Skip to main content

Advertisement

SpringerLink
Log in

Risk of serious infections in biological treatment of patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

The objective of the study is to quantitatively assess the risk of serious infections in patients with axial spondyloarthritis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) treated by biologics enrolled in randomized controlled trials (RCTs). A systematic literature searches of MEDLINE (via PubMed), EMBASE, the Cochrane Library and abstracts archives of the annual scientific meetings of both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) was conducted through October 2015. The RCTs that compared the safety of any biologics treatment for AS or nr-axSpA with placebo and/or non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional disease modifying antirheumatic drugs (DMARDs) with a minimum of 12 weeks of follow-up were selected independently by 2 reviewers. Twenty-five RCTs with data from 2403 patients were analyzed in the analysis. Patients included active AS in 21 studies and nr-axSpA in 4 studies were treated by 5 TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab and infliximab) and 3 non-TNF inhibitors (sarilumab, tocilizumab, secukinumab). The risk of serious infections has no difference and numerically was only slightly increased in patients with AS and nr-axSpA treated by biologics compared with controls (OR = 1.42; 95%CI 0.58–3.47). Stratified analysis yielded the pooled risk differences (RDs) of 0.00 (95%CI, − 0.01 to 0.01), 0.01 (95%CI − 0.01 to 0.03), − 0.00 (95%CI −0.01 to 0.01), 0.00 (95%CI − 0.02 to 0.02), 0.01 (95%CI −0.01 to 0.03) and 0.01 (95%CI −0.02 to 0.04) for adalimumab, certolizumab, etanercept, golimumab, infliximab and non-TNF inhibitors respectively. There are also no significant effect of biologics on serious infections was observed compared with controls in patients with AS (p = 0.29) and nr-axSpA (p = 0.89). The use of biologics among patients with AS and nr-axSpA included in RCTs was not significantly associated with an increased risk of serious infections compared with placebo or NSAIDs or DMARDs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27(4):361–368. https://doi.org/10.1002/art.1780270401

    Article  PubMed  Google Scholar 

  2. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, Braun J, Chou CT, Collantes-Estevez E, Dougados M, Huang F, Gu J, Khan MA, Kirazli Y, Maksymowych WP, Mielants H, Sorensen IJ, Ozgocmen S, Roussou E, Valle-Onate R, Weber U, Wei J, Sieper J (2009) 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. https://doi.org/10.1136/ard.2009.108233

    Article  CAS  PubMed  Google Scholar 

  3. Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369(9570):1379–1390. https://doi.org/10.1016/S0140-6736(07)60635-7

    Article  PubMed  Google Scholar 

  4. Brown MA, Kenna T, Wordsworth BP (2016) Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol 12(2):81–91. https://doi.org/10.1038/nrrheum.2015.133

    Article  CAS  PubMed  Google Scholar 

  5. Akkoc N, Khan MA (2005) Overestimation of the prevalence of ankylosing spondylitis in the Berlin study: comment on the article by Braun et al. Arthritis Rheum 52(12):4048–4049. https://doi.org/10.1002/art.21492

    Article  PubMed  Google Scholar 

  6. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, Cueto JP, Gonzales-Crespo MR, Fulton S, Suarez-Almazor ME (2012) Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 308(9):898–908. https://doi.org/10.1001/2012.jama.10857

    Article  CAS  PubMed  Google Scholar 

  7. Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, Dagfinrud H, Dijkmans B, Dougados M, Emery P, Geher P, Hammoudeh M, Inman R, Jongkees M, Khan M, Kiltz U, Kvien T, Leirisalo-Repo M, Maksymowych W, Olivieri I, Pavelka K, Sieper J, Stanislawska-Biernat E, Wendling D, Ozgocmen S, van Drogen C, van Royen B, van der Heijde D (2011) 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 70(6):896–904. https://doi.org/10.1136/ard.2011.151027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roychowdhury B, Bintley-Bagot S, Bulgen DY, Thompson RN, Tunn EJ, Moots RJ (2002) Is methotrexate effective in ankylosing spondylitis? Rheumatology (Oxford) 41(11):1330–1332. https://doi.org/10.1093/rheumatology/41.11.1330

