Rheumatoid Arthritis

  • Matthew L. StollEmail author
  • S. Louis BridgesJr.
  • Maria I. Danila


Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with both environmental and genetic factors but of unknown cause. There are >100 associated gene loci, the most significant of which is HLA-DRB1 in the major histocompatibility complex region. Recent work has also highlighted important roles of the human mucosal microbiota, at both the gingival as well as the intestinal surfaces. Periodontal disease and alterations in the gingival microbiota, including overgrowth of Porphyromonas gingivalis, are associated with RA. A key hallmark of RA is serum anti-citrullinated protein antibodies reactive against a variety of posttranslationally citrullinated proteins, which are enriched in RA, particularly in patients with HLA-DRB1 risk alleles. Citrullination of arginine residues is catalyzed by peptidylarginine deiminases (PADs). Of note, P. gingivalis produces its own PAD enzyme (PPAD), which may contribute to the citrullination of native proteins. Differences in the intestinal microbiota, particularly overgrowth of Prevotella copri, are associated with early RA, perhaps compensating for the absence of HLA-DRB1 risk alleles in some patients. As the role of the microbiota in RA is elucidated, targeted interventions to manipulate the microbiome to prevent or treat RA may emerge.


Antibiotics Microbiota Periodontitis Probiotics Rheumatoid arthritis 



Anti-cyclic citrullinated peptide antibody


Chronic rheumatoid arthritis


Disease activity score


Dendritic cells


Healthy control




Juvenile idiopathic arthritis


Matrix metalloproteinase


New-onset rheumatoid arthritis


Nonsteroidal anti-inflammatory drug




Peptidylarginine deiminase


Periodontal disease


P. gingivalis peptidylarginine deiminase


Rheumatoid arthritis


Shared epitope


Scaling and root planning


Tumor necrosis factor inhibitor


  1. 1.
    Bailey CF. The treatment of chronic rheumatic and rheumatoid arthritis by radiant heat and cataphoresis. Br Med J. 1909;1:13–5.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mayberry J. The history of 5-ASA compounds and their use in ulcerative colitis--trailblazing discoveries in gastroenterology. J Gastrointestin Liver Dis. 2013;22:375–7.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol. 2008;35:1500–5.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Shinebaum R, Neumann VC, Cooke EM, Wright V. Comparison of faecal florae in patients with rheumatoid arthritis and controls. Br J Rheumatol. 1987;26:329–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Severijnen AJ, Kool J, Swaak AJ, Hazenberg MP. Intestinal flora of patients with rheumatoid arthritis: induction of chronic arthritis in rats by cell wall fragments from isolated Eubacterium aerofaciens strains. Br J Rheumatol. 1990;29:433–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Dearlove SM, Barr K, Neumann V, Isdale A, Bird HA, Gooi HC, et al. The effect of non-steroidal anti-inflammatory drugs on faecal flora and bacterial antibody levels in rheumatoid arthritis. Br J Rheumatol. 1992;31(7):443.CrossRefPubMedGoogle Scholar
  7. 7.
    Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Goodman AL, Kallstrom G, Faith JJ, Reyes A, Moore A, Dantas G, et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc Natl Acad Sci U S A. 2011;108:6252–7.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Toivanen P. Normal intestinal microbiota in the aetiopathogenesis of rheumatoid arthritis. Ann Rheum Dis. 2003;62:807–11.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473:174–80.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30:1205–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016;68(11):2646–61.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J, et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016;8:43.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21:895–905.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cao Y, Shen J, Ran ZH. Association between Faecalibacterium prausnitzii reduction and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Gastroenterol Res Pract. 