Review Article | Published:

Pharmacogenetics: implications for therapy in rheumatic diseases

Nature Reviews Rheumatology volume 7, pages 537550 (2011) | Download Citation

  • A Corrigendum to this article was published on 10 March 2015

This article has been updated

Abstract

DMARDs not only improve the joint pain and swelling associated with rheumatoid arthritis (RA), but also slow down the joint damage associated with the disease. The efficacy of biologic therapies, introduced in the past decade for the treatment of RA, has been unequivocally established. Similarly, in addition to traditional drugs such as hydroxychloroquine, new biologic agents such as rituximab have been introduced for systemic lupus erythematosus in recent years. However, considerable variability occurs in the responses of patients to these therapies. Pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs, is a rapidly progressing field in rheumatology. Pharmacogenetic applications, particularly to the old vanguard DMARD, methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible. The pharmacogenetics of commonly used DMARDs and of biologic therapies are described in this Review.

Key points

  • Responses to therapies used in rheumatic diseases vary considerably between individual patients

  • Pharmacogenetics—how drug efficacy and toxicity are affected by variations in genes encoding drug metabolizing enzymes, transporters and targets—is a nascent, promising area of research in rheumatology

  • Pharmacogenetic applications, both for traditional agents such as methotrexate, and for biologic agents, might facilitate individualized therapy in rheumatoid arthritis and systemic lupus erythematosus

  • The importance of a few genetic variants has been established by reproducibility, notably 677C>T polymorphism of methylene tetrahydrofolate reductase, and thiopurine S-methyltransferase allelic variants—markers of methotrexate and azathioprine toxicity, respectively

  • Although more research is needed to replicate preliminary findings, and to formally validate established markers, several exploratory, promising new markers are showing the future potential of this exciting field

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Change history

  • 10 March 2015

    There are two errors in Table 5 on page 546 of this article. The reported clinical effects of variant -308 G>A from Seitz et al. (2007) and Cuchacovich et al. (2006) should both read 'Associated with decreased efficacy' not 'Associated with increased efficacy' as originally printed. The error has been corrected for the HTML and PDF versions of the article.

References

  1. 1.

    et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).

  2. 2.

    & Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).

  3. 3.

    & Pharmacogenomics: unlocking the human genome for better drug therapy. Annu. Rev. Pharmacol. Toxicol. 41, 101–121 (2001).

  4. 4.

    et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822 (1985).

  5. 5.

    & A long-term prospective study of the use of methotrexate in rheumatoid arthritis. Update after a mean of fifty-three months. Arthritis Rheum. 31, 577–584 (1988).

  6. 6.

    & Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71, 537–592 (2002).

  7. 7.

    , & The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. 42, 1007–1017 (2001).

  8. 8.

    Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate. Mol. Pharmacol. 17, 105–110 (1980).

  9. 9.

    , , , & Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin. Arthritis Rheum. 27, 277–292 (1998).

  10. 10.

    et al. Human thymidylate synthetase—III. Effects of methotrexate and folate analogs. Biochem. Pharmacol. 28, 2633–2637 (1979).

  11. 11.

    & Molecular action of methotrexate in inflammatory diseases. Arthritis Res. 4, 266–273 (2002).

  12. 12.

    et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann. Rheum. Dis. 58, 79–84 (1999).

  13. 13.

    et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum. 44, 2525–2530 (2001).

  14. 14.

    et al. Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann. Rheum. Dis. 63, 1227–1231 (2004).

  15. 15.

    et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics 12, 183–190 (2002).

  16. 16.

    & Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J. Rheumatol. 36, 539–545 (2009).

  17. 17.

    & Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin. Drug Investig. 30, 101–108 (2010).

  18. 18.

    , , , & Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct. 20, 191–197 (1995).

  19. 19.

    , , & Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 19, 3249–3252 (1999).

  20. 20.

