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Neutropenia in the Elderly: A Rheumatology Perspective

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Abstract

The majority of rheumatic diseases are chronic and require long-term use of disease-modifying agents to confer the best chance of controlling the disease. A significant proportion of these drugs have a risk, albeit small, of potentially serious side effects, such as neutropenia; therefore, there has been an understandable concern over the use of potentially toxic rheumatic drugs in the elderly. Factors that may contribute to this concern include age, pre-existing co-morbidities, polypharmacy, difficulty in monitoring side effects, and patient perception. The risk of using such medication needs to be balanced with their benefits in controlling chronic disease. This review discusses how rheumatic disease and anti-rheumatic medication are associated with neutropenia in an older age group. Of the rheumatic diseases, we give special focus to rheumatoid arthritis and the use of methotrexate, as well as touching on management considerations in neutropenia.

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References

  1. Todd I, Spickett G. Immunology. 6th ed. Oxford: Wiley-Blackwell; 2010.

    Google Scholar 

  2. National Cancer Institute. common terminology criteria for adverse events version 3.0. DCTD, NCI, NIH, DHHS. March 2003 (Publish date August 2006). NIH publication # 03-5410. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 23 June 2016.

  3. Andersen CL, Tesfa D, Siersma VD, Sandholdt H, Hasselbalch H, Bjerrum OW, Felding P, Lind B, Olivarius NF, Palmblad J. Prevalence and clinical significance of neutropenia discovered in routine complete blood cell counts: a longitudinal study. J Intern Med. 2016;279(6):566–75.

    Article  CAS  PubMed  Google Scholar 

  4. Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol Educ Program. 2012;2012:174–82. doi:10.1182/asheducation-2012.1.174.

    PubMed  Google Scholar 

  5. Shi X, Sims MD, Hanna MM, Xie M, Gulick PG, Zheng YH, Basson MD, Zhang P. Neutropenia during HIV infection: adverse consequences and remedies. Int Rev Immunol. 2014;33(6):511–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Palmblad J, Dufour C, Papadaki HA. How we diagnose neutropenia in the adult and elderly patient. Haematologica. 2014;99(7):1130–3.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lazaro E, Morel J. Management of neutropenia in patients with rheumatoid arthritis. Joint Bone Spine. 2015;82(4):235–9.

    Article  CAS  PubMed  Google Scholar 

  8. Newman KA, Akhtari M. Management of autoimmune neutropenia in Felty’s syndrome and systemic lupus erythematosus. Autoimmun Rev. 2011;10(7):432–7.

    Article  CAS  PubMed  Google Scholar 

  9. Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005;7(5):208–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ribera E, Ocaña I, Almirante B, Gómez J, Monreal P, Martínez Vázquez JM. Autoimmune neutropenia and thrombocytopenia associated with development of antibodies to human immunodeficiency virus. J Infect. 1989;18(2):167–70.

    Article  CAS  PubMed  Google Scholar 

  11. Gupta V, Eden AJ, Mills MJ. Helicobacter pylori and autoimmune neutropenia. Clin Lab Haematol. 2002;24(3):183–5.

    Article  CAS  PubMed  Google Scholar 

  12. Kozuka T, Kojima K, Kaneda K, Takenaka K, Manabe Y, Hirata Y, Okuma S, Toki H, Tanimoto M. Autoimmune neutropenia associated with multiple sclerosis. Intern Med. 2003;42(1):102–4.

    Article  PubMed  Google Scholar 

  13. Hellmich B, Ciaglo A, Schatz H, Coakley G. Autoantibodies against granulocyte-macrophage colony stimulating factor and interleukin-3 are rare in patients with Felty’s syndrome. Ann Rheum Dis. 2004;63(7):862–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wester AL, Dunlop O, Melby KK, Dahle UR, Wyller TB. Age-related differences in symptoms, diagnosis and prognosis of bacteremia. BMC Infect Dis. 2013;13:346.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34(1):15–21.

    Article  PubMed  Google Scholar 

  16. Hernández C, Fehér C, Soriano A, Marco F, Almela M, Cobos-Trigueros N, De La Calle C, Morata L, Mensa J, Martínez JA. Clinical characteristics and outcome of elderly patients with community-onset bacteremia. J Infect. 2015;70(2):135–43.

