Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.
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Malmstrom, V., Catrina, A. I. & Klareskog, L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat. Rev. Immunol. 17, 60–75 (2017).
Myasoedova, E., Crowson, C. S., Kremers, H. M., Therneau, T. M. & Gabriel, S. E. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum. 62, 1576–1582 (2010).
Tobon, G. J., Youinou, P. & Saraux, A. The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. J. Autoimmun 35, 10–14 (2010).
Malemba, J. J. et al. The epidemiology of rheumatoid arthritis in Kinshasa, Democratic Republic of Congo—a population-based study. Rheumatology 51, 1644–1647 (2012).
Peschken, C. A. & Esdaile, J. M. Rheumatic diseases in North America's indigenous peoples. Semin. Arthritis Rheum. 28, 368–391 (1999).
Kawatkar, A. A., Portugal, C., Chu, L.-H. & Iyer, R. Racial/ethnic trends in incidence and prevalence of rheumatoid arthritis in a large multi-ethnic managed care population [abstract]. Arthritis Rheum. 64, S1061 (2012).
MacGregor, A. J. et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 43, 30–37 (2000).
Stahl, E. A. et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat. Genet. 44, 483–489 (2012).
Padyukov, L. et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann. Rheum. Dis. 70, 259–265 (2011).
Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987). This is the single most important paper on the genetics of RA, after the seminal work of Peter Stastny detecting the association between RA and HLA-DR4, and explains the differences in associations found between different populations by a short amino acid sequence common to all these molecules.
Weyand, C. M., Hicok, K. C., Conn, D. L. & Goronzy, J. J. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann. Intern. Med. 117, 801–806 (1992).
Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).
Raychaudhuri, S. et al. Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat. Genet. 41, 1313–1318 (2009).
Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).
Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).
Remmers, E. F. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).
Thomson, W. et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).
Barton, A. et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat. Genet. 40, 1156–1159 (2008).
Raychaudhuri, S. Recent advances in the genetics of rheumatoid arthritis. Curr. Opin. Rheumatol 22, 109–118 (2010).
Karlson, E. W. et al. Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk. Ann. Rheum. Dis. 69, 1077–1085 (2010).
Viatte, S. et al. Replication of associations of genetic loci outside the HLA region with susceptibility to anti-cyclic citrullinated peptide-negative rheumatoid arthritis. Arthritis Rheumatol. 68, 1603–1613 (2016).
Viatte, S. et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann. Rheum. Dis. 71, 1984–1990 (2012).
Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124–130 (2013).
Martin, P. et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat. Commun. 6, 10069 (2015).
McGovern, A. et al. Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23. Genome Biol. 17, 212 (2016).
Viatte, S. et al. Association between genetic variation in FOXO3 and reductions in inflammation and disease activity in inflammatory polyarthritis. Arthritis Rheumatol. 68, 2629–2636 (2016).
Krabben, A., Huizinga, T. W. & Mil, A. H. Biomarkers for radiographic progression in rheumatoid arthritis. Curr. Pharm. Des. 21, 147–169 (2015).
Lee, J. C. et al. Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway. Cell 155, 57–69 (2013).
Oliver, J., Plant, D., Webster, A. P. & Barton, A. Genetic and genomic markers of anti-TNF treatment response in rheumatoid arthritis. Biomark Med. 9, 499–512 (2015).
Gomez-Cabrero, D. et al. High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis. Genome Med. 8, 124 (2016).
Liu, Y. et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. 31, 142–147 (2013). This paper describes the importance of epigenetic modifications beyond genetic factors in the pathogenesis of RA.
Meng, W. et al. DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis. Arthritis Res. Ther. 19, 71 (2017).
Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).
Ngo, S. T., Steyn, F. J. & McCombe, P. A. Gender differences in autoimmune disease. Front. Neuroendocrinol. 35, 347–369 (2014).
Crowson, C. S. et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 63, 633–639 (2011).
Alpizar-Rodriguez, D., Pluchino, N., Canny, G., Gabay, C. & Finckh, A. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology 56, 1254–1263 (2017).
Alamanos, Y., Voulgari, P. V. & Drosos, A. A. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin. Arthritis Rheum. 36, 182–188 (2006).
Sugiyama, D. et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis. 69, 70–81 (2010).
Vesperini, V. et al. Association of tobacco exposure and reduction of radiographic progression in early rheumatoid arthritis: results from a French multicenter cohort. Arthritis Care Res. 65, 1899–1906 (2013).
Kallberg, H. et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann. Rheum. Dis. 70, 508–511 (2011).
Sokolove, J. et al. Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans. Rheumatology 55, 1969–1977 (2016).
Svendsen, A. J. et al. Differentially methylated DNA regions in monozygotic twin pairs discordant for rheumatoid arthritis: an epigenome-wide study. Front. Immunol. 7, 510 (2016).