2014;2014:872725.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Stoll ML, Kumar R, Morrow CD, Lefkowitz EJ, Cui X, Genin A, et al. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis Res Ther. 2014;16:486.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Di Paola M, Cavalieri D, Albanese D, Sordo M, Pindo M, Donati C, et al. Alteration of Fecal Microbiota profiles in juvenile idiopathic arthritis. Associations with HLA-B27 allele and disease status. Front Microbiol. 2016;7:1703.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008;27:104–19.CrossRefPubMedGoogle Scholar
  21. 21.
    Pianta A, Arvikar S, Strle K, Drouin EE, Wang Q, Costello CE, et al. Evidence for immune relevance of Prevotella copri, a gut microbe, in patients with rheumatoid arthritis. Arthritis Rheumatol. 2016;69(5):964–75.CrossRefGoogle Scholar
  22. 22.
    Cuvelier C, Barbatis C, Mielants H, De Vos M, Roels H, Veys E. Histopathology of intestinal inflammation related to reactive arthritis. Gut. 1987;28:394–401.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hindryckx P, Laukens D, Serry G, Van Praet L, Cuvelier C, Mielants H, et al. Subclinical gut inflammation in spondyloarthritis is associated with a pro-angiogenic intestinal mucosal phenotype. Ann Rheum Dis. 2011;70:2044–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontology 2000. 2014;64:57–80.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bingham CO 3rd, Moni M. Periodontal disease and rheumatoid arthritis: the evidence accumulates for complex pathobiologic interactions. Curr Opin Rheumatol. 2013;25:345–53.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Scher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, Viale A, et al. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 2012;64(10):3083–94.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Scaling HD. Root planning is recommended in the nonsurgical treatment of chronic periodontitis. J Evid Based Dent Pract. 2016;16:56–8.CrossRefGoogle Scholar
  28. 28.
    de Pablo P, Dietrich T, McAlindon TE. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J Rheumatol. 2008;35:70–6.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Dev YP, Khuller N, Basavaraj P, Suresh G. Rheumatoid Arthritis among periodontitis patients in Baddi industrial Estate of Himachal Pradesh, India: a cross sectional study. J Clin Diagnos Res. 2013;7:2334–7.Google Scholar
  30. 30.
    Joseph R, Rajappan S, Nath SG, Paul BJ. Association between chronic periodontitis and rheumatoid arthritis: a hospital-based case-control study. Rheumatol Int. 2013;33:103–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wolff B, Berger T, Frese C, Max R, Blank N, Lorenz HM, et al. Oral status in patients with early rheumatoid arthritis: a prospective, case-control study. Rheumatology (Oxford). 2014;53:526–31.CrossRefGoogle Scholar
  32. 32.
    Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38–46.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kinane DF, Chestnutt IG. Smoking and periodontal disease. Crit Rev Oral Biol Med. 2000;11:356–65.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Reichert S, Haffner M, Keysser G, Schafer C, Stein JM, Schaller HG, et al. Detection of oral bacterial DNA in synovial fluid. J Clin Periodontol. 2013;40:591–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Temoin S, Chakaki A, Askari A, El-Halaby A, Fitzgerald S, Marcus RE, et al. Identification of oral bacterial DNA in synovial fluid of patients with arthritis with native and failed prosthetic joints. J Clin Rheumatol. 2012;18:117–21.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Johnson S, Sidebottom D, Bruckner F, Collins D. Identification of mycoplasma fermentans in synovial fluid samples from arthritis patients with inflammatory disease. J Clin Microbiol. 2000;38:90–3.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Johnson SM, Bruckner F, Collins D. Distribution of mycoplasma pneumoniae and mycoplasma salivarium in the synovial fluid of arthritis patients. J Clin Microbiol. 2007;45:953–7.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wilkinson NZ, Kingsley GH, Jones HW, Sieper J, Braun J, Ward ME. The detection of DNA from a range of bacterial species in the joints of patients with a variety of arthritides using a nested, broad-range polymerase chain reaction. Rheumatology (Oxford). 1999;38:260–6.CrossRefGoogle Scholar