    & The role of thymidylate synthase as a molecular biomarker. Clin. Cancer Res. 10, 411–412 (2004).

  21. 21.

    et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 1, 65–70 (2001).

  22. 22.

    et al. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol. Biomarkers Prev. 9, 1381–1385 (2000).

  23. 23.

    , & Regulatory functions of 3′UTRs. Biochem. Biophys. Res. Commun. 288, 291–295 (2001).

  24. 24.

    , , , & Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int. J. Mol. Med. 11, 593–600 (2003).

  25. 25.

    et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 54, 2830–2839 (2006).

  26. 26.

    et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin. Exp. Rheumatol. 24, 546–554 (2006).

  27. 27.

    Effects of DMARDs on IL-1Ra levels in rheumatoid arthritis: is there any evidence? Clin. Exp. Rheumatol. 20 (Suppl. 27), S26–S31 (2002).

  28. 28.

    , & Pretreatment cytokine profiles of peripheral blood mononuclear cells and serum from patients with rheumatoid arthritis in different American College of Rheumatology response groups to methotrexate. J. Rheumatol. 30, 28–35 (2003).

  29. 29.

    et al. IL-1B and IL-1RN gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy. Pharmacogenomics 7, 683–695 (2006).

  30. 30.

    et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 50, 2766–2774 (2004).

  31. 31.

    et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum. 54, 607–612 (2006).

  32. 32.

    et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 56, 1765–1775 (2007).

  33. 33.

    et al. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics 11, 163–175 (2010).

  34. 34.

    et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 14, 181–187 (2004).

  35. 35.

    et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6, 279–290 (1996).

  36. 36.

    et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608–614 (1997).

  37. 37.

    et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am. J. Hum. Genet. 58, 694–702 (1996).

  38. 38.

    , , , & Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Proc. Natl Acad. Sci. USA 94, 6444–6449 (1997).

  39. 39.

    et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J. Clin. Oncol. 19, 2293–2301 (2001).

  40. 40.

    et al. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum. 38, 142–145 (1995).

  41. 41.

    et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 41, 1858–1866 (1998).

  42. 42.

    et al. Azathioprine-induced fatal myelosuppression in systemic lupus erythematosus patient carrying TPMT*3C polymorphism. Lupus 17, 132–134 (2008).

  43. 43.

    , , & Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 11, 177–188 (2010).

  44. 44.

    , , , & Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology (Oxford) 38, 640–644 (1999).

  45. 45.

    et al. Genetic polymorphisms of thiopurine S-methyltransferase in a cohort of patients with systemic autoimmune diseases. Clin. Exp. Rheumatol. 27, 321–324 (2009).

  46. 46.

    Polymorphism of human acetyltransferases. Environ. Health Perspect. 102 (Suppl. 6), 213–216 (1994).

  47. 47.

    , , & Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N. Engl. J. Med. 289, 491–495 (1973).

  48. 48.

    & Variables affecting efficacy and toxicity of sulphasalazine in rheumatoid arthritis. A review. Drugs 32 (Suppl. 1), 54–57 (1986).

  49. 49.

    , , & Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis. Pharmacogenetics 10, 35–41 (2000).

  50. 50.

    et al. Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J. Rheumatol. 29, 2492–2499 (2002).

  51. 51.

    et al. Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet. Genomics 17, 383–390 (2007).

  52. 52.

    et al. NAT2 genotyping and efficacy of sulfasalazine in patients with chronic discoid lupus erythematosus. Pharmacogenetics 7, 131–135 (1997).

  53. 53.

    & Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc. Natl Acad. Sci. USA 75, 3327–3331 (1978).

  54. 54.

    , , , & Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 15, 268–275 (2006).

  55. 55.

    & Chloroquine interferes with lipopolysaccharide-induced TNF-α gene expression by a nonlysosomotropic mechanism. J. Immunol. 165, 1534–1540 (2000).

  56. 56.