    Article  CAS  Google Scholar 

  9. Regel A, Sepriano A, Baraliakos X, van der Heijde D, Braun J, Landewé R, van den Bosch F, Falzon L, Ramiro S (2017) Efficacy and safety of non-pharmacological and non-biological pharmacological treatment: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis. RMD Open 3(1):e000397. https://doi.org/10.1136/rmdopen-2016-000397

    Article  PubMed  PubMed Central  Google Scholar 

  10. Macfarlane GJ, Barnish MS, Jones EA, Kay L, Keat A, Meldrum KT, Pathan E, Sturrock RD, Zabke C, McNamee P, Jones GT (2015) The British Society for Rheumatology Biologics Registers in Ankylosing Spondylitis (BSRBR-AS) study: protocol for a prospective cohort study of the long-term safety and quality of life outcomes of biologic treatment. BMC Musculoskelet Disord 16(1):347. https://doi.org/10.1186/s12891-015-0805-x

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, Gossec L, Landewe R, Smolen JS, Buch MH (2014) Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 73(3):516–528. https://doi.org/10.1136/annrheumdis-2013-204577

    Article  CAS  PubMed  Google Scholar 

  12. Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL, Kupper H, Braun J, Sieper J (2008) Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 58(7):1981–1991. https://doi.org/10.1002/art.23606

    Article  CAS  PubMed  Google Scholar 

  13. Brandt J, Khariouzov A, Listing J, Haibel H, Sörensen H, Grassnickel L, Rudwaleit M, Sieper J, Braun J (2003) Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 48(6):1667–1675. https://doi.org/10.1002/art.11017

    Article  CAS  PubMed  Google Scholar 

  14. Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser AD, Cawkwell LS, Bennett A, McGonagle D, Emery P (2009) Clinical and imaging efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum 60(4):946–954. https://doi.org/10.1002/art.24408

    Article  CAS  PubMed  Google Scholar 

  15. Bao C, Huang F, Khan MA, Fei K, Wu Z, Han C, Hsia EC (2014) Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial. Rheumatology (Oxford) 53(9):1654–1663. https://doi.org/10.1093/rheumatology/keu132

    Article  CAS  Google Scholar 

  16. Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, McInnes I, van Laar JM, Landewé R, Wordsworth P, Wollenhaupt J, Kellner H, Paramarta J, Wei J, Brachat A, Bek S, Laurent D, Li Y, Wang YA, Bertolino AP, Gsteiger S, Wright AM, Hueber W (2013) Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382(9906):1705–1713. https://doi.org/10.1016/S0140-6736(13)61134-4

    Article  CAS  PubMed  Google Scholar 

  17. Landewe R, Braun J, Deodhar A et al (2014) 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. https://doi.org/10.1136/annrheumdis-2013-204231

    Article  CAS  PubMed  Google Scholar 

  18. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M (2014) Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 73(1):95–100. https://doi.org/10.1136/annrheumdis-2013-203559

    Article  CAS  PubMed  Google Scholar 

  19. Sieper J, Braun J, Kay J, Badalamenti S, Radin AR, Jiao L, Fiore S, Momtahen T, Yancopoulos GD, Stahl N, Inman RD (2015) Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis 74(6):1051–1057. https://doi.org/10.1136/annrheumdis-2013-204963

    Article  CAS  PubMed  Google Scholar 

  20. Cludts I, Spinelli FR, Morello F, Hockley J, Valesini G, Wadhwa M (2017) Anti-therapeutic antibodies and their clinical impact in patients treated with the TNF antagonist adalimumab. Cytokine 96:16–23. https://doi.org/10.1016/j.cyto.2017.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Baraliakos X, Listing J, Brandt J, Haibel H, Rudwaleit M, Sieper J, Braun J (2007) Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology (Oxford) 46(9):1450–1453. https://doi.org/10.1093/rheumatology/kem166

