treatment [Kary et al. 2006; Wendling et al. 2008]. TNF-α inhibitors showed quite different effects on the bowel. IFX and ADA are effective in SpA and IBD, while GOL is not approved for the treatment of Crohn’s disease, but only for moderately-to-severely active ulcerative colitis [Braun et al. 2007; Rutgeerts et al. 2005; Sandborn et al. 2007]. In a meta-analysis of trials on the use of TNF-α-inhibitors in patients with AS, it was demonstrated ETN and ADA cause increased incidence of flares or new onset of IBD when compared with IFX [Braun et al. 2007]. Furthermore, in patients with a history of IBD flares, these were more likely to occur in patients with AS receiving ETN or ADA than in those treated with IFX.
TNF-α inhibitors might decrease the cardiovascular manifestations and atherosclerotic cardiovascular risk in SpA patients [Di Minno et al. 2011, 2012, 2015; Costa et al. 2012]. Moreover, regardless of the type of diet, a successful weight loss (⩾5% from baseline values) is associated with a higher rate of achievement of MDA in overweight/obese SpA patients who start treatment with TNF-α inhibitors [Di Minno et al. 2014].
According to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis guidelines (GRAPPA) [Acosta Felquer et al. 2014], in patients with peripheral PsA, administration of at least one tDMARD for more than 3 months is useful.
Before starting TNF-α inhibitor therapy, it is necessary to screen patients for latent tuberculosis and viral infections [Sanduzzi et al. 2012; Atteno et al. 2014] to identify promptly people at high risk of reactivating the disease [Peluso et al. 2013b; Costa et al. 2014].
However, since TNF-α inhibitors in some patients fail to control the disease, or are contraindicated or able to induce paradoxical and side effects, new options in the therapeutic area have been explored in order to offer an alternative to SpA refractory subjects. Loss of efficacy of TNF-α inhibitors could appear over time also in patients who are initially responders to these drugs. New molecules targeting pathways other than TNF-α-mediated one are emerging for the treatment of SpA. However, clinical trials on biological therapies that were conducted over the past years, have showed that they are effective in rheumatoid arthritis (RA), but they have not yielded relevant improvements in patients with axial and/or peripheral SpA.
In detail, abatacept (ABA) has no significant effect on clinical features of SpA in the short term. Recently, Song and colleagues studied the efficacy of ABA in 30 patients with AS (15 TNF-α-inhibitor-naive patients and 15 nonresponders to TNF-α inhibitors) and demonstrated that ASAS-40 was reached by 13% of the TNF-α-inhibitor-naive patients and by none of the nonresponders to TNF-α inhibitors [Song et al. 2011]. More recently, Lekpa and colleagues showed the lack of efficacy of ABA in axial SpA [Lekpa et al. 2012a].
Tocilizumab (TOC) is a humanized monoclonal antibody that competitively inhibits interleukin (IL)-6 by blocking the binding site to the IL-6R, and is approved for patients with refractory RA. TOC is emerging as a potential therapeutic strategy in other rheumatic disorders for its IL-6-mediated effects on immune system and inflammatory processes [Woodrick and Ruderman, 2012; Abisror et al. 2013]. However, TOC did not show any clinical improvement in patients with axial SpA [Lekpa et al. 2012b].
Recently, Sieper and colleagues demonstrated no differences between patients with AS treated with TOC and patients receiving placebo at 12 weeks, although a reduction of C-reactive protein levels was observed in the TOC arm [Sieper et al. 2014c]. However, the decrease of inflammatory markers was not associated with any clinical improvement.
Some case reports have recently been published on treatment of PsA with TOC [Hughes and Chinoy, 2013; Costa et al. 2014]. For two patients, TOC was effective in inducing a resolution of articular manifestations; however, Ogata and colleagues reported an inadequate response to TOC in two PsA patients [Ogata et al. 2012]. TOC could be considered in a subset of PsA patients resembling RA, refractory to conventional and biological (TNF-α inhibitors) therapies, but the number of published reports of use of TOC in PsA is still low.
Sarilumab (SAR) is currently in two phase III studies as a treatment for RA (RA-MOBILITY study). In 2010, a phase III study was started with the aim to evaluate the long-term safety and efficacy of SAR in patients with AS; it was stopped because no improvement in efficacy was observed [Sieper et al. 2012].
Rituximab (RTX) is a chimeric monoclonal antibody against the protein CD20. An open-label study was performed by Song and colleagues on 20 patients with active AS (10 patients were TNF-α-inhibitor naïve), treated with two pulses of RTX, separated by 2 weeks [Song et al. 2010]. At 6 months, the results showed that 40% of patients achieved ASAS-20 and BASDAI-20, while 25% were ASAS-40 and BASDAI-50 responders. Moreover, TNFα-inhibitors naïve patients were found to be better responders, with 50% and 60% achieving ASAS-20 and BASDAI-20, respectively.
