Abstract
TNFα inhibitors are currently the only class of biological agent that has proven to be effective in the treatment of patients with ankylosing spondylitis and/or spondyloarthritis (SpA). These agents have been shown to control inflammatory pain of the axial skeleton, peripheral clinical manifestations, certain extra-articular manifestations as well as systemic and spinal MRI inflammation. Conversely, they are unable to slow radiographic progression in the spine. Since around 20–30% of patients with SpA are considered as nonmajor responders to TNFα inhibitors, there is a need for alternative therapies. Biological agents that target IL-1, IL-6, B cells and costimulatory pathways are not effective in SpA. Conversely, novel biological agents blocking IL-23 or IL-17 are promising in SpA, especially secukinumab, an anti-IL-17A monoclonal antibody.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Spondyloarthritis. Lancet 377(9783), 2127–2137 (2011).
- 2 . Classification, diagnosis, and referral of patients with axial spondyloarthritis. Rheum. Dis. Clin. North Am. 38(3), 477–485 (2012).
- 3 . Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 27(4), 361–368 (1984).
- 4 Magnetic resonance imaging in ankylosing spondylitis. Curr. Opin. Rheumatol. 19(4), 346–352 (2007).
- 5 The development of assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann. Rheum. Dis. 68(6), 777–783 (2009).
- 6 The assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 70(1), 25–31 (2011).
- 7 . Developments in therapies for sondyloarthritis. Nat. Rev. Rheumatol. 8(5), 280–287 (2012).
- 8 . Current guidelines for the drug treatment of ankylosing spondylitis. Drugs 56(2), 225–240 (1998).• A first complete review of the traditional treatments in ankylosing spondylitis (AS) before the era of biologics.
- 9 Pharmacological treatment of ankylosing spondylitis: a systematic review. Drugs 6(15), 2111–2127 (2005).•• Second complete review of the traditional treatments in AS before the era of biologics.
- 10 . Treatment of ankylosing spondylitis and other spondyloarthritides. Curr. Opin. Rheumatol. 21(4), 324–334 (2009).
- 11 . A systematic medline analysis of therapeutic approaches in ankylosing spondylitis. Rheumatol. Int. 29(10), 1123–1135 (2009).
- 12 . Appropriate management of axial spondyloarthritis. Curr. Rheumatol. Rep. 9(5), 375–382 (2007).
- 13 . Treatments of spondyloarthropathy: the potential for agents other than TNF inhibitors. Curr. Opin. Rheumatol. 25(4), 455–459 (2013).
- 14 Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 359(9313), 1187–1193 (2002).
- 15 Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized controlled trial. Arthritis Rheum. 48(11), 3230–3236 (2003).
- 16 Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo controlled trial. Arthritis Rheum. 54(7), 2136–2146 (2006).
- 17 Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, Phase III trial. Arthritis Rheum. 58(11), 3402–3412 (2008).
- 18 Update on biological therapy in the management of axial spondyloarthritis. Curr. Rheumatol. Rep. 12(5), 325–331 (2010).
- 19 Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomized, double blind, placebo controlled study (SPINE). Ann. Rheum. Dis. 70(5), 799–804 (2011).
- 20 . Update of the literature review on treatment with biologics as a basis for the first update of the ASAS/EULAR management recommendations of ankylosing spondylitis. Rheumatology 51(3), 1378–1387 (2012).
- 21 . How important is early therapy in axial spondyloarhritis. Rheum. Dis. Clin. North Am. 38(3), 635–642 (2012).
- 22 . Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann. Rheum. Dis. 72(1), 23–28 (2013).
- 23 . Comparison of high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non radiographic axial spondyloarthritis. Ann. Rheum. Dis. 69(7), 1338–1341 (2010).
- 24 Efficacy of adalimumab in the treatment of axial spondyloarthritis without radiographically defined sacroiliitis. Results of a twelve-week randomized, double blind, placebo-controlled trial followed by an open label extension up to fivty-two. Arthritis Rheum. 58(7), 1981–1991 (2008).
- 25 Clinical and imaging efficacy of infliximab in HLA-B27 positive patients with magnetic resonance imaging–determined early sacroiliitis. Arthritis Rheum. 60(4), 946–954 (2009).
- 26 Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI(ESTHER): a 48 week randomised controlled trial. Ann. Rheum. Dis. 70(4), 590–596 (2011).
- 27 Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomized placebo-controlled trial (ABILITY-1). Ann. Rheum. Dis. 72(6), 815–822 (2013).
- 28 Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double blind randomised placebo controlled Phase 3 study. Ann. Rheum. Dis. 73(1), 39–47 (2014).
