Table 1. Areas for future research in polymyalgia rheumatica and giant cell arteritis: pathogenic mechanisms with matching clinical phenotypes, imaging modalities, possible biomarkers and possible therapies Pathogenetic mechanism Matching clinical symptoms Imaging findings Possible Biomarkers* Possible treatment targets* Trigger/activation of innate immunity, DCs, T-cells, B-cells 78 ‘flu-like’ symptoms, fever, night sweats No known imaging technique phase response, possibly IL-6 anti-infection therapies; immunisation; blockade of DC activation (anti-IL1 inhibition with canakinumab/ gevokizumab/ leflunomide); costimulatory blockade (abatacept); IL-6 blockade (tocilizumab, sirukumab) Arterial Inflammatory infiltrate88,104,142,143 Headache, scalp pain, thickened arteries, painful arteries, constitutional symptoms Characteristic inflammatory imaging findings such as ‘Halo’ sign (GCA) with sonography, MRA and/or PET phase response, neutrophilia costimulatory blockade (abatacept); JAK inhibitors (tofacitinib, Baricitinib); cytokine blockade (IL-6, IFN, TNF, IL-17, IL-23) Vascular smooth muscle cell and intimal proliferation 90 Jaw claudication, necrosis, visual and other ischemic manifestations Imaging signs of inflammation and damage: ‘Halo’ sign, occlusion, stenosis; OCT-A changes of retinal and choroidal vessels, as well as nerve head Vascular biomarkers anti-VEGF; anti-IFN; anti-IL-17 (secukinumab) inihibitors of neurotrophins inihibitors of endothelin Neo-angiogenesis, possible haemorrhage of media 90,114 Jaw claudication, ischemic damage such Increased axillary and carotid thickness of media, occlusion, stenosis and Angiogenesis markers such as elevated VEGF anti-VEGF; inhibitors of proteases (MMPs, cathepsins, elastase)
Table 2. Clinical trials of biological agents for the treatment of polymyalgia rheumatica and giant cell arteritis Mechanism of action Publicat. type information Sample size Study population Durat. Main results Ref. Polymyalgia rheumatica Infliximab TNF- blocker Full paper Randomized, double-blinded 51 PMR, new untreated 52 weeks Did not achieve primary and main secondary endpoints Salvarani 2007 130 Etanercept TNF- blocker Full paper Randomized, single-centre, double-blinded 22 PMR, new untreated 14 days Did not achieve primary and main secondary endpoints Kreiner 2010 134 Tocilizumab IL-6 receptor blocker Full paper Not randomized, single-centre 20 PMR, new treated with GCs ≤1 month 15 months Relapse-free remission off GCs at 6 months: 100% in TCZ vs. 0% in control group Cumulative GC dose: 1.1g in TCZ vs. 2.6g in control group (p=0.01) Duration of GC exposure: 3.9 in TCZ vs. 14.1 months in control (p=0.002) Lally 2016 135 Tocilizumab IL-6 receptor blockade Full paper Single group, multi-centre open-label 20 PMR <12mo, GC-naive or GCs<1mo + off GCs 7 days 24 weeks PMR-AS≤10 at 12weeks: 100%, no flares Cumulative GC dose: 0.8g 2016 136 AIN457 ACZ885 IL-17 blocker IL1 blocker Final report Randomized, Proof of Concept Study 16 PMR, new 2 weeks Did not achieve primary endpoint Matteson 2014 146
Giant cell arteritis Infliximab TNF- blocker Full paper Randomized, multi-centre, double-blinded 44 GCA, new (cranial) 54 weeks Did not achieve primary and main secondary endpoints Hoffman 2007 130 Etanercept TNF- blocker Full Randomized, multi-centre, double-blinded 17 GCA in remission, stable oral prednisone 15 months Cumulative GC dose: 1.5g in ETN vs. 3.0g in control (p=0.03) outcomes negative 2008 133 Adalimumab TNF- blocker Full Randomized, double-blinded 70 GCA, new (cranial) 52 weeks Did not achieve primary and main secondary endpoints Seror 2014 132 Tocilizumab IL-6 receptor blockade Full paper Randomized, single-centre, double-blinded 30 GCA, new or relapsing 52 weeks Complete remission at 12/52 weeks: 85%/85% in TCZ vs. 40%/20% in control group (p=0.03/p=0.001) Time to relapse: 50 weeks in TCZ vs. 25 weeks in control group (p<0.001) Discontinuation of GCs: 80% in TCZ vs. 20% in control group (p=0.004) Cumulative GC dose: 43mg/kg in TCZ vs. 110mg/kg in control group (p<0.001) Villiger 2016 15 Tocilizumab IL-6 receptor blockade Abstract Randomized, multi-centre, double-blinded 251 GCA, New or refractory 52 weeks + 52 weeks open label Sustained remission at 12 months: 56% (weekly injections), 53% (bi-weekly injections) in TCZ vs. 14% in control (p < 0.0001) Stone 2016 16
phase Cumulative GC dose at 12 months:1.8g in both TCZ groups compared to 3.3g and 3.8g in the 2 placebo groups (one with a short and one with a long GC tapering course) Sirukumab IL-6 blocker Ongoing study Randomized, double-blinded 204 GCA, active 52 weeks + 52 weeks open label Results available by end of 2018 Abatacept CTLA-4 Ig Full paper Randomized, multi-centre, double-blinded 49 GCA, new or relapsing 12 months Relapse free remission at 12 months: 48% in abatacept vs. 31% in control group (p=0.049) Langford 2015 144 Abatacept CTLA-4 Ig Study completed Randomized, double-blinded 98 GCA or TAK, active 48 months Results not yet available Abatacept CTLA-4 Ig Recruiting Randomized, multi-centre, double-blinded 200 GCA, new 52 weeks Estimated completion by 2021 ETN, etanercept; Durat., Duration; GC(s), glucocorticoid(s); GCA, giant cell arteritis; IL, interleukin; mo, months; PMR, polymyalgia rheumatica; PMR-AS, polymyalgia rheumatica activity score; Public., Publication; Ref., Reference; TAK, Takayasu arteritis TCZ, tociliumab; TNF, tumor necrosis factor;