Rheumatoid arthritis The Lancet Prof Josef S Smolen, MD, Daniel Aletaha, MD, Prof Iain B McInnes, MD  The Lancet  Volume 388, Issue 10055, Pages 2023-2038 (October 2016) DOI: 10.1016/S0140-6736(16)30173-8 Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 1 Important loci associated with risk and progression of rheumatoid arthritis Key immune cells implicated in the pathogenesis of rheumatoid arthritis. Th1=T-helper-1. Th17=T-helper-17. Treg=regulatory T. mDC=myeloid dendritic cell. pDC=plasmacytoid dendritic cell. The Lancet 2016 388, 2023-2038DOI: (10.1016/S0140-6736(16)30173-8) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 2 Pathways to rheumatoid arthritis In a genetically predisposed host with susceptibility genes, environmental insults, epigenetic modifications, and post-translational modifications can lead to loss of tolerance with subsequent asymptomatic synovitis, ultimately leading to clinically overt arthritis. ACPA=autoantibodies against citrullinated peptides. RF=rheumatoid factor. Adapted from Smolen and colleagues33 by permission of Elsevier, and McInnes and Schett34 by permission of the Massachusetts Medical Society. The Lancet 2016 388, 2023-2038DOI: (10.1016/S0140-6736(16)30173-8) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 3 Pathogenetic pathways in rheumatoid arthritis Green text shows molecules or cells which are successfully targeted by respective therapies. Red text relates to molecules or cells for which targeting was not effective. Adapted from Smolen and colleagues33 by permission of Elsevier, Mavers and colleagues57 by permission of Springer, and Smolen and Steiner58 by permission of Nature Publishing Group. The Lancet 2016 388, 2023-2038DOI: (10.1016/S0140-6736(16)30173-8) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 4 Therapeutic approaches to rheumatoid arthritis (A) General strategy. (B) Early treatment phase. (C) Treatment approach if methotrexate (plus glucocorticoid) does not achieve the treatment target. (D) Treatment approach after a first biologic has failed. The recommendation to potentially use a TNF inhibitor after another TNF inhibitor has failed is based on the available evidence for biological DMARDs, but in some countries switching to another mode of action is recommended or mandated (against this evidence). Treatment algorithm based on EULAR recommendations.89,100 DMARD=disease-modifying antirheumatic drug. tsDMARD=targeted synthetic DMARD. csDMARD=conventional synthetic DMARD. bDMARD=biological DMARD. ACR=American College of Rheumatology. EULAR=European League Against Rheumatism. CDAI=clinical disease activity index. HDA=high disease activity. MDA=moderate disease activity. LDA=low disease activity. REM=remission. TNF=tumour necrosis factor. The Lancet 2016 388, 2023-2038DOI: (10.1016/S0140-6736(16)30173-8) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 5 Response to different DMARD therapies (A) Abatacept (inhibition of T-cell co-stimulation). (B) Golimumab (TNF inhibitor). (C) Tocilizumab (anti-interleukin 6 receptor antibody). (D) Rituximab (anti-CD20 mediated B-cell depletion). (E) Tofacitinib (pan-JAK inhibitor). (F) Baricitinib (JAK1/2 inhibitor; Eli Lilly, Indianapolis, IN, USA). ACR70 improvement rates as a surrogate for profound treatment responses. Baricitinib is not yet approved by regulatory authorities but has completed phase 3 trials. For the full list of references, see appendix. DMARD=disease-modifying antirheumatic drug. MTX=methotrexate. Adapted from Smolen and Aletaha2 by permission of Nature Publishing Group. The Lancet 2016 388, 2023-2038DOI: (10.1016/S0140-6736(16)30173-8) Copyright © 2016 Elsevier Ltd Terms and Conditions