    Article  CAS  Google Scholar 

  22. Braun J, van der Horst-Bruinsma IE, Huang F, Burgos-Vargas R, Vlahos B, Koenig AS, Freundlich B (2011) Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial. Arthritis Rheum 63(6):1543–1551. https://doi.org/10.1002/art.30223

    Article  CAS  PubMed  Google Scholar 

  23. Marzo-Ortega H, McGonagle D, Jarrett S, Haugeberg G, Hensor E, O'connor P, Tan AL, Conaghan PG, Greenstein A, Emery P (2005) Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study. Ann Rheum Dis 64(11):1568–1575. https://doi.org/10.1136/ard.2004.022582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sampaio-Barros PD, van der Horst-Bruinsma IE (2014) Adverse effects of TNF inhibitors in SpA: are they different from RA? Best Pract Res Clin Rheumatol 28(5):747–763. https://doi.org/10.1016/j.berh.2014.10.001

    Article  PubMed  Google Scholar 

  25. Ozguler Y, Hatemi G, Ugurlu S, Seyahi E, Melikoglu M, Borekci S, Atahan E, Ongen G, Hamuryudan V (2016) Re-initiation of biologics after the development of tuberculosis under anti-TNF therapy. Rheumatol Int 36(12):1719–1725. https://doi.org/10.1007/s00296-016-3575-3

    Article  CAS  PubMed  Google Scholar 

  26. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, Ghogomu ET, Coyle D, Clifford T, Tugwell P, Wells GA (2015) Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet 386(9990):258–265. https://doi.org/10.1016/S0140-6736(14)61704-9

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295(19):2275–2285. https://doi.org/10.1001/jama.295.19.2275

    Article  CAS  PubMed  Google Scholar 

  28. Salliot C, Dougados M, Gossec L (2009) Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 68(1):25–32. https://doi.org/10.1136/ard.2007.083188

    Article  CAS  PubMed  Google Scholar 

  29. Thompson AE, Rieder SW, Pope JE (2011) Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 63(6):1479–1485. https://doi.org/10.1002/art.30310

    Article  CAS  PubMed  Google Scholar 

  30. Fouque-Aubert A, Jette-Paulin L, Combescure C, Basch A, Tebib J, Gossec L (2010) Serious infections in patients with ankylosing spondylitis with and without TNF blockers: a systematic review and meta-analysis of randomised placebo-controlled trials. Ann Rheum Dis 69(10):1756–1761. https://doi.org/10.1136/ard.2008.098822

    Article  CAS  PubMed  Google Scholar 

  31. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12. https://doi.org/10.1016/0197-2456(95)00134-4

    Article  CAS  PubMed  Google Scholar 

  32. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-lhle E, Kellner H, Krause A, Schneider M, Sörensen H, Zeidler H, Thriene W, Sieper J (2002) Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 359(9313):1187–1193. https://doi.org/10.1016/S0140-6736(02)08215-6

    Article  CAS  PubMed  Google Scholar 

  33. Gorman JD, Sack KE, Davis JC Jr (2002) Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346(18):1349–1356. https://doi.org/10.1056/NEJMoa012664

    Article  CAS  PubMed  Google Scholar 

  34. Van Den Bosch F, Kruithof E, Baeten D et al (2002) Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 46(3):755–765. https://doi.org/10.1002/art.511

    Article  Google Scholar 

  35. Davis JC Jr, Van Der Heijde D, Braun J et al (2003) Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 48:3230–3236

    Article  CAS  PubMed  Google Scholar 

  36. Calin A, Dijkmans BA, Emery P, Hakala M, Kalden J, Leirisalo-Repo M, Mola EM, Salvarani C, Sanmartí R, Sany J, Sibilia J, Sieper J, van der Linden S, Veys E, Appel AM, Fatenejad S (2004) Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 63(12):1594–1600. https://doi.org/10.1136/ard.2004.020875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, Braun J, Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group (2005) Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 52(2):582–591. https://doi.org/10.1002/art.20852

