Emerging cell and cytokine targets in rheumatoid arthritis

Journal name:
Nature Reviews Rheumatology
Volume:
10,
Pages:
77–88
Year published:
DOI:
doi:10.1038/nrrheum.2013.168
Published online

Abstract

Despite major progress in the treatment of rheumatoid arthritis (RA), strong unmet medical need remains, as only a minor proportion of patients reach sustained clinical remission. New approaches are therefore necessary, and include manipulation of regulatory T cells, which might be able to restore the disturbed immune system and could even lead to a cure if this restored regulation were to prove sustainable. Logistical and conceptual problems, however, beset this attractive therapeutic approach, including difficulties with ex vivo expansion of cells, specificity of targeting and the optimal time point of administration. Therefore, alternative avenues are being investigated, such as targeting B-cell effector functions and newly identified proinflammatory cytokines. On the basis of success with B-cell depleting therapy using anti-CD20 agents, further treatment modalities are now exploring direct or indirect interference in B-cell-mediated immunity with the use of agents directed against other B-cell surface molecules. Novel approaches target intracellular B-cell signalling and regulatory B cells. New cytokine-directed therapies target important proinflammatory mediators such as GM-CSF, new members of the IL-1 family, IL-6 and its receptor, IL-17, IL-20, IL-21, IL-23 as well as synovium-specific targets. This article reviews these emerging cell and cytokine targets with special focus on biologic agents, some of which might reach the clinic soon whereas others will require considerable time in development. Nevertheless, these exciting new approaches will considerably enhance our repertoire in the battle against this potentially devastating disease.

At a glance

Figures

  1. Stepwise development of arthritis in RA.
    Figure 1: Stepwise development of arthritis in RA.

    a | Induction phase: initial activation of the (auto)immune system leads to an inflammatory cascade. Possible triggers are injuries, infections and exposures to toxic substances (smoking). These events, which involve APCs and the citrullination of relevant proteins, might occur outside of the joints as well as within them. Along with monocyte/macrophage infiltration into the synovium, local synovial cells, notably fibroblasts and macrophages, are activated leading to the secretion of proinflammatory cytokines of both the innate and adaptive immune systems. b | Inflammation phase: self antigens, notably citrullinated proteins, are presented in the context of HLA class II molecules that are characteristic of RA. This presentation leads to polyclonal activation of T cells and B cells, and the formation of germinal-like centres in the synovial tissue. This process is insufficiently controlled by TREG cells. c | Self perpetuation: cartilage autoantigens, which are not normally accessible to the immune system, become exposed by damage and are presented, activating the immune system against cartilage tissue with further infiltration of pannus into the joints resulting in further destruction. d | Destruction phase: synovial fibroblasts and osteoclasts are activated by proinflammatory cytokines such as TNF and IL-6. Destruction of bone and cartilage ensues. Abbreviations: APC, antigen-presenting cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; RA, rheumatoid arthritis; TEFF, effector T (cell); TH, helper T (cell); TH1, type 1 helper T (cell); TH17, type 17 helper T (cell); TREG, regulatory T (cell).

  2. Potential interventions using TREG cells in RA.
    Figure 2: Potential interventions using TREG cells in RA.

    IL-2 treatment might directly restore and/or initiate the growth and/or function of CD25-positive TREG cells in vivo. TREG cells might be expanded in vitro and potentially be modified through genetic manipulation to target antigens present in the inflamed joint. These cells could then be transferred back to the patient. Another approach would be to specifically activate TREG cells using the anti-CD4 monoclonal antibody tregalizumab. Finally, Tregitopes—peptides derived from human IgG—might be used to specifically activate TREG cells, dampening an autoimmune response. Abbreviations: DC, dendritic cell; IDO, indolamin-2,3-dioxygenase; RA, rheumatoid arthritis; TCR, T-cell receptor; TREG, regulatory T (cell).