Jiang, X., Alfredsson, L., Klareskog, L. & Bengtsson, C. Smokeless tobacco (moist snuff) use and the risk of developing rheumatoid arthritis: results from a case-control study. Arthritis Care Res. 66, 1582–1586 (2014).
Naranjo, A. et al. Smokers and non smokers with rheumatoid arthritis have similar clinical status: data from the multinational QUEST-RA database. Clin. Exp. Rheumatol. 28, 820–827 (2010).
Stolt, P. et al. Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann. Rheum. Dis. 64, 582–586 (2005).
Webber, M. P. et al. Nested case-control study of selected systemic autoimmune diseases in World Trade Center rescue/recovery workers. Arthritis Rheumatol. 67, 1369–1376 (2015).
Too, C. L. et al. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study. Ann. Rheum. Dis. 75, 997–1002 (2016).
Hajishengallis, G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15, 30–44 (2015).
Kharlamova, N. et al. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Arthritis Rheumatol. 68, 604–613 (2016).
Konig, M. F. et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci. Transl Med. 8, 369ra176 (2016).
Chen, J. et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 8, 43 (2016).
Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).
Pianta, A. et al. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J. Clin. Invest. 127, 2946–2956 (2017).
Naciute, M. et al. Frequency and significance of parvovirus B19 infection in patients with rheumatoid arthritis. J. Gen. Virol. 97, 3302–3312 (2016).
Gasque, P., Bandjee, M. C., Reyes, M. M. & Viasus, D. Chikungunya pathogenesis: from the clinics to the bench. J. Infect. Dis. 214 (Suppl. 5), S446–S448 (2016).
Tan, E. M. & Smolen, J. S. Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. J. Exp. Med. 213, 1937–1950 (2016).
Ljung, L. & Rantapaa-Dahlqvist, S. Abdominal obesity, gender and the risk of rheumatoid arthritis — a nested case-control study. Arthritis Res. Ther. 18, 277 (2016).
Lu, B., Solomon, D. H., Costenbader, K. H. & Karlson, E. W. Alcohol consumption and risk of incident rheumatoid arthritis in women: a prospective study. Arthritis Rheumatol. 66, 1998–2005 (2014).
Lee, Y. C. et al. Post-traumatic stress disorder and risk for incident rheumatoid arthritis. Arthritis Care Res. 68, 292–298 (2016).
Camacho, E. M., Verstappen, S. M. & Symmons, D. P. Association between socioeconomic status, learned helplessness, and disease outcome in patients with inflammatory polyarthritis. Arthritis Care Res. 64, 1225–1232 (2012).
Radner, H., Lesperance, T., Accortt, N. A. & Solomon, D. H. Incidence and prevalence of cardiovascular risk factors among patients with rheumatoid arthritis, psoriasis, or psoriatic arthritis. Arthritis Care Res. 69, 1510–1518 (2017).
Lopez-Mejias, R. et al. Cardiovascular risk assessment in patients with rheumatoid arthritis: the relevance of clinical, genetic and serological markers. Autoimmun. Rev. 15, 1013–1030 (2016).
Sparks, J. A. et al. Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses’ Health Study. Arthritis Care Res. 68, 753–762 (2016).
Markusse, I. M. et al. Long-term outcomes of patients with recent-onset rheumatoid arthritis after 10 years of tight controlled treatment: a randomized trial. Ann. Intern. Med. 164, 523–531 (2016).
Masi, A. T. Articular patterns in the early course of rheumatoid arthritis. Am. J. Med. 75, 16–26 (1983).
Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).
Dissick, A. et al. Association of periodontitis with rheumatoid arthritis: a pilot study. J. Periodontol. 81, 223–230 (2010).
Holers, V. M. Autoimmunity to citrullinated proteins and the initiation of rheumatoid arthritis. Curr. Opin. Immunol. 25, 728–735 (2013).
Muller, S. & Radic, M. Citrullinated autoantigens: from diagnostic markers to pathogenetic mechanisms. Clin. Rev. Allergy Immunol. 49, 232–239 (2015).
Trouw, L. A., Huizinga, T. W. & Toes, R. E. Autoimmunity in rheumatoid arthritis: different antigens — common principles. Ann. Rheum. Dis. 72 (Suppl. 2), ii132–ii136 (2013).
Aletaha, D. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 69, 1580–1588 (2010). This article explains that after almost 25 years, new RA classification criteria were developed in a data-driven, consensus process; these criteria also allow classification of patients with early RA who failed to be classified with the previous criteria.
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004). After the seminal observations of Kimmo Aho on the presence of RF and anti-keratin antibodies (which later became known as ACPAs), this paper reveals that ACPA (and RF) precedes the clinical symptoms of RA by assessing sera from blood donors.
Aletaha, D., Alasti, F. & Smolen, J. S. Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials. Arthritis Res. Ther. 17, 229 (2015).
Laurent, L. et al. IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies. Ann. Rheum. Dis. 74, 1425–1431 (2015).