- 29 Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiogarphic axial spondyloarthritis. A multicentre, randomised, double blind, placebo controlled trial. Arthritis Rheumatol. 66(8), 2091–2102 (2014).•• Along with [27,28]: the trials demonstrating the efficacy of TNFα inhibitors in patients with early nonradiographic axial spondyloarthritis (SpA).
- 30 The concept of axial spondyloarthritis. Joint statement of the spondyloarthritis research and treatment network and the assessment of spondyloarthritis international society in response to the US Food and Drug Administration's comments and concerns. Arthritis Rheumatol. 66(10), 2649–2656 (2014).• Position of the US FDA concerning nonradiographic axial SpA and its treatment by biological agents.
- 31 . A randomized multicentre, double blind, placebo controlled trial of etanercept in adults with refractory heel enthesitis in spondyloarthritis: the Heel trial. Ann. Rheum. Dis. 69(8), 1430–1435 (2010).• A randomized trial showing the efficacy of TNFα blocking agent on heel enthesitis.
- 32 . A survey of European and Canadian rheumatologists regarding the treatment of patients with ankylosing spondylitis and extra articular manifestations. Clin. Rheumatol. 29(3), 281–288 (2010).
- 33 Etanercept for active Crohn's disease: a randomized double blind, placebo-controlled trial. Gastroenterology 121(5), 1088–1094 (2001).
- 34 Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti TNF agents infliximab and etanercept. Arthritis Rheum. 52(8), 2447–2451 (2005).
- 35 Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann. Rheum. Dis. 63(6), 665–670 (2004).
- 36 MRI in predicting a major clinical response to anti tumor necrosis factor treatment in ankylosing spondylitis. Ann. Rheum. Dis. 67(9), 1276–1281 (2008).
- 37 Baseline radiographic damage, elevated acute phase reactant levels and cigarette smoking status predict spinal radiographic progression in early axial spondyloarthritis. Arthritis Rheum. 64(5), 1388–1398 (2012).
- 38 The 308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford) 46(1), 93–96 (2007).
- 39 Association of TNF-α polymorphism with prediction of response to TNF blockers in spondyloarthritis and inflammatory bowel disease: a meta-analysis. Pharmacogenomics 14(14), 1691–1700 (2013).
- 40 The comparative one year performance of anti tumour necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: results from a longitudinal, observational, multicentre study. Arthritis Rheum. 59(2), 234–240 (2008).
- 41 Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years – early clinical response predicts long term outcome. Rheumatology 50(6), 1690–1699 (2011).
- 42 . Can structural damage be prevented in ankylosing spondylitis. Curr. Opin. Rheumatol. 21(4), 335–339 (2009).
- 43 Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 58(10), 3063–3070 (2008).
- 44 Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 58(5), 1324–1331 (2008).
- 45 Assessment of radiographic progression in the spine of patients with ankylosing spondylitis treated with adalimumab for up to two years. Arthritis Res. Ther. 11(5), R127 (2009).
- 46 The impact of tumor necrosis factor inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 65(10), 2645–2654 (2013).• A study that did not confirm previous findings (detailed in [41–43]) on the potential of TNFα inhibitors to prevent the progression of spinal ossifications.
- 47 ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann. Rheum. Dis. 65(4), 442–52 (2006).
- 48 Recommendations of the french society for rheumatology regarding TNFα antagonist therapy in patients with ankylosing spondylitis or psoriatic arthritis. Joint Bone Spine 74(6), 638–646 (2007).
- 49 First update of the international ASAS consensus statement for the use of anti-TNF α agents in patients with ankylosing spondylitis. Ann. Rheum. Dis. 65(3), 316–320 (2006).
- 50 EULAR 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann. Rheum. Dis. 70(6), 896–904 (2011).
- 51 Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3 E initiative in rheumatology involving a broad panel of experts and practicing rheumatologists. Rheumatology 47(3), 355–361 (2008).• Specific recommendations from both experts and practicing rheumatologists reviewing diagnosis and management of AS.
- 52 Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann. Rheum. Dis. 73(1), 6–16 (2014).
- 53 Treating axial and peripheral spondyloarthritis, including psoriatic arthritis, to target: results of a systematic literature search to support an international treat-to-target recommendation in spondyloarthritis. Ann. Rheum. Dis. 73(1), 238–242 (2014).
- 54 Ankylosing spondylitis assessment group preliminary definition improvement in ankylosing spondylitis. Arthritis Rheum. 44(8), 1876–1886 (2001).
- 55 Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann. Rheum. Dis. 68(1), 18–24 (2009).
