Autoinflammatory disorders RMD Open: first published as 10.1136/rmdopen-2018-000694 on 4 June 2018. Downloaded from

Editorial Polymyalgia rheumatica: an autoinflammatory disorder?

Alberto Floris,1 Matteo Piga,1 Alberto Cauli,1 Carlo Salvarani,2,3 Alessandro Mathieu1

To cite: Floris A, Piga M, Cauli A, Polymyalgia rheumatica (PMR) is an (figure 2A).6 Further, after low-dose gluco- et al. Polymyalgia rheumatica: elderly onset syndrome characterised by corticoid therapy initiation, patients with an autoinflammatory aching and stiffness in the and the PMR experience a rapid improvement of disorder?. RMD Open 2018;4:e000694. doi:10.1136/ pelvic girdle associated to increased levels symptoms, generally within 24–72 hours, and rmdopen-2018-000694 of acute phase reactants and rapid response more than 40% of them achieve complete to glucocorticoids.1 Although the cause of response within 3 weeks.1 Similarly, in rare ►► Prepublication history for PMR remains unknown, most of the evidence monogenic AIDs, a rapid remission of symp- this paper is available online. suggest a multifactorial aetiology inducing an toms and significant reduction in frequency To view these files, please visit immunomediated pathogenesis.1 2 of inflammatory attacks is rapidly achieved the journal online (http://​dx.​doi.​ org/10.​ ​1136/rmdopen-​ ​2018-​ According to the ‘immunological with specific treatment, such as colchicine in 000694). continuum model’ proposed by McGonagle familial Mediterranean fever (FMF) and inter- in 2006, all immune-mediated diseases can leukin-1β (IL-1β) blockade in cryopyrin-as- Received 4 April 2018 be conceptualised as predominantly auto- sociated periodic syndrome.7 Conversely, a Accepted 8 May 2018 inflammatory, predominantly autoimmune chronic or relapsing-remitting course, with a or mixed, on the basis of the relative contri- minimal residual disease activity and progres- butions of innate and adaptive immune sive damage accrual, is frequently recorded in responses.3 Autoinflammatory diseases ADs (figure 2B).8

(AIDs) are characterised by tissue inflam- Age of onset and gender distribution are http://rmdopen.bmj.com/ mation mainly due to aberrant activation of inconclusive in discriminating the prevalent innate without autoantibodies autoinflammatory or autoimmune nature production and autoreactive T lymphocyte of PMR (figure 2C). Indeed, both in ADs activation. In contrast, autoimmune diseases and AIDs elderly onset is rare, and the main (ADs) are typically depicted by an abnormal determinant of the onset age is the mono- activation of the adaptive immune system.4 genic (childhood) or polygenic (adulthood) However, the emerging understanding of the nature of the disease.4 9 Further, the prefer-

close linkage between innate and adaptive ential involvement of woman in PMR (female on September 28, 2021 by guest. Protected copyright. immunity led to consider the rare monogenic to male ratio=2:1) seems related to a different AIDs and ADs as the two opposite ends into and currently unknown mechanism than the a continuum of immune-mediated disor- arise in oestrogen production reported as ders, where middle entities are recognised one of the main determinants of the female (figure 1).3 prevalence in typical ADs, such as systemic In the view of this background, we tried to erythematosus (SLE) (female to male 1 9 1Rheumatology and envisage the most suitable place for PMR into ratio=9:1). Unit, University the spectrum of the autoinflammatory/auto- Laboratory findings lean towards a predom- Clinic AOU of Cagliari, Cagliari, immune disorders by reviewing and inter- inant role of innate immune response in Italy preting current evidence. PMR. Indeed, a remarkable increase of 2 Rheumatology and Clear indication for a prevalent autoinflam- inflammatory markers is one of the most Rheumatology Unit, Università di Modena e Reggio Emilia, Reggio matory background of PMR is related to the consistent features in patients with both PMR Emilia, Italy disease onset and course. Actually, starting and AIDs, so that it is included into the diag- 3Azienda USL-IRCCS di Reggio of symptoms is generally over a few days or nostic criteria and monitoring parameters for Emilia, Reggio Emilia, Italy overnight in PMR,1 as well as in inflammatory both conditions.1 7 Increase of acute phase 5 Correspondence to periodic-recurring occurrence of AIDs, but reactants can also occur in ADs, but with Dr Alberto Floris; in contrast to classic polygenic ADs where lower frequency and diagnostic accuracy albertofloris1@​ ​gmail.com​ a subacute onset is frequently recorded (figure 2D).4 Further, autoantibodies carrying