  39. 39.
    van der Heijden IM, Wilbrink B, Tchetverikov I, Schrijver IA, Schouls LM, Hazenberg MP, et al. Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum. 2000;43:593–8.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sandhya P, Danda D, Sharma D, Scaria V. Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. Int J Rheum Dis. 2016;19:8–20.CrossRefPubMedGoogle Scholar
  41. 41.
    Johansson L, Sherina N, Kharlamova N, Potempa B, Larsson B, Israelsson L, et al. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res Ther. 2016;18:201.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Erciyas K, Sezer U, Ustun K, Pehlivan Y, Kisacik B, Senyurt SZ, et al. Effects of periodontal therapy on disease activity and systemic inflammation in rheumatoid arthritis patients. Oral Dis. 2013;19:394–400.CrossRefPubMedGoogle Scholar
  43. 43.
    Biyikoglu B, Buduneli N, Aksu K, Nalbantsoy A, Lappin DF, Evrenosoglu E, et al. Periodontal therapy in chronic periodontitis lowers gingival crevicular fluid interleukin-1beta and DAS28 in rheumatoid arthritis patients. Rheumatol Int. 2013;33:2607–16.CrossRefPubMedGoogle Scholar
  44. 44.
    Ribeiro J, Leao A, Novaes AB. Periodontal infection as a possible severity factor for rheumatoid arthritis. J Clin Periodontol. 2005;32:412–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Ortiz P, Bissada NF, Palomo L, Han YW, Al-Zahrani MS, Panneerselvam A, et al. Periodontal therapy reduces the severity of active rheumatoid arthritis in patients treated with or without tumor necrosis factor inhibitors. J Periodontol. 2009;80:535–40.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Bonfil JJ, Dillier FL, Mercier P, Reviron D, Foti B, Sambuc R, et al. A “case control” study on the role of HLA DR4 in severe periodontitis and rapidly progressive periodontitis. Identification of types and subtypes using molecular biology (PCR.SSO). J Clin Periodontol. 1999;26:77–84.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44:291–6.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Schaefer AS, Jochens A, Dommisch H, Graetz C, Jockel-Schneider Y, Harks I, et al. A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis. J Clin Periodontol. 2014;41:1122–31.CrossRefPubMedGoogle Scholar
  49. 49.
    Preshaw PM, Taylor JJ. How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis? J Clin Periodontol. 2011;38(Suppl 11):60–84.CrossRefPubMedGoogle Scholar
  50. 50.
    Okada M, Kobayashi T, Ito S, Yokoyama T, Komatsu Y, Abe A, et al. Antibody responses to periodontopathic bacteria in relation to rheumatoid arthritis in Japanese adults. J Periodontol. 2011;82:1433–41.CrossRefPubMedGoogle Scholar
  51. 51.
    Ogrendik M, Kokino S, Ozdemir F, Bird PS, Hamlet S. Serum antibodies to oral anaerobic bacteria in patients with rheumatoid arthritis. MedGenMed. 2005;7:2.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Mikuls TR, Payne JB, Reinhardt RA, Thiele GM, Maziarz E, Cannella AC, et al. Antibody responses to Porphyromonas gingivalis (P. Gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int Immunopharmacol. 2009;9:38–42.CrossRefPubMedGoogle Scholar
  53. 53.