Sokolove, J. et al. Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol. 66, 813–821 (2014).
van Beers, J. J. et al. ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression. Arthritis Res. Ther. 15, R140 (2013).
Deane, K. D. et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum. 62, 3161–3172 (2010).
de Hair, M. J. et al. Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis. Arthritis Rheumatol. 66, 513–522 (2014).
Kraan, M. C. et al. Asymptomatic synovitis precedes clinically manifest arthritis. Arthritis Rheum. 41, 1481–1488 (1998).
Arend, W. P. & Firestein, G. S. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat. Rev. Rheumatol. 8, 573–586 (2012).
Steiner, G. Auto-antibodies and autoreactive T-cells in rheumatoid arthritis: pathogenetic players and diagnostic tools. Clin. Rev. Allergy Immunol. 32, 23–36 (2007).
Kinslow, J. D. et al. Elevated IgA plasmablast levels in subjects at risk of developing rheumatoid arthritis. Arthritis Rheumatol. 68, 2372–2383 (2016).
Shi, J. et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann. Rheum. Dis. 73, 780–783 (2014).
Bohler, C., Radner, H., Smolen, J. S. & Aletaha, D. Serological changes in the course of traditional and biological disease modifying therapy of rheumatoid arthritis. Ann. Rheum. Dis. 72, 241–244 (2013).
Klarenbeek, P. L. et al. Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease. Ann. Rheum. Dis. 71, 1088–1093 (2012).
Ai, R. et al. DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 67, 1978–1980 (2015).
Castor, C. W. The microscopic structure of normal human synovial tissue. Arthritis Rheum. 3, 140–151 (1960).
McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).
Bartok, B. & Firestein, G. S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev. 233, 233–255 (2010).
Stanczyk, J. et al. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 58, 1001–1009 (2008).
Philippe, L. et al. MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. Ann. Rheum. Dis. 72, 1071–1079 (2013).
Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).
Ziff, M. Relation of cellular infiltration of rheumatoid synovial membrane to its immune response. Arthritis Rheum. 17, 313–319 (1974).
Humby, F. et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLOS Med. 6, e1 (2009).
Randen, I. et al. Clonally related IgM rheumatoid factors undergo affinity maturation in the rheumatoid synovial tissue. J. Immunol. 148, 3296–3301 (1992).
Catrina, A. I., Ytterberg, A. J., Reynisdottir, G., Malmstrom, V. & Klareskog, L. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 645–653 (2014).
Orr, C. et al. Synovial tissue research: a state-of-the-art review. Nat. Rev. Rheumatol 13, 463–475 (2017).
Kiener, H. P. et al. Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 60, 1305–1310 (2009).
Keyszer, G. et al. Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Arthritis Rheum. 41, 1378–1387 (1998).
Bottini, N. & Firestein, G. S. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9, 24–33 (2013).
Muller-Ladner, U. et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607–1615 (1996).
Tak, P. P., Zvaifler, N. J., Green, D. R. & Firestein, G. S. Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases. Immunol. Today 21, 78–82 (2000).
Ai, R. et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat. Commun. 7, 11849 (2016).
Schett, G. & Gravallese, E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat. Rev. Rheumatol. 8, 656–664 (2012).
Redlich, K. & Smolen, J. S. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat. Rev. Drug Discov. 11, 234–250 (2012).
Harre, U. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012).
Krishnamurthy, A. et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis. 75, 721–729 (2016).
Hayer, S. et al. Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis. Arthritis Rheum. 56, 79–88 (2007).
Nakano, S. et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology 54, 1498–1506 (2015).
Behrens, F. et al. MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann. Rheum. Dis. 74, 1058–1064 (2015).
Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).
Genovese, M. C. et al. Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374, 1243–1252 (2016).
Boyle, D. L. et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann. Rheum. Dis. 74, 1311–1316 (2015).
Genovese, M. C. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 60, 317–320 (2009).
Genovese, M. C. et al. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-alpha antagonist. J. Rheumatol. 41, 2120–2128 (2014).
Firestein, G. S. The disease formerly known as rheumatoid arthritis. Arthritis Res. Ther. 16, 114 (2014).
Smolen, J. S. et al. Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis activity. Arthritis Rheum. 38, 38–43 (1995).
Koduri, G. et al. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology 49, 1483–1489 (2010).
Bongartz, T. et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 62, 1583–1591 (2010).
Minichiello, E., Semerano, L. & Boissier, M. C. Time trends in the incidence, prevalence, and severity of rheumatoid arthritis: a systematic literature review. Joint Bone Spine 83, 625–630 (2016).
Theander, L. et al. Severe extraarticular manifestations in a community-based cohort of patients with rheumatoid arthritis: risk factors and incidence in relation to treatment with tumor necrosis factor inhibitors. J. Rheumatol 44, 981–987 (2017).
Aggarwal, R. et al. Distinctions between diagnostic and classification criteria? Arthritis Care Res. 67, 891–897 (2015).