    , , & Differential effect of IL10 and TNFα genotypes on determining susceptibility to discoid and systemic lupus erythematosus. Ann. Rheum. Dis. 64, 1605–1610 (2005).

  57. 57.

    , , , & Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms. Transplantation 75, 711–717 (2003).

  58. 58.

    et al. An investigation of polymorphism in the interleukin-10 gene promoter. Eur. J. Immunogenet. 24, 1–8 (1997).

  59. 59.

    , , , & Cytokine polymorphisms influence treatment outcomes in SLE patients treated with antimalarial drugs. Arthritis Res. Ther. 8, R42 (2006).

  60. 60.

    , , , & The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry 35, 1270–1273 (1996).

  61. 61.

    & Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr. Opin. Immunol. 8, 710–720 (1996).

  62. 62.

    et al. The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 10, 303–309 (2009).

  63. 63.

    , , , & Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis. Ann. Rheum. Dis. 68, 1367–1368 (2009).

  64. 64.

    , , , & The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 12, 41–47 (2010).

  65. 65.

    et al. Estrogens interfere with leflunomide modulation of cytokine production by human activated monocytes. Ann. NY Acad. Sci. 1193, 30–35 (2010).

  66. 66.

    et al. Sex hormones modulate the effects of Leflunomide on cytokine production by cultures of differentiated monocyte/macrophages and synovial macrophages from rheumatoid arthritis patients. J. Autoimmun. 32, 254–260 (2009).

  67. 67.

    et al. In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes. Drug Metab. Dispos. 31, 1240–1250 (2003).

  68. 68.

    et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur. J. Clin. Pharmacol. 64, 871–876 (2008).

  69. 69.

    et al. Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum. 50, 2202–2210 (2004).

  70. 70.

    et al. Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br. J. Clin. Pharmacol. 62, 457–472 (2006).

  71. 71.

    , & Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 45, 51–88 (2005).

  72. 72.

    , & The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

  73. 73.

    , & Is there a future for TNF promoter polymorphisms? Genes Immun. 5, 315–329 (2004).

  74. 74.

    , & Is there a future for TNF promoter polymorphisms? Genes Immun. 5, 315–329 (2004).

  75. 75.

    et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-α production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin. Exp. Immunol. 113, 401–406 (1998).

  76. 76.

    et al. Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit. Care Med. 28, 2733–2736 (2000).

  77. 77.

    et al. Secretion of tumour necrosis factor α and lymphotoxin α in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand. J. Immunol. 43, 456–463 (1996).

  78. 78.

    Polymorphism of the human TNF-α promoter—random variation or functional diversity? Mol. Immunol. 36, 1017–1027 (1999).

  79. 79.

    , , & In vivo characterization of regulatory polymorphisms by allele-specific quantification of RNA polymerase loading. Nat. Genet. 33, 469–475 (2003).

  80. 80.

    et al. TNF-α promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. J. Neuroimmunol. 72, 149–153 (1997).

  81. 81.

    et al. Tumor necrosis factor- α gene polymorphism in severe and mild–moderate rheumatoid arthritis. J. Rheumatol. 29, 29–33 (2002).

  82. 82.

    et al. Association of tumor necrosis factor receptor type II polymorphism 196R with systemic lupus erythematosus in the Japanese: molecular and functional analysis. Arthritis Rheum. 44, 2819–2827 (2001).

  83. 83.

    , , , & Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics 16, 180–186 (1993).

  84. 84.

    et al. A novel polymorphism of FcγRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J. Clin. Invest. 100, 1059–1070 (1997).

  85. 85.

    , , & The 158V polymorphism of Fcγ receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project). Rheumatology (Oxford) 44, 1294–1298 (2005).

  86. 86.

    et al. FcgammaRIIIA-158V and rheumatoid arthritis: a confirmation study. Rheumatology 42, 528–533 (2003).