    Kharlamova N, Jiang X, Sherina N, Potempa B, Israelsson L, Quirke AM, et al. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis Etiology. Arthritis Rheumatol. 2016;68:604–13.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hitchon CA, Chandad F, Ferucci ED, Willemze A, Ioan-Facsinay A, van der Woude D, et al. Antibodies to porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives. J Rheumatol. 2010;37:1105–12.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Mikuls TR, Payne JB, Yu F, Thiele GM, Reynolds RJ, Cannon GW, et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66:1090–100.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Seror R, Le Gall-David S, Bonnaure-Mallet M, Schaeverbeke T, Cantagrel A, Minet J, et al. Association of anti-porphyromonas gingivalis antibody Titers with Nonsmoking status in early rheumatoid arthritis: results from the prospective French cohort of patients with early rheumatoid arthritis. Arthritis Rheumatol. 2015;67:1729–37.CrossRefPubMedGoogle Scholar
  57. 57.
    Wegner N, Wait R, Sroka A, Eick S, Nguyen KA, Lundberg K, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010;62:2662–72.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Taylor P, Gartemann J, Hsieh J, Creeden J. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis. 2011;2011:815038.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Mechin MC, et al. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 2007;56:3541–53.CrossRefPubMedGoogle Scholar
  60. 60.
    Chang X, Yamada R, Suzuki A, Sawada T, Yoshino S, Tokuhiro S, et al. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford). 2005;44:40–50.CrossRefGoogle Scholar
  61. 61.
    Kinloch A, Lundberg K, Wait R, Wegner N, Lim NH, Zendman AJ, et al. Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. Arthritis Rheum. 2008;58:2287–95.CrossRefPubMedGoogle Scholar
  62. 62.
    Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402.CrossRefPubMedGoogle Scholar
  63. 63.
    Poor G, Nagy ZB, Schmidt Z, Brozik M, Meretey K, Gergely P Jr. Genetic background of anticyclic citrullinated peptide autoantibody production in Hungarian patients with rheumatoid arthritis. Ann N Y Acad Sci. 2007;1110:23–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Du Y, Liu X, Guo JP, Liu X, Li R, Zhao Y, et al. Association between PADI4 gene polymorphisms and anti-cyclic citrullinated peptide antibody positive rheumatoid arthritis in a large Chinese Han cohort. Clin Exp Rheumatol. 2014;32:377–82.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Yamamoto K, Yamada R. Genome-wide single nucleotide polymorphism analyses of rheumatoid arthritis. J Autoimmun. 2005;25(Suppl):12–5.CrossRefPubMedGoogle Scholar
  66. 66.
    Gabarrini G, de Smit M, Westra J, Brouwer E, Vissink A, Zhou K, et al. The peptidylarginine deiminase gene is a conserved feature of Porphyromonas gingivalis. Sci Rep. 2015;5:13936.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Maresz KJ, Hellvard A, Sroka A, Adamowicz K, Bielecka E, Koziel J, et al. Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLoS Pathog. 2013;9:e1003627.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Kuhn KA, Kulik L, Tomooka B, Braschler KJ, Arend WP, Robinson WH, et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Investig. 2006;116:961–73.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Cui J, Taylor KE, Destefano AL, Criswell LA, Izmailova ES, Parker A, et al. Genome-wide association study of determinants of anti-cyclic citrullinated peptide antibody titer in adults with rheumatoid arthritis. Mol Med. 2009;15:136–43.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kokkonen H, Brink M, Hansson M, Lassen E, Mathsson-Alm L, Holmdahl R, et al. Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis. Arthritis Res Ther. 2015;17:125.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Doyle TJ, Dellaripa PF, Batra K, Frits ML, Iannaccone CK, Hatabu H, et al. Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest. 2014;146:41–50.CrossRefPubMedGoogle Scholar
  72. 72.
    Scher JU, Joshua V, Artacho A, Abdollahi-Roodsaz S, Ockinger J, Kullberg S, et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome. 2016;4:60.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Segata N, Haake SK, Mannon P, Lemon KP, Waldron L, Gevers D, et al. Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biol. 2012;13:R42.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Nordstrom D, Lindy O, Lauhio A, Sorsa T, Santavirta S, Konttinen YT. Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis. Rheumatol Int. 1998;17:175–80.CrossRefPubMedGoogle Scholar