Floris A, et al. RMD Open 2018;4:e000694. doi:10.1136/rmdopen-2018-000694 1 RMD Open RMD Open: first published as 10.1136/rmdopen-2018-000694 on 4 June 2018. Downloaded from

Figure 1 Simplified classification of immune-mediated disease by McGonagle and McDermott.3 a significant pathogenic and/or diagnostic role have not Regarding the cytokine profile, evidence of a IL-6 been identified in PMR, as well as in AIDs,4 whereas they central pathophysiological role in PMR has been are frequently associated to prototypical ADs (eg, anti- provided. Remarkably, among rheumatic diseases, the double-stranded DNA in SLE, anti-citrullinated peptide highest serum levels of IL-6 were found in patients in rheumatoid arthritis (RA)) (figure 2E).4 10 Noteworthy, affected by PMR and GCA17 as well as in EORA.18 The lack of pathogenetic autoantibodies is typically recorded latter presents some not canonical features compared with in other immune-mediated diseases, such as the major traditional ADs (eg, lower prevalence of autoantibodies, histocompatibility complex class I (MHC-I)-pathies reduced prevalence in females, less straight association (eg, ankylosing spondylitis, psoriatic arthritis) that are with HLA-II) and might be part of an autoinflammatory– reported as prototypical mixed autoinflammatory/auto- autoimmune mixed subtype of RA.19 Further, in contrast immune disorders in the immunological continuum.3 to several ADs, increased levels of serum interferon-γ Similar to AIDs and in contrast to what is reported (IFN-γ) were not found in PMR. Moreover, IFN-γ was for typical ADs, not significant overlap has been identi- observed in the temporal artery biopsy (TAB) specimens fied between PMR and other immunological disorders, of GCA patients, while it was not seen in TAB of patients excepting for (GCA).11 However, it is with isolated PMR, suggesting a key role of this cytokine still unclear whether GCA represents a separate condi- in the progression to overt arteritis.20 Finally, increased tion from PMR or a potential expression of the same level of circulating type I IFN has not been reported http://rmdopen.bmj.com/ disease (figure 2).3 12 Further, a mixed contribution of neither on PMR and GCA21 and no data are currently innate and adaptive immunity, supported by the bringing available on type I IFN signature, which is considered an function of Th17 cells, has been recognised in the GCA.1 hallmark of several ADs (figure 2H). Despite the widely incomplete knowledge on pathogen- Further pathobiological findings supporting the key esis of PMR, some suggestions for a predominant autoin- role of innate immunity in PMR pathogenesis are repre- flammatory nature of the disease arise from the genetic sented by the increased expression of toll-like receptor background and cytokine profile. Indeed, a clear associ- (TLR)-7 and TLR-9 in peripheral blood monocytic cells ation between (HLA) class II and the emerging involvement of Th17 cells.22 on September 28, 2021 by guest. Protected copyright. alleles (especially HLA-DRB1*0401) and isolated PMR To date, glucocorticoids remain the cornerstone of has not been definitely demonstrated due to conflicting treatment for PMR, whereas poor evidence is available data from different populations.1 On the other hand, on the effectiveness of traditional immunosuppres- HLA class II alleles have been found to associate with sants. Methotrexate (MTX) is the most used glucocor- GCA susceptibility and GCA with PMR symptoms, as ticoid-sparing agent in PMR, although randomised well as in most of ADs (figure 2G).13–15 Polymorphisms controlled trials data on relapse rate and cumulative of additional genes involved in initiating and regulating glucocorticoid dose reduction are conflicting.23 Poten- inflammatory response, such as intercellular adhesion tial benefit of MTX may be related to antinflammatory molecule-1, tumour necrosis factor (TNF), interleukin 6 effects, resulting from reduced monocytic cell activation, (IL-6) and interleukin 1 (IL-1) receptor antagonist decreased IL-1 and IL-6 secretion, as well as from inhi- (IL-1RN) have also been identified as possible suscepti- bition of cyclo-oxygenases synthesis, neutrophil chemo- bility factors for PMR.16 Interestingly, Alvarez-Rodriguez taxis and adhesion molecules expression.24 Traditional reported that the IL-1RN*2 polymorphism in a homo- immunosuppressants are generally not used in AIDs zygous state associated to higher susceptibility to PMR because of the poor effectiveness in the management of when compared with healthy controls and GCA, as well as attacks and prevention of relapse.7 25 Conversely, tradi- to elderly onset RA (EORA) when compared with young- tional immunosuppressants are the first-line treatment onset RA.15 in most of ADs, while glucocorticoids can be associated

2 Floris A, et al. RMD Open 2018;4:e000694. doi:10.1136/rmdopen-2018-000694 Autoinflammatory disorders RMD Open: first published as 10.1136/rmdopen-2018-000694 on 4 June 2018. Downloaded from http://rmdopen.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Figure 2 Summary of our interpretation of scientific data on polymyalgia rheumatica, in the view of its classification in the spectrum of immune-mediated diseases.