    Article  PubMed  Google Scholar 

  17. Bain BJ. Ethnic and sex differences in the total and differential white cell count and platelet count. J Clin Pathol. 1996;49:664–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the US population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007;146(7):486–92.

    Article  PubMed  Google Scholar 

  19. van Staa TP, Boulton F, Cooper C, Hagenbeek A, Inskip H, Leufkens HG. Neutropenia and agranulocytosis in England and Wales: incidence and risk factors. Am J Hematol. 2003;72(4):248–54.

    Article  PubMed  Google Scholar 

  20. Migdady Y, Olszewski AJ. Evaluation of incidental neutropenia in a multi-ethnic setting. Int J Lab Hematol. 2013;35(1):e6–8.

    Article  CAS  PubMed  Google Scholar 

  21. Fattizzo B, Zaninoni A, Consonni D, Zanella A, Gianelli U, Cortelezzi A, Barcellini W. Is chronic neutropenia always a benign disease? Evidences from a 5-year prospective study. Eur J Intern Med. 2015;26(8):611–5.

    Article  PubMed  Google Scholar 

  22. Lee CC, Hsieh CC, Lee NY, Chan TY, Hong MY, Chi CH, Ko WC. Different clinical presentation of community-onset bacteremia among neutropenic adults in the ED. Am J Emerg Med. 2015;33(7):907–12.

    Article  PubMed  Google Scholar 

  23. Le Boëdec M, Marhadour T, Devauchelle-Pensec V, Jousse-Joulin S, Binard A, Fautrel B, Flipo RM, Le Loët X, Ménard JF, Saraux A. Baseline laboratory test abnormalities are common in early arthritis but rarely contraindicate methotrexate: study of three cohorts (ESPOIR, VErA, and Brittany). Semin Arthritis Rheum. 2013;42(5):474–81.

    Article  PubMed  Google Scholar 

  24. Rosenstein ED, Kramer N. Felty’s and pseudo-Felty’s syndromes. Semin Arthritis Rheum. 1991;21(3):129–42.

    Article  CAS  PubMed  Google Scholar 

  25. Armstrong RD, Fernandes L, Gibson T, Kauffmann EA. Felty’s syndrome presenting without arthritis. Br Med J (Clin Res Ed). 1983;287(6405):1620.

    Article  CAS  Google Scholar 

  26. Bucknall RC, Davis P, Bacon P, Jones JV. Neutropenia in rheumatoid arthritis: studies on possible contributing factors. Ann Rheum Dis. 1982;41:242–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Owlia MB, Newman K, Akhtari M. Felty’s syndrome, insights and updates. Open Rheumatol J. 2014;31(8):129–36.

    Article  Google Scholar 

  28. Kobak S. Demographic, clinical, and serological features of Turkish patients with rheumatoid arthritis: evaluation of 165 patients. Clin Rheumatol. 2011;30(6):843–7.

    Article  PubMed  Google Scholar 

  29. Al-Ghamdi A, Attar SM. Extra-articular manifestations of rheumatoid arthritis: a hospital-based study. Ann Saudi Med. 2009;29(3):189–93.

    PubMed  PubMed Central  Google Scholar 

  30. Calgüneri M, Ureten K, Akif Oztürk M, Onat AM, Ertenli I, Kiraz S, Akdogan A. Extra-articular manifestations of rheumatoid arthritis: results of a university hospital of 526 patients in Turkey. Clin Exp Rheumatol. 2006;24(3):305–8.

    PubMed  Google Scholar 

  31. Ward MM. Decreases in rates of hospitalizations for manifestations of severe rheumatoid arthritis, 1983–2001. Arthritis Rheum. 2004;50(4):1122–31.

    Article  PubMed  Google Scholar 

  32. Hellmich B, Schnabel A, Gross WL. Treatment of severe neutropenia due to Felty’s syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor. Semin Arthritis Rheum. 1999;29(2):82–99.