Radner, H., Neogi, T., Smolen, J. S. & Aletaha, D. Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: a systematic literature review. Ann. Rheum. Dis. 73, 114–123 (2014).
Hazlewood, G. et al. Algorithm for identification of undifferentiated peripheral inflammatory arthritis: a multinational collaboration through the 3e initiative. J. Rheumatol. Suppl. 87, 54–58 (2011).
Kurko, J. et al. Genetics of rheumatoid arthritis — a comprehensive review. Clin. Rev. Allergy Immunol. 45, 170–179 (2013).
Aletaha, D. & Smolen, J. S. Joint damage in rheumatoid arthritis progresses in remission according to the Disease Activity Score in 28 joints and is driven by residual swollen joints. Arthritis Rheum. 63, 3702–3711 (2011).
Gormley, G. J. et al. Can diagnostic triage by general practitioners or rheumatology nurses improve the positive predictive value of referrals to early arthritis clinics? Rheumatology 42, 763–768 (2003).
Villeneuve, E. et al. A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis. Ann. Rheum. Dis. 72, 13–22 (2013).
de Rooy, D. P., van der Linden, M. P., Knevel, R., Huizinga, T. W. & van der Helm-van Mil, A. H. Predicting arthritis outcomes — what can be learned from the Leiden Early Arthritis Clinic? Rheumatology 50, 93–100 (2011).
van der Helm- van Mil, A. H. et al. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 56, 433–440 (2007).
van Aken, J. et al. Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study). Ann. Rheum. Dis. 73, 396–400 (2014).
Weinblatt, M. E. Efficacy of methotrexate in rheumatoid arthritis. Br. J. Rheumatol 34 (Suppl. 2), 43–48 (1995).
Visser, K. & van der Heijde, D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann. Rheum. Dis. 68, 1094–1099 (2009).
van Ede, A. E. et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 44, 1515–1524 (2001). This study changed the approach to methotrexate therapy, showing that folate substitution does not reduce the efficacy but highly improves the tolerability of methotrexate, thus allowing optimal dosing of the drug.
Felson, D. T. et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 38, 727–735 (1995).
van der Heijde, D. M. et al. Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann. Rheum. Dis. 51, 177–181 (1992). This article presents the first definition of a continuous measure for disease activity; its derivative, DAS28, became more widely used because it is less time-consuming to evaluate and further simplifications of composite measures were developed with CDAI and SDAI.
Smolen, J. S. et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 42, 244–257 (2003).
van der Heide, A. et al. The effectiveness of early treatment with “second-line” antirheumatic drugs. A randomized, controlled trial. Ann. Intern. Med. 124, 699–707 (1996). This is one of the first studies to reveal the importance of the early institution of DMARD therapy and thus the inappropriateness of the pyramid approach, although patients still had relatively long-standing disease.
Huizinga, W. J., Machold, K. P., Breedveld, F. C., Lipsky, P. E. & Smolen, J. S. Criteria for early rheumatoid arthritis: From Bayes’ law revisited to new thoughts on pathogenesis. (Conference summary). Arthritis Rheum. 46, 1155–1159 (2002).
Nell, V. et al. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology 43, 906–914 (2004).
McCarty, D. J. Suppress rheumatoid inflammation early and leave the pyramid to the Egyptians. J. Rheumatol 17, 1117–1118 (1990).
Grigor, C. et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 364, 263–269 (2004).
Aletaha, D. et al. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum. 52, 2625–2636 (2005).
Felson, D. T. et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann. Rheum. Dis. 70, 404–413 (2011). This paper provides a new definition for remission that is sufficiently stringent to be associated with lack of considerable residual disease activity, functional impairment and progression of damage.
Smolen, J. S. et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann. Rheum. Dis. 75, 3–15 (2016). This study defines the pathways to optimizing disease control in RA on the basis of available evidence and consensus finding,
Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994). This is the first controlled study showing the efficacy of a biological agent in RA — namely, the anti-TNF antibody infliximab.
Maini, R. N. et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552–1563 (1998).
Mierau, M. et al. Assessing remission in clinical practice. Rheumatology 46, 975–979 (2007).
Verstappen, S. M. M. et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann. Rheum. Dis. 66, 1443–1449 (2007).
Klarenbeek, N. B. et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann. Rheum. Dis. 70, 1039–1046 (2011).
Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann. Rheum. Dis. 76, 960–977 (2017).
Singh, J. A. et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 68, 1–25 (2016).
Lau, C. S. et al. APLAR rheumatoid arthritis treatment recommendations. Int. J. Rheum. Dis. 18, 685–713 (2015).
Smolen, J. S., Aletaha, D., Grisar, J. C., Stamm, T. A. & Sharp, J. T. Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials. Ann. Rheum. Dis. 69, 1058–1064 (2010).