  3. Direct and indirect B-cell targeting.
    Figure 3: Direct and indirect B-cell targeting.

    Direct targets of anti-B cell therapy comprise surface molecules expressed by B cells or their subsets, such as type I CD20 (target of rituximab and ofatumumab), CD22 (target of epratuzumab, which is not in development for RA), CD19, CD52 (targeted by alemtuzumab, which also co-targets T cells), and receptor–ligand pairs in co-stimulatory pathways, such as CD40–CD40L, CD80/CD86–CTLA-4 (inhibited by abatacept) and inducible T-cell co-stimulator (ICOS)–ICOS ligand. FcγRIIb is thought to be an inhibitory receptor that controls B-cell activation. Inhibiting cytokines involved in B-cell differentiation and maintenance is an indirect anti-B cell principle. These molecules include BAFF (specifically targeted by belimumab and tabalumab), APRIL (atacicept simultaneously blocks BAFF and APRIL), IL-21, IL-6–IL-6R, IL-1 and others, which fuel the inflammatory response via activation of other immune cells (T cells, macrophages, neutrophils) resulting into co-activation of B cells and effector functions. Abbreviations: APRIL, a proliferation-inducing ligand (TNF ligand superfamily member 13); BAFF, B-cell activating factor (TNF ligand superfamily member 13B); BAFF-R, BAFF receptor (TNF receptor superfamily member 13C); BCMA, B-cell maturation protein (TNF receptor superfamily member 17); CTLA-4; cytotoxic T-lymphocyte protein 4; DC, dendritic cell; FcγRIIb, Fcγ receptor IIb; TACI, transmembrane activator and CAML interactor (TNF receptor superfamily member 13B); TCR, T-cell receptor. Adapted from Gregersen, J. W. & Jayne, D. R. W. Nat. Rev. Nephrol. (2012).120 © NPG.

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Affiliations

  1. Department of Rheumatology and Clinical Immunology, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

    • Gerd R. Burmester,
    • Eugen Feist &
    • Thomas Dörner

Contributions

All author contributed substantially to each stage of the preparation of this manuscript for submission.

Competing interests statement

G. R. Burmester declares that he has received speakers' honoraria and has acted as a consultant for AbbVie, BMS, MedImmune, MSD, Pfizer, Roche/Chugai and UCB. E. Feist declares that he has received speakers' honoraria and has acted as a consultant for BMS, Pfizer, Novartis and Roche/Chugai. T. Dörner declares that he has received speakers' honoraria and has acted as a consultant for Elli Lilly, NovoNordisk, Roche/Chugai, Takeda and UCB, and has received research/grant support from Roche/Chugai, UCB, Takeda, Janssen/J&J and Sanofi.

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Author details

  • Gerd R. Burmester

    Gerd R. Burmester MD is Professor of Medicine and Director of the Department of Rheumatology and Clinical Immunology at the Charité-Universitätsmedizin, Berlin, Germany, Free University and Humboldt University of Berlin. His research interests include rheumatoid arthritis, Lyme borreliosis, immunotherapy, cellular activation mechanisms in inflammatory joint diseases and tissue engineering. Professor Burmester served as President of the German Society of Rheumatology from 2001–2002 and is currently President-elect of EULAR.

  • Eugen Feist

    Eugen Feist MD is Head of the Clinical Trial Unit in the Department of Rheumatology and Clinical Immunology at the Charité-Universitätsmedizin, Berlin, Germany, and studied medicine in Kiev, Ukraine and Berlin, Germany from 1989–1995. He specialized in Internal Medicine (2003) and Rheumatology (2005). His main scientific interests are autoantibody diagnostics and the role of the proteasome system in autoimmunity. He was awarded with the MSD-grant “Arthrose/Arthritis” in 2005 and worked as a post-doctoral fellow in the Institute of Immunobiology at Harvard Medical School, Boston, USA in 2006.

  • Thomas Dörner

    Thomas Dörner is a Professor of Rheumatology and Clinical Immunology (Innovative Therapies for Autoimmune Diseases) and leads the Clinical Hemostaseology group at the Charité University Medicine, Berlin, and the B cell memory group at the German Rheumatology Research Center, Berlin. His major scientific interests are the role and differentiation of B cells in autoimmune diseases, innovative immune therapies for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and Sjögren's syndrome, and the relationship between inflammation and coagulation.

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