    Article  CAS  PubMed  Google Scholar 

  33. Shah A, Diehl LF, St Clair EW. T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia. Clin Immunol. 2009;132(2):145–52.

    Article  CAS  PubMed  Google Scholar 

  34. Sokol L, Loughran TP Jr. Large granular lymphocyte leukemia. Oncologist. 2006;11(3):263–73.

    Article  CAS  PubMed  Google Scholar 

  35. Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, Schleinitz N, Tournilhac O, Roussel M, Fest T, Lamy T. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010;95:1534–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Verhoeven F, Guillot X, Prati C, Wendling D. Treatment of pseudo Felty’s syndrome: is there a place for rituximab? Joint Bone Spine. 2015;82(3):196–9.

    Article  CAS  PubMed  Google Scholar 

  37. Dearden C. Large granular lymphocytic leukaemia pathogenesis and management. Br J Haematol. 2011;152(3):273–83.

    Article  PubMed  Google Scholar 

  38. Komrokji RS, Kulasekararaj A, Al Ali NH, Kordasti S, Bart-Smith E, Craig BM, Padron E, Zhang L, Lancet JE, Pinilla-Ibarz J, List AF, Mufti GJ, Epling-Burnette PK. Autoimmune diseases and myelodysplastic syndromes. Am J Hematol. 2016;91(5):E280–3.

    Article  PubMed  Google Scholar 

  39. Chandran G, Ahern MJ, Seshadri P, Coghlan D. Rheumatic manifestations of the myelodysplastic syndromes: a comparative study. Aust N Z J Med. 1996;26(5):683–8.

    Article  CAS  PubMed  Google Scholar 

  40. George SW, Newman ED. Seronegative inflammatory arthritis in the myelodysplastic syndromes. Semin Arthritis Rheum. 1992;21(6):345–54.

    Article  CAS  PubMed  Google Scholar 

  41. White DH, Chapman PT, O’Donnell JL, James J, Frampton C, Stamp LK. Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving long-term methotrexate for rheumatoid arthritis. Intern Med J. 2010;40(8):561–5.

    Article  CAS  PubMed  Google Scholar 

  42. Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. Q J Med. 2001;94(6):309–19.

    Article  CAS  Google Scholar 

  43. Yazici Y, Sokka T, Kautiainen H, Swearingen C, Kulman I, Pincus T. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities. Ann Rheum Dis. 2005;64:207–11.

    Article  CAS  PubMed  Google Scholar 

  44. Weinblatt ME, Weissman BN, Holdsworth DE, Fraser PA, Maier AL, Falchuk KR, Coblyn JS. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update. Arthritis Rheum. 1992;35(2):129–37.

    Article  CAS  PubMed  Google Scholar 

  45. Salaffi F, Carotti M, Sartini A, Cervini C. A prospective study of the long-term efficacy and toxicity of low-dose methotrexate in rheumatoid arthritis. Clin Exp Rheumatol. 1995;13(1):23–8.

    CAS  PubMed  Google Scholar 

  46. Yamanaka H, Inoue E, Tanaka E, Nakajima A, Taniguchi A, Terai C, Hara M, Tomatsu T, Kamatani N. Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients: evidence based on the variety of prescribing approaches among practicing Japanese rheumatologists in a single institute-based large observational cohort (IORRA). Mod Rheumatol. 2007;17(2):98–105.

    Article  CAS  PubMed  Google Scholar 

  47. Tishler M, Caspi D, Yaron M. Long-term experience with low dose methotrexate in rheumatoid arthritis. Rheumatol Int. 1993;13(3):103–6.

    Article  CAS  PubMed  Google Scholar 

  48. Szanto E. Low-dose methotrexate treatment of rheumatoid arthritis; long-term observation of efficacy and safety. Clin Rheumatol. 1989;8(3):323–30.

    Article  CAS  PubMed  Google Scholar 

  49. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum. 1986;29(7):822–31.

    Article  CAS  PubMed  Google Scholar 

  50. Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA. Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. J Rheumatol. 1990;17(12):1628–35.

    CAS  PubMed  Google Scholar 

  51. Alarcón GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis: toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum. 1989;32(6):671–6.

