This editorial refers to Differential effects of biological DMARDs on peripheral immune cell phenotypes in patients with rheumatoid arthritis

Falconer, Jane

Sunderland University Institutional Repository

EditorialToward cellular biomarkers for rheumatoid arthritisBiomarkers in RAThis editorial refers to Differential effects of biologicalDMARDs on peripheral immune cell phenotypes in pa-tients with rheumatoid arthritis, Shingo Nakayamadaet al., on pages 164–74.RA, like many chronic immune-mediated inflammatorydiseases, has benefited from the advent of biological dis-ease-modifying therapies (biologics), which target specificelements of the disease process. Used as part of a strategicmanagement approach, these treatments have significantlyimproved outcomes for patients. However, restoration ofimmune homeostasis and treatment-free remission are yetto be achieved. Frustrated rheumatologists describe atherapeutic ceiling to be breached only through an im-proved understanding of RA pathophysiology [1].The important contribution of immune cells to RA patho-genesis is evident in the local and systemic manifestationsof disease and is confirmed by genome-wide associationstudies, epigenetic screens and in vivo model systems.Their role is further highlighted by the efficacy of drugs tar-geting the molecules and cells of the immune system,including TNFa and IL-6, the Janus kinase signalling path-way, T-cell co-stimulation and antibody-producing B cells.But which biologic is most appropriate for any individualpatient? And at what stage of disease is each drug mostefficacious? Current treatment regimens do not accom-modate these questions, and instead, drugs are adminis-tered in a conserved sequence until a favourable responseis achieved [2]. As it is now accepted that there are mul-tiple disease endotypes encompassed within the diagno-sis of RA and that there is a strategic window for treatingpatients, after which favourable outcomes are reduced [3],we have better reason than ever to search for new bio-markers for stratification of patients to predict drug effi-cacy, biomarkers for early diagnosis and drug targets forpatients unresponsive to existing therapies [1].Although molecular techniques have proved useful inpredicting drug responses [4], immune cells have beenheralded as particularly promising biomarkers becausethey both orchestrate the disease processes and are thetargets of existing therapies [5]. However, the relativecontributions, spatiotemporal arrangement and effectorprofile of individual cell types across disease stages arenot well understood, a factor which limits our therapeuticexploitation of molecular products including cytokines,chemokines, receptors, adhesion molecules and kinases.One of the sticking points in improving our understand-ing of immune-mediated inflammatory disease pathogen-esis is the standardization of assays to assess cellphenotypes and show true pathological changes ratherthan technical artefacts. The Human Immunology ProjectConsortium (HIPC) is a grouping of six leading US re-search institutes that have come together to addressthis, producing methods for comparable immune profilingacross studies and research centres [6]. An article byShingo Nakayamada et al. [7] has applied these protocolsto the study of RA for the first time (published atRheumatology online ahead of print in March 2017).In a large and complex experiment, the group used 25antibodies and eight colour flow cytometry panels to pro-file the differentiation status and effector phenotype ofmajor lymphocytic and myeloid cells in the peripheralblood. The group analysed 108 RA patients and 33 age-and sex-matched healthy control individuals. Among theRA cohort, clinical and cellular measurements were madeat baseline and after 24weeks of treatment with a bio-logic, targeting IL-6 (tocilizumab, n = 22), T-cell co-stimu-lation (abatacept, n = 40) or TNFa (etanercept, infliximab,adalimumab, golimumab or certolizumab pegol, n = 46)[7]. A summary of findings is shown in Fig. 1.Unsurprisingly, each drug gave rise to a distinct periph-eral immune profile, reflective of the diversity of moleculestargeted. Indeed, many of the cellular responses observedhave been shown in smaller studies looking at individualtherapies or focused upon particular components of theimmune response. However, analysis of this large data settogether has provided a picture of the immune compart-ments affected downstream of different drug targets, withpossible implications for combining biological therapies toimprove patient outcomes in the future.Of course, there are shortcomings and limitations to thescope of this study. For example, the fact that the patientgroup was composed largely of individuals under treat-ment with but unresponsive to MTX imposed limitationsupon comparisons with healthy controls. Furthermore, thesmall number of healthy controls may have contributed tothe poor statistical power of the study and could havebeen addressed. However, a number of important correl-ations could be observed using abundant clinical datawithin the RA group alone, showing relationships betweendisease activity markers and the percentage of circulatingCD4+ memory T cells, Th17 cells, T-follicular helper (Tfh)cells, CD8+ T cells, plasmablasts, IgM memory B cells,classical and non-classical monocytes [7].Importantly, the findings of this paper have contributedto the hot topic areas of plasmacytoid dendritic