Aletaha, D., Smolen, J. & Ward, M. M. Measuring function in rheumatoid arthritis: identifying reversible and irreversible components. Arthritis Rheum. 54, 2784–2792 (2006).
Aletaha, D., Alasti, F. & Smolen, J. S. Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point. Ann. Rheum. Dis.https://doi.org/10.1136/annrheumdis-2015-208324 (2015).
Haraoui, B. et al. Treating rheumatoid arthritis to target: a Canadian physician survey. J. Rheumatol. 39, 949–953 (2012).
Pascual-Ramos, V., Contreras-Yanez, I., Villa, A. R., Cabiedes, J. & Rull-Gabayet, M. Medication persistence over 2 years of follow-up in a cohort of early rheumatoid arthritis patients: associated factors and relationship with disease activity and with disability. Arthritis Res. Ther. 11, R26 (2009).
Schoenthaler, A. M., Schwartz, B. S., Wood, C. & Stewart, W. F. Patient and physician factors associated with adherence to diabetes medications. Diabetes Educ. 38, 397–408 (2012).
Kuusalo, L. et al. Impact of physicians’ adherence to treat-to-target strategy on outcomes in early rheumatoid arthritis in the NEO-RACo trial. Scand. J. Rheumatol 44, 449–455 (2015).
Solomon, D. H. et al. Implementation of treat to target in rheumatoid arthritis through a learning collaborative: results of the TRACTION trial. Arthritis Rheumatol. (in press).
Smolen, J. S. & Aletaha, D. Forget personalised medicine and focus on abating disease activity. Ann. Rheum. Dis. 72, 3–6 (2013).
Van der Heijde, D. M.F. M., van't Hof, M., van Riel, P. L. & van de Putte, L. B. A. Development of a disease activity score based on judgement in clinical practice by rheumatologists. J. Rheumatol 20, 579–581 (1993).
Prevoo, M. L. L., van't Hof, M. A., Kuper, H. H., van de Putte, L. B. A. & van Riel, P. L.C. M. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 38, 44–48 (1995).
Bakker, M. F., Jacobs, J. W., Verstappen, S. M. & Bijlsma, J. W. Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann. Rheum. Dis. 66 (Suppl. 3), iii56–iii60 (2007).
Smolen, J. S. & Aletaha, D. The assessment of disease activity in rheumatoid arthritis. Clin. Exp. Rheumatol. 28 (Suppl. 59), S18–S27 (2010).
Smolen, J. S. et al. Brief Report: Remission rates with tofacitinib treatment in rheumatoid arthritis: a comparison of various remission criteria. Arthritis Rheumatol. 69, 728–734 (2017).
Smolen, J. S. & Aletaha, D. Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants. Arthritis Rheum. 63, 43–52 (2011).
Emery, P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann. Rheum. Dis. 67, 1516–1523 (2008).
Schoels, M., Alasti, F., Smolen, J. S. & Aletaha, D. Evaluation of newly proposed remission cut-points for disease activity score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition. Arthritis Res. Ther. 19, 155 (2017).
Studenic, P., Smolen, J. S. & Aletaha, D. Near misses of ACR/EULAR criteria for remission: effects of patient global assessment in Boolean and index-based definitions. Ann. Rheum. Dis. 71, 1702–1705 (2012).
Aletaha, D., Martinez-Avila, J., Kvien, T. K. & Smolen, J. S. Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index. Ann. Rheum. Dis. 71, 1190–1196 (2012).
Dorner, T. et al. The changing landscape of biosimilars in rheumatology. Ann. Rheum. Dis. 75, 974–982 (2016).
Schneider, C. K. Biosimilars in rheumatology: the wind of change. Ann. Rheum. Dis. 72, 315–318 (2013).
van der Goes, M. C. et al. Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann. Rheum. Dis. 69, 1913–1919 (2010).
Verschueren, P. et al. Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Ann. Rheum. Dis. 74, 27–34 (2015).
de Jong, P. H. et al. Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial. Ann. Rheum. Dis. 73, 1331–1339 (2014).
Nam, J. L. et al. Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study). Ann. Rheum. Dis. 73, 75–85 (2014). This is an important study showing that methotrexate plus glucocorticoids is not inferior to methotrexate plus anti-TNF in early RA, thus refuting the use of biological agents before methotrexate.
LaRochelle, G. E. Jr, LaRochelle, A. G., Ratner, R. E. & Borenstein, D. G. Recovery of the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am. J. Med. 95, 258–264 (1993).
Pincus, T., Sokka, T., Castrejon, I. & Cutolo, M. Decline of mean initial prednisone dosage from 3 to 3.6 mg/day to treat rheumatoid arthritis between 1980 and 2004 in one clinical setting, with long-term effectiveness of dosages less than 5 mg/day. Arthritis Care Res. 65, 729–736 (2013).
del Rincón, I., Battafarano, D. F., Restrepo, J. F., Erikson, J. M. & Escalante, A. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol. 66, 264–272 (2014).