  75. 75.
    O’Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, et al. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum. 2006;54:621–7.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Vaghef-Mehrabany E, Alipour B, Homayouni-Rad A, Sharif SK, Asghari-Jafarabadi M, Zavvari S. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition. 2014;30:430–5.CrossRefPubMedGoogle Scholar
  77. 77.
    Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E, Sharif SK, Vaghef-Mehrabany L, Asghari-Jafarabadi M, et al. Effects of lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double-blind clinical trial. Int J Rheum Dis. 2014;17:519–27.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Mandel DR, Eichas K, Holmes J. Bacillus coagulans: a viable adjunct therapy for relieving symptoms of rheumatoid arthritis according to a randomized, controlled trial. BMC Complement Altern Med. 2010;10(1):1.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G. Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev. 2009;1:CD006400.Google Scholar
  82. 82.
    Kang C, Zhang Y, Zhu X, Liu K, Wang X, Chen M, et al. Healthy subjects differentially respond to dietary capsaicin correlating with the specific gut enterotypes. J Clin Endocrinol Metab. 2016;101(12):4681–9. jc20162786.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Borg AA, Davis MJ, Fowler PD, Shadforth MF, Dawes PT. Rifampicin in early rheumatoid arthritis. Scand J Rheumatol. 1993;22:39–42.CrossRefPubMedGoogle Scholar
  84. 84.
    Ogrendik M. Levofloxacin treatment in patients with rheumatoid arthritis receiving methotrexate. South Med J. 2007;100:135–9.CrossRefPubMedGoogle Scholar
  85. 85.
    Ogrendik M. Effects of clarithromycin in patients with active rheumatoid arthritis. Curr Med Res Opin. 2007;23:515–22.CrossRefPubMedGoogle Scholar
  86. 86.
    Saviola G, Abdi-Ali L, Campostrini L, Sacco S, Baiardi P, Manfredi M, et al. Clarithromycin in rheumatoid arthritis: the addition to methotrexate and low-dose methylprednisolone induces a significant additive value--a 24-month single-blind pilot study. Rheumatol Int. 2013;33:2833–8.CrossRefPubMedGoogle Scholar
  87. 87.
    Ogrendik M. Efficacy of roxithromycin in adult patients with rheumatoid arthritis who had not received disease-modifying antirheumatic drugs: a 3-month, randomized, double-blind, placebo-controlled trial. Clin Ther. 2009;31:1754–64.CrossRefPubMedGoogle Scholar
  88. 88.
    Ogrendik M, Karagoz N. Treatment of rheumatoid arthritis with roxithromycin: a randomized trial. Postgrad Med. 2011;123:220–7.CrossRefPubMedGoogle Scholar
  89. 89.
    Sreekanth VR, Handa R, Wali JP, Aggarwal P, Dwivedi SN. Doxycycline in the treatment of rheumatoid arthritis--a pilot study. J Assoc Physicians India. 2000;48:804–7.PubMedPubMedCentralGoogle Scholar
  90. 90.
    St Clair EW, Wilkinson WE, Pisetsky DS, Sexton DJ, Drew R, Kraus VB, et al. The effects of intravenous doxycycline therapy for rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2001;44:1043–7.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    van der Laan W, Molenaar E, Ronday K, Verheijen J, Breedveld F, Greenwald R, et al. Lack of effect of doxycycline on disease activity and joint damage in patients with rheumatoid arthritis. A double blind, placebo controlled trial. J Rheumatol. 2001;28:1967–74.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Pillemer S, Gulko P, Ligier S, Yarboro C, Gourley M, Goldbach-Mansky R, et al. Pilot clinical trial of intravenous doxycycline versus placebo for rheumatoid arthritis. J Rheumatol. 2003;30:41–3.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C, Dijkmans BA. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum. 1994;37:629–36.CrossRefPubMedGoogle Scholar
  94. 94.
    Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA trial group. Ann Intern Med. 1995;122:81–9.CrossRefPubMedGoogle Scholar
  95. 95.