Floris A, et al. RMD Open 2018;4:e000694. doi:10.1136/rmdopen-2018-000694 3 RMD Open RMD Open: first published as 10.1136/rmdopen-2018-000694 on 4 June 2018. Downloaded from as adjuvant therapy, especially in the induction phase of References the treatment (figure 2I).26 1. González-Gay MA, Matteson EL, Castañeda S. Polymyalgia rheumatica. The Lancet 2017;390:1700–12. Experience from patients with PMR symptoms in GCA 2. Pipitone N, Salvarani C. Update on polymyalgia rheumatica. Eur J and data from an open-label uncontrolled study on 20 Intern Med 2013;24:583–9. 3. McGonagle D, McDermott MF. A proposed classification of the subjects with isolated PMR suggest anti-IL-6R therapy as immunological diseases. PLoS Med 2006;3:e297. an effective option in reducing Disease Activity Score and 4. Doria A, Zen M, Bettio S, et al. Autoinflammation and autoimmunity: bridging the divide. Autoimmun Rev 2012;12:22–30. reducing cumulative exposition to glucocorticoids (gluco- 5. Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional 27 corticoid-sparing effect at 24 weeks is 70.2%). Anti- clinical classification criteria for autoinflammatory periodic fevers. IL-6R also showed promising results in several AIDs, such Ann Rheum Dis 2015;74:799–805. 6. Arbuckle MR, McClain MT, Rubertone MV, et al. Development as systemic juvenile idiopathic arthritis, Behçet disease, of autoantibodies before the clinical onset of systemic lupus FMF and TNF receptor-associated periodic syndrome.28 erythematosus. N Engl J Med 2003;349:1526–33. 7. ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations Most of current data on anti-TNFα treatment suggest it is for the management of autoinflammatory diseases. Ann Rheum Dis ineffective, expensive and potentially harmful in patients 2015;74:1636–44. 1 8. Barr SG, Zonana-Nacach A, Magder LS, et al. Patterns of with PMR. Positive results in terms of effectiveness were disease activity in systemic lupus erythematosus. Arthritis Rheum detected for connective tissue diseases and other ADs, 1999;42:2682–8. but its use is limited by the observation of several cases 9. Cooper GS, Stroehla BC. The epidemiology of autoimmune 29 diseases. Autoimmun Rev 2003;2:119–25. of anti-TNFα-induced autoimmune disorders. Inter- 10. Floris A, Piga M, Cauli A, et al. Predictors of flares in systemic estingly, PMR is not reported among the immune-me- lupus erythematosus: preventive therapeutic intervention based on serial anti-dsDNA antibodies assessment. Analysis diated paradoxical effect of anti-TNFα (figure 2J). Data of a monocentric cohort and literature review. Autoimmun Rev on anti-IL-1β are limited to a single blind study, where 2016;15:656–63. canakinumab was administered to three patients with 11. Chuang TY, Hunder GG, Ilstrup DM, et al. Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med new-onset PMR, with not conclusive results in terms of 1982;97:672–80. effectiveness.30 Therefore, further data from large trial 12. Cantini F, Niccoli L, Storri L, et al. Are polymyalgia rheumatica and the same disease? Semin Arthritis Rheum on anti-IL-1β in PMR would be warranted. 2004;33:294–301. In summary, despite the incomplete knowledge of 13. Fernando MM, Stevens CR, Walsh EC, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet PMR pathophysiology and the lack of validate discrimina- 2008;4:e1000024. tive criteria for polygenic AIDs, current evidence suggests 14. Gonzalez-Gay MA. Genetic epidemiology. Giant cell arteritis and that PMR does not easily fit into any of the two pure ends polymyalgia rheumatica. Arthritis Res 2001;3:154–7. 15. Dababneh A, Gonzalez-Gay MA, Garcia-Porrua C, et al. Giant cell in the spectrum of the immune-mediated disorders, but arteritis and polymyalgia rheumatica can be differentiated by distinct a greater affinity for AIDs seems to emerge. patterns of HLA class II association. J Rheumatol 1998;25:2140–5. 16. Alvarez-Rodriguez L, Carrasco-Marin E, Lopez-Hoyos M, et al. In our opinion, this interpretation of the available scien-