- 56 Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment. Arthritis Rheum. 58(1), 88–97 (2008).
- 57 Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis. Br. J. Pharmacol. 73(1), 55–65 (2012).
- 58 Real life experience confirms sustained response to long term biologics and switching in ankylosing spondylitis. Rheumatology 47(6), 897–900 (2008).
- 59 A tailored approach to reduce dose of anti-TNF drugs may be equally effective but substantially less costly than standard dosing in patients with ankylosing spondylitis over 1 year: a propensity score matched cohort study. Ann. Rheum. Dis. (2014) (Epub ahead of print).• A study suggesting that the administered dose of TNFα inhibitors may be reduced in patients with AS.
- 60 High dose etanercept in ankylosing spondylitis: results of a 12 week randomized, double blind, controlled multicenter study (LOADET study). Rheumatology 51(6), 1828–1837 (2011).
- 61 . Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives? Curr. Opin. Rheumatol. 24(3), 252–260 (2012).
- 62 . Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumor necrosis factor alpha in two patients with early disease and transforming growth factor beta in three more advanced cases. Ann. Rheum. Dis. 65(6), 713–720 (2006).
- 63 Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17 mediated adaptive immune response. Arthritis Res. Ther. 13(3), R95 (2011).
- 64 Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 38(4), 499–505 (1995).
- 65 . Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann. Rheum. Dis. 64(2), 296–298 (2005).
- 66 Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann. Rheum. Dis. 63(9), 1041–1045 (2004).
- 67 Different response to rituximab in tumor necrosis factor blocking naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed. A twenty four week clinical trial. Arthritis Rheum. 62(5), 1290–1297 (2010).
- 68 One-year follow up of ankylosing spondylitis patients responding to rituximab treatment and re-treated in case of a flare. Ann. Rheum. Dis. 72(2), 305–306 (2013).
- 69 Peripheral blood subsets and BAFF/APRIL levels and their receptors are disturbed in rheumatoid arthritis but not in ankylosing spondylitis. J. Clin. Cell Immunol. 4(5), 1–7 (2013).
- 70 Treatment of active ankylosing spondylitis with abatacept: an open label 24 week pilot study. Ann. Rheum. Dis. 70(6), 1108–1110 (2011).
- 71 . Assessement of short-term efficacy of tocilizumab in ankylosing spondylitis: results of randomized, placebo-controled trials. Ann. Rheum. Dis. 73(1), 95–100 (2014).
- 72 Sarilumab for the treatment of ankylosing spondylitis: results of a Phase 2, randomized, double blind, placebo controlled study (ALIGN). Ann. Rheum. Dis. (2014) (Epub ahead of print).
- 73 . The interleukin-23/interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis. Curr. Opin. Rheumatol. 26(4), 361–370 (2014).
- 74 Anti -interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382(9906), 1705–1713 (2013).•• The first randomized proof of concept trial suggesting an effect of an anti-IL-17A agent in AS.
- 75 Secukinumab, a monoclonal antibody to interleukin-17A, significantly improves signs and symptoms of active ankylosing spondylitis: results of a 52-week Phase 3 placebo controlled trail with intravenous loading and subcutaneous maintenance dosing. Arthritis Rheumatol. 66(Suppl. 11), S360 (2014) (Abstract).
- 76 . The IL-23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm. Allergy Drug Targets 11(2), 159–168 (2012).
- 77 IL-23 induces spondylarthropathy by acting on ROR-γt + CD3+CD4-CD8- entheseal resident T cells. Nat. Med. 18(7), 1069–1076 (2012).•• A major study demonstrating the involvement of IL-23+ cells in targeted tissue in an animal model of SpA.
- 78 . Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof of concept study (TOPAS). Ann. Rheum. Dis. 73(5), 817–823 (2014).
- 79 Proposal for new nomenclature of disease modifying antirheumatic drugs. Ann. Rheum. Dis. 73(5), 902–905 (2014).
- 80 Efficacy and safety of apremilast, an oral phosphodiesterase inhibitor in ankylosing spondylitis. Ann. Rheum. Dis. 72(9), 1475–1480 (2013).
- 81 . Novel small molecule therapeutics in rheumatoid arthritis. Rheumatology (Oxford) 52(7), 1155–1162 (2013).
- 82 . Evaluation of the treatment effect of NSAIDs/TNF blockers according to different domains in ankylosing spondylitis: results of a meta-analysis. Rheumatology 49(4), 1317–1325 (2010).
- 83 Secukinumab in plaque psoriasis. Results of two Phase 3 trials. N. Engl. J. Med. 371(4), 326–338 (2014).