    Article  PubMed  Google Scholar 

  52. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68(7):1100–4.

    Article  CAS  PubMed  Google Scholar 

  53. Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology (Oxford). 2005;44(8):1051–5.

    Article  CAS  PubMed  Google Scholar 

  54. Williams HJ, Willkens RF, Samuelson CO Jr, Alarcón GS, Guttadauria M, Yarboro C, Polisson RP, Weiner SR, Luggen ME, Billingsley LM, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum. 1985;28(7):721–30.

    Article  CAS  PubMed  Google Scholar 

  55. Gutierrez-Ureña S, Molina JF, García CO, Cuéllar ML, Espinoza LR. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum. 1996;39(2):272–6.

    Article  PubMed  Google Scholar 

  56. Kuitunen T, Malmström J, Palva E, Pettersson T. Pancytopenia induced by low-dose methotrexate: a study of the cases reported to the Finnish Adverse Drug Reaction Register from 1991 to 1999. Scand J Rheumatol. 2005;34(3):238–41.

    Article  CAS  PubMed  Google Scholar 

  57. Kivity S, Zafrir Y, Loebstein R, Pauzner R, Mouallem M, Mayan H. Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients. Autoimmun Rev. 2014;13(11):1109–13.

    Article  CAS  PubMed  Google Scholar 

  58. Verstappen SM, Bakker MF, Heurkens AH, van der Veen MJ, Kruize AA, Geurts MA, Bijlsma JW, Jacobs JW, Utrecht Rheumatoid Arthritis Cohort Study Group. Adverse events and factors associated with toxicity in patients with early rheumatoid arthritis treated with methotrexate tight control therapy: the CAMERA study. Ann Rheum Dis. 2010;69(6):1044–8.

    Article  CAS  PubMed  Google Scholar 

  59. Aslibekyan S, Brown EE, Reynolds RJ, Redden DT, Morgan S, Baggott JE, Sha J, Moreland LW, O’Dell JR, Curtis JR, Mikuls TR, Bridges SL Jr, Arnett DK. Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Pharmacogenom J. 2014;14(1):48–53.

    Article  CAS  Google Scholar 

  60. Sosin M, Handa S. Low dose methotrexate and bone marrow suppression. BMJ. 2003;326:266.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Singh YP, Aggarwal A, Misra R, Agarwal V. Low-dose methotrexate-induced pancytopenia. Clin Rheumatol. 2007;26(1):84–7.

    Article  Google Scholar 

  62. Cambridgeshire Health Authority. Methotrexate toxicity: an enquiry into the death of a Cambridgeshire patient in April 2000. 2000. http://www.blacktriangle.org/methotrexate-toxicity.pdf. Accessed 5 Apr 2016.

  63. Pamuk ON, Kisacik B, Pamuk GE, Onat AM, Sayarlioglu M, Donmez S, Pehlivan Y, Keystone EC. Do impaired memory, cognitive dysfunction and distress play a role in methotrexate-related neutropenia in rheumatoid arthritis patients? A comparative study. Rheumatol Int. 2013;33(10):2631–5.

    Article  CAS  PubMed  Google Scholar 

  64. Rheumatoid Arthritis Clinical Trial Archive Group. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. J Rheumatol. 1995;22(2):218–23.

    Google Scholar 

  65. Bressolle F, Bologna C, Kinowski JM, Arcos B, Sany J, Combe B. Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis: a comparison with young patients. J Rheumatol. 1997;24(10):1903–9.

    CAS  PubMed  Google Scholar 

  66. Bressolle F, Bologna C, Kinowski JM, Sany J, Combe B. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients. Ann Rheum Dis. 1998;57:110–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Boey O, Van Hooland S, Woestenburg A, Van der Niepen P, Verbeelen D. Methotrexate should not be used for patients with end-stage kidney disease. Acta Clin Belg. 2006;61(4):166–9.

  68. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL Jr, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O’Dell J, Turkiewicz AM, Furst DE, American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762–84.