  87. 87.

    et al. Role of Fcγ receptors IIA, IIIA, and IIIB in susceptibility to rheumatoid arthritis. J. Rheumatol. 30, 926–933 (2003).

  88. 88.

    et al. The F158V polymorphism in FcγRIIIA shows disparate associations with rheumatoid arthritis in two genetically distinct populations. Ann. Rheum. Dis. 61, 1021–1023 (2002).

  89. 89.

    et al. Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease. Aliment. Pharmacol. Ther. 19, 511–519 (2004).

  90. 90.

    et al. Fcγ receptor type IIIA genotype and response to tumor necrosis factor α blocking agents in patients with rheumatoid arthritis. Arthritis Rheum. 56, 448–452 (2007).

  91. 91.

    , , & The --308 tumour necrosis factor- α gene polymorphism predicts therapeutic response to TNFα-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology 46, 93–96 (2007).

  92. 92.

    et al. Tumour necrosis factor (TNF)α -308 G/G promoter polymorphism and TNFα levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scand. J. Rheumatol. 35, 435–440 (2006).

  93. 93.

    , , & Associations between tumor necrosis factor-α (TNF α) -308 and -238 G/A polymorphisms and shared epitope status and responsiveness to TNF-α blockers in rheumatoid arthritis: a metaanalysis update. J. Rheumatol. 37, 740–746 (2010).

  94. 94.

    et al. Tumor necrosis factor-α receptor II polymorphism in patients from southern Europe with mild–moderate and severe rheumatoid arthritis. J. Rheumatol. 29, 1847–1850 (2002).

  95. 95.

    et al. Polymorphisms spanning the TNFR2 and TACE genes do not contribute towards variable anti-TNF treatment response. Pharmacogenet. Genomics 20, 338–341 (2010).

  96. 96.

    et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum. 50, 1077–1082 (2004).

  97. 97.

    et al. The influence of genetic variation in the HLA-DRB1 and LTA–TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 50, 2750–2756 (2004).

  98. 98.

    et al. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor α therapy. Arthritis Rheum. 62, 1849–1861 (2010).

  99. 99.

    , & CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

  100. 100.

    , , & CD45-induced tumor necrosis factor α production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-κB-independent. J. Biol. Chem. 274, 33455–33461 (1999).

  101. 101.

    & Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis. Am. J. Pathol. 164, 177–184 (2004).

  102. 102.

    et al. Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann. Rheum. Dis. 70, 98–103 (2011).

  103. 103.

    et al. Monoclonal anti-CD20 antibodies: mechanisms of action and monitoring of biological effects. Joint Bone Spine 76, 458–463 (2009).

  104. 104.

    et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99, 754–758 (2002).

  105. 105.

    et al. Fc γ RIIIa and Fc γ RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 103, 1472–1474 (2004).

  106. 106.

    et al. BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren's syndrome. Arthritis Rheum. 56, 1464–1477 (2007).

  107. 107.

    et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48, 455–459 (2003).

  108. 108.

    et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann. Rheum. Dis. 65, 1213–1218 (2006).

  109. 109.

    et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J. Rheumatol. 35, 572–579 (2008).

  110. 110.

    & Conference Scene: The great debate: genome-wide association studies in pharmacogenetics research, good or bad? Pharmacogenomics 11, 305–308 (2010).

  111. 111.

    , & Assessing the cost-effectiveness of pharmacogenomics. AAPS PharmSci. 2, E29 (2000).

  112. 112.

    , & Practical pharmacogenetics: the cost effectiveness of screening for thiopurine S-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J. Rheumatol. 29, 2507–2512 (2002).

  113. 113.

    International HapMap Project. NIH , (2011).

  114. 114.

    Pharmacogenomics Research Network. National Institute of General Medical Sciences, NIH , (2011).

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  1. Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8045, St Louis, MO 63110, USA

    • Lesley Davila
    •  & Prabha Ranganathan

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https://doi.org/10.1038/nrrheum.2011.117

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