Smolen, J. S. et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate without or with concomitant infliximab. Results from the ASPIRE trial. Arthritis Rheum. 54, 702–710 (2006).
Kiely, P., Walsh, D., Williams, R. & Young, A. Outcome in rheumatoid arthritis patients with continued conventional therapy for moderate disease activity—the early RA network (ERAN). Rheumatology 50, 926–931 (2011).
van der Lubbe, P. A., Dijkmans, B. S., Markusse, H., Nassander, U. & Breedveld, F. C. A randomized, double-blind, placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis [abstract]. Arthritis Rheum. 38, 1097–1106 (1995).
Blanco, F. J. et al. Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheumatol. 69, 1144–1153 (2017).
Bonelli, M. et al. Abatacept (CTLA-4IG) treatment reduces the migratory capacity of monocytes in patients with rheumatoid arthritis. Arthritis Rheum. 65, 599–607 (2013).
Buch, M. H. et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 909–920 (2011).
Nam, J. L. et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis. 76, 1113–1136 (2017).
Chatzidionysiou, K. et al. Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis. 76, 1102–1107 (2017).
Fleischmann, R. et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 69, 506–517 (2017).
Fleischmann, R. et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 390, 457–468 (2017).
Weinblatt, M. E. et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 65, 28–38 (2013).
Porter, D. et al. Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet 388, 239–247 (2016).
Smolen, J. S. et al. Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study. Lancet 388, 2763–2774 (2016).
Taylor, P. C. et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N. Engl. J. Med. 376, 652–662 (2017). This is the first study to show any drug being superior to an anti-TNF in RA, here using baricitinib, an oral (small-molecule) DMARD that inhibits JNK1 and JNK2 (to learn more about the clinical implications of these data, more studies are needed).
Smolen, J. S. et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 383, 321–332 (2014).
Kavanaugh, A. et al. Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis. Ann. Rheum. Dis.https://doi.org/10.1136/annrheumdis-2017-211871 (2017).
Kavanaugh, A. et al. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann. Rheum. Dis. 72, 64–71 (2013).
Quinn, M. A. et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 52, 27–35 (2005).
Stamm, T. et al. Induction of sustained remission in ealry inflammatory arthritis with the combination of infliximab plus methotrexate, methotrexate alone or placebo: the DINORA trial [abstract]. Ann. Rheum. Dis. 76 (Suppl. 2), 560 (2017).
Emery, P. et al. Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study. Ann. Rheum. Dis. 74, 979–984 (2015).
Holloway, K. & van Dijk, L. The World Medicines Situation 2011, Rational Use of Medicines 3rd edn (World Health Organzization, Geneva, 2011).
Jorgensen, K. K. et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet 389, 2304–2316 (2017).
Kay, J. et al. Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. Ann. Rheum. Dis.https://doi.org/10.1136/annrheumdis-2017-211937 (2017).
Scheiman, J. M. NSAID-induced gastrointestinal injury: a focused update for clinicians. J. Clin. Gastroenterol. 50, 5–10 (2016).
Nissen, S. E. et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N. Engl. J. Med. 375, 2519–2529 (2016).
Strehl, C. et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann. Rheum. Dis. 75, 952–957 (2016).
Burmester, G. R. et al. Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Ann. Rheum. Dis. 76, 414–417 (2017).
DRFZ. RABBIT Risk Score of Infections. RABBIThttp://www.biologika-register.de/en/home/risk-score/ (2017).
Strangfeld, A. et al. Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res. Ther. 12, R5 (2010).
Burmester, G. R., Panaccione, R., Gordon, K. B., McIlraith, M. J. & Lacerda, A. P. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann. Rheum. Dis. 72, 517–524 (2013).
Strangfeld, A. et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann. Rheum. Dis. 76, 504–510 (2017).
Molloy, E. S., Calabrese, C. M. & Calabrese, L. H. The risk of progressive multifocal leukoencephalopathy in the biologic era: prevention and management. Rheum. Dis. Clin. North Am. 43, 95–109 (2017).
Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol 13, 234–243 (2017).
Kubo, S., Nakayamada, S. & Tanaka, Y. Baricitinib for the treatment of rheumatoid arthritis. Expert Rev. Clin. Immunol. 12, 911–919 (2016).
Strand, V. et al. Use of “spydergrams” to present and interpret SF-36 health-related quality of life data across rheumatic diseases. Ann. Rheum. Dis. 68, 1800–1804 (2009).
Matcham, F. et al. The impact of rheumatoid arthritis on quality-of-life assessed using the SF-36: a systematic review and meta-analysis. Semin. Arthritis Rheum. 44, 123–130 (2014).
Hewlett, S. et al. Patients’ perceptions of fatigue in rheumatoid arthritis: overwhelming, uncontrollable, ignored. Arthritis Rheum. 53, 697–702 (2005).