    Article  CAS  PubMed  Google Scholar 

  69. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists, Chakravarty K, McDonald H, Pullar T, Taggart A, Chalmers R, Oliver S, Mooney J, Somerville M, Bosworth A, Kennedy T, On behalf of the British Society for Rheumatology, British Health Professionals in Rheumatology Standards. Guidelines and Audit Working Group in consultation with the British Association of Dermatologists. Rheumatology (Oxford). 2008;47(6):924–5.

    Article  CAS  Google Scholar 

  70. Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology. 2004;43:267–71.

    Article  CAS  PubMed  Google Scholar 

  71. van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB. 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. 2001;44(7):1515–24.

    Article  PubMed  Google Scholar 

  72. Mayall B, Poggi G, Parkin JD. Neutropenia due to low-dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal. Med J Aust. 1991;155(7):480–4.

    CAS  PubMed  Google Scholar 

  73. Colebatch AN, Marks JL, van der Heijde DM, Edwards CJ. Safety of nonsteroidal antiinflammatory drugs and/or paracetamol in people receiving methotrexate for inflammatory arthritis: a Cochrane systematic review. J Rheumatol Suppl. 2012;90:62–73.

    Article  CAS  PubMed  Google Scholar 

  74. Bourré-Tessier J, Haraoui B. Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review. J Rheumatol. 2010;37(7):1416–21.

    Article  PubMed  CAS  Google Scholar 

  75. Le Boëdec M, Marhadour T, Devauchelle-Pensec V, Jousse-Joulin S, Binard A, Fautrel B, Flipo RM, Le Loët X, Ménard JF, Saraux A. Baseline laboratory test abnormalities are common in early arthritis but rarely contraindicate methotrexate: study of three cohorts (ESPOIR, VErA, and Brittany). Semin Arthritis Rheum. 2013;42(5):474–81.

    Article  PubMed  Google Scholar 

  76. Marabani M, Madhok R, Capell HA, Hunter JA. Leucopenia during sulphasalazine treatment for rheumatoid arthritis. Ann Rheum Dis. 1989;48(6):505–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Farr M, Tunn EJ, Symmons DP, Scott DG, Bacon PA. Sulphasalazine in rheumatoid arthritis: haematological problems and changes in haematological indices associated with therapy. Br J Rheumatol. 1989;28(2):134–8.

    Article  CAS  PubMed  Google Scholar 

  78. Amos RS, Pullar T, Bax DE, Situnayake D, Capell HA, McConkey B. Sulphasalazine for rheumatoid arthritis: toxicity in 774 patients monitored for one to 11 years. Br Med J (Clin Res Ed). 1986;293(6544):420–3.

    Article  CAS  Google Scholar 

  79. Amos RS, Bax DE. Leucopenia in rheumatoid arthritis: relationship to gold or sulphasalazine therapy. Br J Rheumatol. 1988;27(6):465–8.

    Article  CAS  PubMed  Google Scholar 

  80. Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M, Meusser S, Paimela L, Rau R, Zeidler H, Leirisalo-Repo M, Peldan K. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis. 1999;58(4):220–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mitrane MP, Singh A, Seibold JR. Cholestasis and fatal agranulocytosis complicating sulfasalazine therapy: case report and review of the literature. J Rheumatol. 1986;13(5):969–72.

    CAS  PubMed  Google Scholar 

  82. Kuipers EJ, Vellenga E, de Wolf JT, Hazenberg BP. Sulfasalazine induced agranulocytosis treated with granulocyte-macrophage colony stimulating factor. J Rheumatol. 1992;19(4):621–2.

    CAS  PubMed  Google Scholar 

  83. Chakravarty K, Scott DG, McCann BG. Fatal neutropenic enterocolitis associated with sulphasalazine therapy for rheumatoid arthritis. Br J Rheumatol. 1992;31(5):351–3.

    Article  CAS  PubMed  Google Scholar 

  84. Canvin JM, Gabalawy HS, Chalmers IM. Fatal agranulocytosis with sulfasalazine therapy in rheumatoid arthritis. J Rheumatol. 1993;20(5):909–10.

    CAS  PubMed  Google Scholar 

  85. Marouf ES, Morris IM. Neutropenia in patients with rheumatoid arthritis, treated with sulphasalazine. Br J Rheumatol. 1990;29(5):407–9.