However, a French study on eight patients with SpA receiving RTX showed less favorable outcomes [Nocturne et al. 2010]. Another observational study reported moderate efficacy of RTX in SpA, it was more marked in TNF-α-inhibitor-naive patients [Wendling et al. 2012a].
Among newer therapies studied to date, inhibition of interleukin-17A by secukinumab (SEC), and of the IL-12/23 receptor by ustekinumab (USK), seems to give the best results in SpA [Scarpa et al. 2013].
Baeten and colleagues studied AS patients who were randomly assigned to SEC treatment or placebo infusion [Baeten et al. 2013]; they demonstrated that 61% of patients treated with SEC achieved ASAS-20 compared with 17% of patients treated with placebo. Moreover, 35% of patients treated with SEC achieved ASAS-40 and ASAS-5/6 responses, respectively. However, these data need to be confirmed by larger randomized placebo-controlled studies with longer duration of follow up.
USK is a fully human immunoglobulin monoclonal antibody direct against a common subunit of IL-12 and IL-23, effective in the management of psoriasis [Gottlieb and Narang, 2013]. Furthermore, USK significantly improved active PsA compared with placebo, therefore it might offer an alternative therapeutic choice to TNF-α inhibitors [McInnes et al. 2013]. Recently, in an open-label clinical trial, USK use was associated with a reduction in signs and symptoms of active AS. In this study, ASAS-20, ASAS-5/6, and ASAS-40 were reached in 75%, 50%, and 65% of the patients, respectively. Moreover, a significant improvement in other patient-reported outcome parameters and active inflammation (as detected by MRI), as well as a significant reduction of NSAIDs intake, occurred during USK treatment [Poddubnyy et al. 2014].
Apremilast (APM) represents a molecule that specifically targets phosphodiesterase 4 (PDE4). Recently, large double-blind and randomized multicenter studies demonstrated that APM is effective in the treatment of psoriasis, PsA, and AS, with significantly higher numbers of patients achieving the endpoints compared with baseline [Pathan et al. 2013; Schett et al. 2012].
Anakinra (ANK) (IL-1 receptor antagonist) has been approved for active RA patients and it is useful in many inflammatory diseases [Néel et al. 2014; Cantarini et al. 2014]. There are no large trials evaluating its efficacy in SpA patients but, among available data, some reports showed a clinical benefit only in a small number of patients, without showing MRI improvement. In these studies, carried out in PsA and AS patients [Jung et al. 2010; Haibel et al. 2005b; Bennett et al. 2008], adverse events were mainly mild and the most frequent were injection site reactions.
Conclusions
The main goal of the management of SpA is to reduce disease activity and to control joint damage and extra-articular manifestations, improving the quality of life and preserving the functional abilities of patients as well as autonomy and social participation by an active cooperation between physicians. Further, patient information and education, also by rehabilitation, represent key determinants for improving SpA outcomes.
A crucial point for clinicians is represented by the management of the individual patient with his/her heterogeneous complexity, which dictates that the pharmacological management of SpA needs to be varied.
Traditional therapies consist of different choices ranging from NSAIDs and steroids in early phases and/or mild forms of the disease, to monotherapy or combined therapy with tDMARDs for the suppression of inflammation in refractory peripheral joint disease.
NSAIDs, low-dosage oral and intra-articular steroids are commonly used in SpA and often represent the first choice of therapy. These therapies have not been extensively studied and available data are not conclusive in defining their efficacy in improving disease outcome.
In SpA patients with refractory peripheral joint disease, the most used tDMARDs are represented by MTX and SSZ; however, low level of scientific evidence can justify their use. Over the last decade, due to the high expectations that biologic drugs such as TNF-α inhibitors are raising remarkable changes have also been obtained in the field of SpA therapies. TNF-α inhibitors could be considered an effective treatment for patients in whom conventional therapy with NSAIDs and/or tDMARDs have failed.
Although the TNF-α inhibitors have proven to be effective in the treatment of SpA, there is a clinical need for new therapies with other mechanisms of action in these conditions; this need is due to the increasing number of nonresponder patients for whom TNF-α-inhibitor therapy is contraindicated. Among the newer therapies, targeting of IL-17, IL-12/23, and PDE4, seems to show more promising results than therapies targeting T-cell co-stimulation, B-cell surface antigens, and IL-6 (Table 1).
Biological therapies for spondyloarthritis.
Approved by the European Medicines Agency.
Approved by the US Food and Drug Administration.
TNF, tumor necrosis factor; IL, interleukin; AS, ankylosing spondylitis; PsA, psoriatic arthritis; nr-axSpA, nonradiographic axial spondyloarthritis; UC, ulcerative colitis; CD, Crohn’s disease.
However, further large controlled studies with longer-term follow-up periods are needed to corroborate recent observations on biological therapies other than TNF-α inhibitors.
Footnotes
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Conflict of interest statement
The authors do not have any conflicts of interest related to the subject matter.