    O’Dell JR, Haire CE, Palmer W, Drymalski W, Wees S, Blakely K, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1997;40:842–8.CrossRefPubMedGoogle Scholar
  96. 96.
    O’Dell JR, Blakely KW, Mallek JA, Eckhoff PJ, Leff RD, Wees SJ, et al. Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum. 2001;44:2235–41.CrossRefPubMedGoogle Scholar
  97. 97.
    Skinner M, Cathcart ES, Mills JA, Pinals RS. Tetracycline in the treatment of rheumatoid arthritis. A double blind controlled study. Arthritis Rheum. 1971;14:727–32.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Gompels LL, Smith A, Charles PJ, Rogers W, Soon-Shiong J, Mitchell A, et al. Single-blind randomized trial of combination antibiotic therapy in rheumatoid arthritis. J Rheumatol. 2006;33:224–7.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Smith A, Dore C, Charles P, Vallance A, Potier T, Mackworth-Young C. Randomised double-blind trial of combination antibiotic therapy in rheumatoid arthritis. Int J Rheumatol. 2011;2011:585497.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Harkness JA, Griffin AJ, Heinrich I, Gibson T, Grahame R. A double-blind comparative study of metronidazole and placebo in rheumatoid arthritis. Rheumatol Rehabil. 1982;21:231–4.CrossRefPubMedGoogle Scholar
  101. 101.
    Marshall DA, Hunter JA, Capell HA. Double blind, placebo controlled study of metronidazole as a disease modifying agent in the treatment of rheumatoid arthritis. Ann Rheum Dis. 1992;51:758–60.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Ogrendik M, Hakguder A, Keser N. Treatment of rheumatoid arthritis with ornidazole. A randomized, double-blind, placebo-controlled study. Rheumatology (Oxford). 2006;45:636–7.CrossRefGoogle Scholar
  103. 103.
    Ash G, Baker R, Rajapakse C, Swinson DR. Study of sulphamethoxazole in rheumatoid arthritis. Br J Rheumatol. 1986;25:285–7.CrossRefPubMedGoogle Scholar
  104. 104.
    Wojtulewski JA, Gow PJ, Walter J, Grahame R, Gibson T, Panayi GS, et al. Clotrimazole in rheumatoid arthritis. Ann Rheum Dis. 1980;39:469–72.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Neumann VC, Grindulis KA, Hubball S, McConkey B, Wright V. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial. Br Med J. 1983;287:1099–102.CrossRefGoogle Scholar
  106. 106.
    Pullar T, Hunter JA, Capell HA. Sulphasalazine in rheumatoid arthritis: a double blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br Med J. 1983;287:1102–4.CrossRefGoogle Scholar
  107. 107.
    Pinals RS, Kaplan SB, Lawson JG, Hepburn B. Sulfasalazine in rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum. 1986;29:1427–34.CrossRefPubMedGoogle Scholar
  108. 108.
    Williams HJ, Ward JR, Dahl SL, Clegg DO, Willkens RF, Oglesby T, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum. 1988;31:702–13.CrossRefPubMedGoogle Scholar
  109. 109.
    Hannonen P, Mottonen T, Hakola M, Oka M. Sulfasalazine in early rheumatoid arthritis. A 48-week double-blind, prospective, placebo-controlled study. Arthritis Rheum. 1993;36:1501–9.CrossRefPubMedGoogle Scholar
  110. 110.
    Hatakka K, Martio J, Korpela M, Herranen M, Poussa T, Laasanen T, et al. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis--a pilot study. Scand J Rheumatol. 2003;32:211–5.CrossRefPubMedGoogle Scholar
  111. 111.
    Pineda Mde L, Thompson SF, Summers K, de Leon F, Pope J, Reid G. A randomized, double-blinded, placebo-controlled pilot study of probiotics in active rheumatoid arthritis. Med Sci Monit. 2011;17:CR347–54.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Matthew L. Stoll
    • 1
    Email author
  • S. Louis BridgesJr.
    • 2
  • Maria I. Danila
    • 3
  1. 1.University of Alabama at Birmingham, Department of PediatricsBirminghamUSA
  2. 2.Division of Clinical Immunology and Rheumatology, Comprehensive Arthritis, Musculoskeletal, Bone, and Autoimmunity Center, UABThe University of Alabama at BirminghamBirminghamUSA
  3. 3.University of Alabama at Birmingham, Division of Clinical Immunology and RheumatologyBirminghamUSA

Personalised recommendations