    Article  CAS  PubMed  Google Scholar 

  86. Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N, Furst D, Sharp J, Moreland L, Caldwell J, Kaine J, Strand V. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum. 2001;44(9):1984–92.

    Article  CAS  PubMed  Google Scholar 

  87. Scott DL, Smolen JS, Kalden JR, van de Putte LB, Larsen A, Kvien TK, Schattenkirchner M, Nash P, Oed C, Loew-Friedrich I, European Leflunomide Study Group. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis. 2001;60(10):913–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Alivernini S, Mazzotta D, Zoli A, Ferraccioli G. Leflunomide treatment in elderly patients with rheumatoid or psoriatic arthritis: retrospective analysis of safety and adherence to treatment. Drugs Aging. 2009;26(5):395–402.

    Article  CAS  PubMed  Google Scholar 

  89. Maddison P, Kiely P, Kirkham B, Lawson T, Moots R, Proudfoot D, Reece R, Scott D, Sword R, Taggart A, Thwaites C, Williams E. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus. Rheumatology (Oxford). 2005;44(3):280–6.

    Article  CAS  PubMed  Google Scholar 

  90. Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf. 2009;32(12):1123–34.

    Article  CAS  PubMed  Google Scholar 

  91. Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, Gömör B, Van Den Bosch F, Nordström D, Bjorneboe O, Dahl R, Horslev-Petersen K, Rodriguez De La Serna A, Molloy M, Tikly M, Oed C, Rosenburg R, Loew-Friedrich I. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2000;39(6):655–65.

  92. Bettembourg-Brault I, Gossec L, Pham T, Gottenberg JE, Damiano J, Dougados M. Leflunomide in rheumatoid arthritis in daily practice: treatment discontinuation rates in comparison with other DMARDs. Clin Exp Rheumatol. 2006;24(2):168–71.

  93. McEwen J, Purcell PM, Hill RL, Calcino LJ, Riley CG. The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate. Pharmacoepidemiol Drug Saf. 2007;16(1):65–73.

    Article  CAS  PubMed  Google Scholar 

  94. Chan J, Sanders DC, Du L, Pillans PI. Leflunomide-associated pancytopenia with or without methotrexate. Ann Pharmacother. 2004; 38(7–8):1206–11.

  95. Savage RL. Leflunomide in combination therapy for rheumatoid arthritis. Drug Saf. 2010;33(6):523–6.

    Article  CAS  PubMed  Google Scholar 

  96. Fries JF, Williams CA, Ramey D, Bloch DA. The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum. 1993;36(3):297–306.

    Article  CAS  PubMed  Google Scholar 

  97. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. 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. 2008;67:1516–23 (Erratum in: Ann Rheum Dis. 2009;68:296).

  98. Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol. 2010;20(3):222–32.

    Article  CAS  PubMed  Google Scholar 

  99. Wright HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford). 2014;53(7):1321–31.

    Article  CAS  PubMed  Google Scholar 

  100. Malaviya AP, Ledingham J, Bloxham J, Bosworth A, Buch M, Choy E, Cope A, Isaacs J, Marshall D, Wright G, Östör AJK, On behalf of the BSR Clinical Affairs Committee and Standards, Audit and Guidelines Working Group and the BHPR. The 2013 BSR and BHPR guideline for the use of intravenous tocilizumab in the treatment of adult patients with rheumatoid arthritis. Oxford: Oxford University Press; 2014.

    Google Scholar 

  101. Szalay B, Acs L, Vásárhelyi B, Kovács L, Balog A. Successful use of tocilizumab in a patient with rheumatoid arthritis following severe pancytopenia during etanercept therapy. J Clin Rheumatol. 2011;17(7):377–9.

    Article  PubMed  Google Scholar 

  102. Shovman O, Shoenfeld Y, Langevitz P. Tocilizumab-induced neutropenia in rheumatoid arthritis patients with previous history of neutropenia: case series and review of literature. Immunol Res. 2015;61(1–2):164–8.

    Article  CAS  PubMed  Google Scholar 

  103. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586–93.