West, E. & Jonsson, S. W. Health-related quality of life in rheumatoid arthritis in Northern Sweden: a comparison between patients with early RA, patients with medium-term disease and controls, using SF-36. Clin. Rheumatol 24, 117–122 (2005).
Buitinga, L. Valuation of quality of life in rheumatoid arthritis. Thesis, Univ. Twente (2012).
Abu al Fadl, E. M., Ismail, M. A., Thabit, M. & El-Serogy, Y. Assessment of health-related quality of life, anxiety, and depression in patients with early rheumatoid arthritis. Egyptian Rheumatol. 36, 51–56 (2014).
Murillo, Y. A., Almagro, R. M., Campos-Gonzales, I. D. & Cardiel, M. H. Health related quality of life in rheumatoid arthritis, osteoarthritis, diabetes mellitus, end stage renal disease and geriatric subjects. Rheumatol. Clin. 11, 68–72 (2017).
Shokri, A., Mottaghi, P. & Qolipour, K. Quality of life and its predictors among Iranian patients with rheumatoid arthritis: a systematic review. J. Health Res. 6, e24636 (2015).
Kwan, Y. H., Koh, E. T., Leong, K. P. & Wee, H. L. Association between helplessness, disability, and disease activity with health-related quality of life among rheumatoid arthritis patients in a multiethnic Asian population. Rheumatol. Int. 34, 1085–1093 (2014).
Scott, I. C., Ibrahim, F., Lewis, C. M., Scott, D. L. & Strand, V. Impact of intensive treatment and remission on health-related quality of life in early and established rheumatoid arthritis. RMD Open 2, e000270 (2016).
Gerhold, K. et al. Health-related quality of life in patients with long-standing rheumatoid arthritis in the era of biologics: data from the German biologics register RABBIT. Rheumatology 54, 1858–1866 (2015).
Strand, V. & Singh, J. in Targeted Treatment of the Rheumatic Diseases 1st edn (ed. Weisman, M. ) (Elsevier, Philadelphia, PA, 2009).
Strand, V. & Singh, J. A. Newer biological agents in rheumatoid arthritis: impact on health-related quality of life and productivity. Drugs 70, 121–145 (2010).
Chen, J. S., Makovey, J., Lassere, M., Buchbinder, R. & March, L. M. Comparative effectiveness of anti-tumor necrosis factor drugs on health-related quality of life among patients with inflammatory arthritis. Arthritis Care Res. 66, 464–472 (2014).
Strand, V. & Khanna, D. The impact of rheumatoid arthritis and treatment on patients’ lives. Clin. Exp. Rheumatol. 28 (Suppl. 59), S32–S40 (2010).
Strand, V. et al. It's good to feel better but it's better to feel good and even better to feel good as soon as possible for as long as possible. Response criteria and the importance of change at OMERACT 10. J. Rheumatol. 38, 1720–1727 (2011).
Wolfe, F., Michaud, K. & Strand, V. Expanding the definition of clinical differences: from minimally clinically important differences to really important differences. Analyses in 8931 patients with rheumatoid arthritis. J. Rheumatol. 32, 583–589 (2005).
Kosinsk, M., Zhao, S. Z., Dedhiya, S., Osterhaus, J. T. & Ware, J. E. Jr. Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum. 43, 1478–1487 (2000).
Ward, M. M., Guthrie, L. C. & Alba, M. I. Clinically important changes in short form 36 health survey scales for use in rheumatoid arthritis clinical trials: the impact of low responsiveness. Arthritis Care Res. 66, 1783–1789 (2014).
Gossec, L. et al. Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative. Ann. Rheum. Dis. 70, 935–942 (2011).
Dougados, M. et al. Defining cut-off values for disease activity states and improvement scores for patient-reported outcomes: the example of the Rheumatoid Arthritis Impact of Disease (RAID). Arthritis Res. Ther. 14, R129 (2012).
Pincus, T., Richardson, B., Strand, V. & Bergman, M. J. Relative efficiencies of the 7 rheumatoid arthritis Core Data Set measures to distinguish active from control treatments in 9 comparisons from clinical trials of 5 agents. Clin. Exp. Rheumatol. 32 (Suppl. 85), 47–54 (2014).
Taylor, P. C., Moore, A., Vasilescu, R., Alvir, J. & Tarallo, M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol. Int. 36, 685–695 (2016).
Franke, L. C., Ament, A. J., van de Laar, M. A., Boonen, A. & Severens, J. L. Cost-of-illness of rheumatoid arthritis and ankylosing spondylitis. Clin. Exp. Rheumatol. 27 (Suppl. 55), S118–S123 (2009).
Lundkvist, J., Kastäng, F. & Kobelt, G. The burden of rheumatoid arthritis and access to treatment: health burden and costs. Eur. J. Health Econ. 8 (Suppl. 2), S49–S60 (2008).
ter Wee, M. M., Lems, W. F., Usan, H., Gulpen, A. & Boonen, A. The effect of biological agents on work participation in rheumatoid arthritis patients: a systematic review. Ann. Rheum. Dis. 71, 161–171 (2012).