    Article  PubMed  Google Scholar 

  38. van der Heijde D, Da Silva JC, Dougados M, Geher P, van der Horst-Bruinsma I, Juanola X, Olivieri I, Raeman F, Settas L, Sieper J, Szechinski J, Walker D, Boussuge MP, Wajdula JS, Paolozzi L, Fatenejad S, for the Etanercept Study 314 Investigators (2006) Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Ann Rheum Dis 65(12):1572–1577. https://doi.org/10.1136/ard.2006.056747

    Article  PubMed  PubMed Central  Google Scholar 

  39. van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BAC, Braun J, Dougados M, Reveille JD, Wong RL, Kupper H, Davis JC, ATLAS Study Group (2006) 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. https://doi.org/10.1002/art.21913

    Article  PubMed  Google Scholar 

  40. Inman RD, Davis JC Jr, Heijde D et al (2008) 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. https://doi.org/10.1002/art.23969

    Article  CAS  PubMed  Google Scholar 

  41. Dougados M, Braun J, Szanto S, Combe B, Elbaz M, Geher P, Thabut G, Leblanc V, Logeart I (2011) Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE). Ann Rheum Dis 70(5):799–804. https://doi.org/10.1136/ard.2010.139261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Horneff G, Fitter S, Foeldvari I, Minden K, Kuemmerle-Deschner J, Tzaribacev N, Thon A, Borte M, Ganser G, Trauzeddel R, Huppertz HI (2012) Double-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): significant short term improvement. Arthritis Res Ther 14(5):R230. https://doi.org/10.1186/ar4072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych WP, Brown MA, Arora V, Pangan AL (2013) Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 72(6):815–822. https://doi.org/10.1136/annrheumdis-2012-201766

    Article  CAS  PubMed  Google Scholar 

  44. Dougados M, van der Heijde D, Sieper J, Braun J, Maksymowych WP, Citera G, Miceli-Richard C, Wei JCC, Pedersen R, Bonin R, Rahman MU, Logeart I, Wajdula J, Koenig AS, Vlahos B, Alvarez D, Bukowski JF (2014) Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 66(8):2091–2102. https://doi.org/10.1002/art.38721

    Article  CAS  PubMed  Google Scholar 

  45. Huang F, Gu J, Zhu P, Bao C, Xu J, Xu H, Wu H, Wang G, Shi Q, Andhivarothai N, Anderson J, Pangan AL (2014) Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: results of a randomised, controlled trial. Ann Rheum Dis 73(3):587–594. https://doi.org/10.1136/annrheumdis-2012-202533

    Article  CAS  PubMed  Google Scholar 

  46. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, Park S, Song Y, Yao R, Chitkara D, Vastesaeger N, on Behalf of All INFAST Investigators (2014) Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, part 1. Ann Rheum Dis 73(1):101–107. https://doi.org/10.1136/annrheumdis-2012-203201

    Article  CAS  PubMed  Google Scholar 

  47. Braun J, Davis J, Dougados M, Sieper J, van der Linden S, van der Heijde D (2006) First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 65(3):316–320. https://doi.org/10.1136/ard.2005.040758

    Article  CAS  PubMed  Google Scholar 

  48. Yun H, Xie F, Delzell E, Chen L, Levitan EB, Lewis JD, Saag KG, Beukelman T, Winthrop K, Baddley JW, Curtis JR (2015) Risk of hospitalised infection in rheumatoid arthritis patients receiving biologics following a previous infection while on treatment with anti-TNF therapy. Ann Rheum Dis 74(6):1065–1071. https://doi.org/10.1136/annrheumdis-2013-204011

    Article  CAS  PubMed  Google Scholar 

  49. Desai RJ, Bateman BT, Huybrechts KF et al (2017) Risk of serious infections associated with use of immunosuppressive agents in pregnant women with autoimmune inflammatory conditions: cohort study. BMJ 356:j895

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Sen Wang, Qian He & Zongwen Shuai

Authors
  1. Sen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zongwen Shuai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zongwen Shuai.

Ethics declarations

Disclosures

None.

Financial support

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, S., He, Q. & Shuai, Z. Risk of serious infections in biological treatment of patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Clin Rheumatol 37, 439–450 (2018). https://doi.org/10.1007/s10067-017-3966-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-017-3966-1

Keywords

Search

Navigation