cell (pDC)biology, cells known for their role in type 1 interferon re-sponses, [8] and Tfh cell [9] biology, cells that orchestrategerminal centre formation and antibody responses. Here,! The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.comRHEUMATOLOGYRheumatology 2018;57:1011doi:10.1093/rheumatology/kex283Advance Access publication 27 July 2017EDITORIALDownloaded from https://academic.oup.com/rheumatology/article-abstract/57/1/10/4049644 by University of Sunderland user on 03 September 2019Nakayamada et al. [7] show plasmacytoid dendritic cellsand Tfh cells to be significant independent predictors ofimprovement in response to TNFa inhibitors and abata-cept, respectively, adding these cells to the armamentar-ium of peripheral blood biomarkers, which might allowclinicians to select the most appropriate treatment for anindividual early in the disease process. However, capita-lizing on this will rely upon the introduction of immuneprofiling to clinical rheumatological practice, as is routinein haematology for the management of lymphoprolifera-tive disease.Although low patient numbers meant that no predictorof tocilizumab response was identified [7], the use of thestandardized HIPC protocol ensures that it is plausible toadd statistical power at a later date to interrogate anti-IL-6responses further. Indeed, it is also tantalizing to imaginecomparing data from other interesting patients, such asthose receiving B-cell-depleting rituximab therapy or pa-tients with other immune-mediated inflammatory diseasesreceiving the same treatments.In fact, it appears from the findings of this article thatsuccessful treatment of RA hinges on control of B-cellresponses. The authors show profound effects on regula-tory, effector and memory B-cell populations which, takentogether with the central role of Tfh cells in orchestratinggerminal centre formation and the role of plasmacytoiddendritic cells in driving plasma cell responses, empha-size that controlling the autoantibody response will be cru-cial to improving outcomes in RA.The immune profiling of peripheral blood as standardizedby HIPC and implemented by Nakayamada et al. [7] hasbroad applications to identify biomarkers and improveknowledge of pathophysiology in immune and inflammatorydiseases and across clinical disciplines. However, this tech-nique can only hint at the spatiotemporal organization ofcells, because elevation in the blood may correspond toproliferation, cell death or a depletion at other sites.Consequently, there is a pressing need for complementarystudies and standardized procedures for analysis ofinflamed tissue and draining lymphoid organs to gain a fullunderstanding and exploit the role of immune cells in RA.AcknowledgementsJ.F. receives support from Arthritis Research UK grant20298.Funding: No specific funding was received from anybodies in the public, commercial or not-for-profit sectorsto carry out the work described in this manuscript.Disclosure statement: The author has declared noconflicts of interest.Jane Falconer11Rheumatology Research Group, Institute of inflammation andAgeing, College of Medical and Dental Sciences, University ofBirmingham, Queen Elizabeth Hospital, Birmingham, UKRevised version accepted 13 June 2017Correspondence to: Jane Falconer, Institute for Inflammationand Ageing, College of Medical and Dental Sciences,University of Birmingham, Queen Elizabeth Hospital,Birmingham B152WD, UK.E-mail: j.falconer@bham.ac.ukReferences1 McInnes IB, Buckley CD, Isaacs JD. Cytokines inrheumatoid arthritis — shaping the immunological land-scape. Nat Rev Rheumatol 2016;12:638.2 Smolen JS, Landewe´ R, Bijlsma J et al. EULAR recom-mendations for the management of rheumatoid arthritiswith synthetic and biological disease-modifying antirheu-matic drugs: 2016 update. Ann Rheum Dis2017;76:96077.3 Raza K, Filer A. The therapeutic window of opportunity inrheumatoid arthritis: does it ever close? Ann Rheum Dis2015;74:79374.4 Guma M, Tiziani S, Firestein GS. Metabolomics inrheumatic diseases: desperately seeking biomarkers. NatRev Rheumatol 2016;12:26981.5 Ermann J, Rao DA, Teslovich NC, Brenner MB,Raychaudhuri S. Immune cell profiling to guide therapeuticdecisions in rheumatic diseases. Nat Rev Rheumatol2015;11:54151.6 Finak G, Langweiler M, Jaimes M et al. Standardizing flowcytometry immunophenotyping analysis from the HumanImmunoPhenotyping Consortium. Sci Rep 2016;6:20686.7 Nakayamada S, Kubo S, Yoshikawa M et al. Differentialeffects of biological DMARDs on peripheral immune cellphenotypes in patients with rheumatoid arthritis.Rheumatology 2018;57:164–74.8 Swiecki M, Colonna M. The multifaceted biology of plas-macytoid dendritic cells. Nat Rev Immunol2015;15:47185.9 Qi H. T follicular helper cells in space-time. Nat RevImmunol 2016;16:61225.FIG. 1 Summary of findings from [7]Dark boxes depict cells which were independent, signifi-cant predictors of a positive response to therapy. (>:increased proportion; <: decreased proportion in periph-eral blood).www.rheumatology.oxfordjournals.org 11EditorialDownloaded from https://academic.oup.com/rheumatology/article-abstract/57/1/10/4049644 by University of Sunderland user on 03 September 2019

Toward cellular biomarkers for rheumatoid arthritis: Biomarkers in RA

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Toward cellular biomarkers for rheumatoid arthritis: Biomarkers in RA

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