Bansback, N. et al. Triple therapy versus biologic therapy for active rheumatoid arthritis: a cost-effectiveness analysis. Ann. Intern. Med. 167, 8–16 (2017).
Dorner, T. et al. The role of biosimilars in the treatment of rheumatic diseases. Ann. Rheum. Dis. 72, 322–328 (2013).
Smolen, J. S., van der Heijde, D., Machold, K. P., Aletaha, D. & Landewe, R. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann. Rheum. Dis. 73, 3–5 (2014).
Her, M. & Kavanaugh, A. Critical analysis of economic tools and economic measurement applied to rheumatoid arthritis. Clin. Exp. Rheumatol 30 (Suppl. 73), S107–S111 (2012).
Smolen, J. S. & Steiner, G. Therapeutic strategies for rheumatoid arthritis. Nat. Rev. Drug Discov. 2, 473–488 (2003).
Gartner, M. et al. Immediate access rheumatology clinic: efficiency and outcomes. Ann. Rheum. Dis. 71, 363–368 (2012).
Puchner, R. et al. Efficacy and outcome of Rapid Access Rheumatology Consultation: an office-based pilot cohort study. J. Rheumatol. 43, 1130–1135 (2016).
Smolen, J. S. & Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289 (2015).
Deane, K. D. et al. Identification of undiagnosed inflammatory arthritis in a community health fair screen. Arthritis Rheum. 61, 1642–1649 (2009).
Sparks, J. A. et al. Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) Family Study: rationale and design for a randomized controlled trial evaluating rheumatoid arthritis risk education to first-degree relatives. Contemp. Clin. Trials 39, 145–157 (2014).
Sparks, J. A. et al. Disclosure of personalized rheumatoid arthritis risk using genetics, biomarkers, and lifestyle factors to motivate health behavior improvements: a randomized controlled trial. Arthritis Care Res.https://doi.org/10.1002/acr.23411 (2017).
van Dongen, H. et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 56, 1424–1432 (2007).
Gerlag, D. M. et al. A single infusion of rituximab delays the onset of arthritis in subjects at high risk of developing RA [abstract]. Arthritis Rheumatol. 68 (Suppl 10), 3028 (2016).
Emery, P. et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann. Rheum. Dis. 69, 510–516 (2010).
Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).
US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02603146 (2017).
Braun, J. & Rau, R. An update on methotrexate. Curr. Opin. Rheumatol. 21, 216–223 (2009).
Keen, H. I., Conaghan, P. G. & Tett, S. E. Safety evaluation of leflunomide in rheumatoid arthritis. Expert Opin. Drug Saf. 12, 581–588 (2013).
J.S.S. has received grant support from and/or provided expert advice to AbbVie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Celgene, Celltrion, Gilead, Glaxo, ILTOO, Janssen, Lilly, Pfizer, MSD, Roche, Samsung, Novartis-Sandoz and UCB. D.A. served as a consultant and/or speaker for AbbVie, AstraZeneca, BMS, Janssen, Medac, MSD, Pfizer, Roche and UCB and received grant support from BMS. A.B. received grants, speaker fees and/or consultancy fees from Pfizer, Eli Lilly, Janssen, Celgene, Roche-Chugai and Boehringer-Ingelheim. G.R.B. received honoraria for consulting and lectures from AbbVie, BMS, MSD, Pfizer, UCB and Roche. P.E. has undertaken clinical trials and provided expert advice to Pfizer, MSD, AbbVie, BMS, UCB, Roche, Novartis, Samsung, Sandoz and Eli Lilly. G.S.F. has received grant funding from Janssen and Gilead. A.K. has served as a consultant and/or performed clinical research for AbbVie, Amgen, Celgene, Janssen, Novartis and UCB. I.B.M. has received grants, speaker fees and/or consultancy fees from BMS, AbbVie, Pfizer, Eli Lilly, GSK, Janssen, Novartis, Celgene, Roche-Chugai, UCB and Boehringer-Ingelheim. D.H.S. serves in unpaid roles on a clinical trial sponsored by Pfizer. V.S. has served as a consultant to AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Celltrion, Genentech/Roche, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sanofi and UCB and is a founding member of the executive of OMERACT (Outcome Measures in Rheumatology; 1992–present), an organization that develops and validates outcome measures in rheumatology randomized controlled trials and longitudinal observational studies and receives arm's-length funding from 36 sponsors. K.Y. received honoraria for consulting and lectures from AbbVie, AYUMI, BMS, Chugai, Eisai, Janssen, Ono, Pfizer, Tanabe-Mitsubishi and UCB.
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Smolen, J., Aletaha, D., Barton, A. et al. Rheumatoid arthritis. Nat Rev Dis Primers 4, 18001 (2018). https://doi.org/10.1038/nrdp.2018.1
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