Interleukin-1RN gene polymorphisms in elderly patients with http://rmdopen.bmj.com/ tific data might represent an insight with a significant rheumatic inflammatory chronic conditions: Association of IL- 1RN*2/2 genotype with polymyalgia rheumatica. Hum Immunol practical implication. Indeed, among the unmet needs in 2009;70:49–54. PMR, there is the availability of effective and safety ther- 17. Salvarani C, Cantini F, Niccoli L, et al. Acute-phase reactants and the apeutic options for patients not adequately responsive or risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study. Arthritis Rheum 2005;53:33–8. requiring longer exposition to glucocorticoids or with 18. Chen DY, Hsieh TY, Chen YM, et al. Proinflammatory cytokine an unfavourable risk profile of steroid-related adverse profiles of patients with elderly-onset rheumatoid arthritis: a comparison with younger-onset disease. Gerontology effects. In this view, the recognition of predominantly 2009;55:250–8. 19. Savic S, Mistry A, Wilson AG, et al. Autoimmune-autoinflammatory autoinflammatory nature of PMR should address future on September 28, 2021 by guest. Protected copyright. rheumatoid arthritis overlaps: a rare but potentially important research aimed to develop targeted therapies. subgroup of diseases. RMD Open 2017;3:e000550. 20. Weyand CM, Hicok KC, Hunder GG, et al. Tissue cytokine patterns Contributors AM: conceived of the present idea. AF and MP: equally contributed in patients with polymyalgia rheumatica and giant cell arteritis. Ann to perform the literature review and draft the manuscript. All authors contributed to Intern Med 1994;121:484–91. the interpretation of the recorded evidence. AC, CS and AM: critically reviewed the 21. van der Geest KS, Abdulahad WH, Rutgers A, et al. Serum markers manuscript. All Authors approved the final version. associated with disease activity in giant cell arteritis and polymyalgia rheumatica. Rheumatology 2015;54:1397–402. Funding The authors have not declared a specific grant for this research from any 22. Guggino G, Ferrante A, Macaluso F, et al. Pathogenesis of funding agency in the public, commercial or not-for-profit sectors. polymyalgia rheumatica. Reumatismo 2018;70:10–17. Competing interests None declared. 23. Buttgereit F, Dejaco C, Matteson EL, et al. Polymyalgia rheumatica and giant cell arteritis: a systematic review. JAMA Patient consent Not required. 2016;315:2442–58. Provenance and peer review Not commissioned; externally peer reviewed. 24. Cutolo M, Sulli A, Pizzorni C, et al. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001;60:729–35. Open Access This is an Open Access article distributed in accordance with the 25. Cantarini L, Lucherini OM, Muscari I, et al. Tumour necrosis factor Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which receptor-associated periodic syndrome (TRAPS): state of the art and permits others to distribute, remix, adapt, build upon this work non-commercially, future perspectives. Autoimmun Rev 2012;12:38–43. and license their derivative works on different terms, provided the original work is 26. Duru N, van der Goes MC, Jacobs JW, et al. EULAR evidence-based properly cited and the use is non-commercial. See: http://​creativecommons.​org/​ and consensus-based recommendations on the management of licenses/by-​ ​nc/4.​ ​0/ medium to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2013;72:1905–13. © Article author(s) (or their employer(s) unless otherwise stated in the text of the 27. Devauchelle-Pensec V, Berthelot JM, Cornec D, et al. Efficacy of article) 2018. All rights reserved. No commercial use is permitted unless otherwise first-line tocilizumab therapy in early polymyalgia rheumatica: a expressly granted. prospective longitudinal study. Ann Rheum Dis 2016;75:1506–10.

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28. Tanaka T, Kishimoto T. Targeting interleukin-6: all the way to 30. Matteson EL, Dasgupta B, Schmidt WA. 2-Week single-blind, treat autoimmune and inflammatory diseases. Int J Biol Sci randomized, 3-arm proof of concept study of the effects of 2012;8:1227–36. secukinumab (anti-IL17 mAb), canakinumab (anti-IL-1 b mAb), or 29. Ramos-Casals M, Roberto-Perez-Alvarez , Diaz-Lagares C, et al. on initial disease activity scores in patients with Autoimmune diseases induced by biological agents: a double-edged PMR, followed by an open-label extension to ssess safety and effect sword? Autoimmun Rev 2010;9:188–93. duration. Arthritis Rheum 2014;66(Suppl):391–2. http://rmdopen.bmj.com/ on September 28, 2021 by guest. Protected copyright.

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