    Article  CAS  PubMed  Google Scholar 

  104. Rajakulendran S, Gadsby K, Allen D, O’Reilly S, Deighton C. Neutropenia while receiving anti-tumour necrosis factor treatment for rheumatoid arthritis. Ann Rheum Dis. 2006;65(12):1678–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hastings R, Ding T, Butt S, Gadsby K, Zhang W, Moots RJ, Deighton C. Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken). 2010;62(6):764–9.

    Article  PubMed  Google Scholar 

  106. Aslanidis S, Pyrpasopoulou A, Triantafyllou A, Anyfanti P, Zamboulis C, Douma S. Tumor necrosis factor antagonist-associated neutropenia: comment on the article by Hastings et al. Arthritis Care Res (Hoboken). 2010;62(12):1813–5.

    Article  Google Scholar 

  107. Fleischmann R, Iqbal I, Nandeshwar P, Quiceno A. Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept. Drug Saf. 2002;25(3):173–97.

    Article  CAS  PubMed  Google Scholar 

  108. Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol. 2003;30(12):2563–71.

    CAS  PubMed  Google Scholar 

  109. Levälampi T, Korpela M, Vuolteenaho K, Moilanen E. Etanercept and adalimumab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons leading to discontinuation of the treatment. Rheumatol Int. 2008;28(3):261–9.

    Article  PubMed  CAS  Google Scholar 

  110. Vidal F, Fontova R, Richart C. Severe neutropenia and thrombocytopenia associated with infliximab. Ann Intern Med. 2003;139(3):W–63.

    Article  PubMed  Google Scholar 

  111. Menon Y, Curcurull E, Espunoza LR. Pancytopenia in a patient with scleroderma treated with infliximab. Rheumatology. 2003;42:1273–4.

    Article  CAS  PubMed  Google Scholar 

  112. Wenham C, Gadsby K, Deighton C. Three significant cases of neutropenia with etanercept. Rheumatology (Oxford). 2008;47(3):376–7.

    Article  CAS  PubMed  Google Scholar 

  113. Szalay B, Acs L, Vásárhelyi B, Kovács L, Balog A. Successful use of tocilizumab in a patient with rheumatoid arthritis following severe pancytopenia during etanercept therapy. J Clin Rheumatol. 2011;17(7):377–9.

    Article  PubMed  Google Scholar 

  114. Montané E, Sallés M, Barriocanal A, Riera E, Costa J, Tena X. Antitumor necrosis factor-induced neutropenia: a case report with double positive rechallenges. Clin Rheumatol. 2007;26(9):1527–9.

    Article  PubMed  Google Scholar 

  115. Breuer GS, Ehrenfeld M, Rosner I, Balbir-Gurman A, Zisman D, Oren S, Paran D. Late-onset neutropenia following rituximab treatment for rheumatologic conditions. Clin Rheumatol. 2014;33(9):1337–40.

    Article  PubMed  Google Scholar 

  116. Abdulkader R, Dharmapalaiah C, Rose G, Shand LM, Clunie GP, Watts RA. Late-onset neutropenia in patients with rheumatoid arthritis after treatment with rituximab. J Rheumatol. 2014;41(5):858–61.

    Article  CAS  PubMed  Google Scholar 

  117. Tesfa D, Ajeganova S, Hägglund H, Sander B, Fadeel B, Hafström I, Palmblad J. Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum. 2011;63(8):2209–14.

    Article  CAS  PubMed  Google Scholar 

  118. Salmon JH, Cacoub P, Combe B, Sibilia J, Pallot-Prades B, Fain O, Cantagrel A, Dougados M, Andres E, Meyer O, Carli P, Pertuiset E, Pane I, Maurier F, Ravaud P, Mariette X, Gottenberg JE. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the Autoimmunity and Rituximab Registry. RMD Open. 2015;1(1):e000034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Besada E, Koldingsnes W, Nossent J. Characteristics of late onset neutropenia in rheumatologic patients treated with rituximab: a case review analysis from a single center. Q J Med. 2012;105(6):545–50.

    Article  CAS  Google Scholar 

  120. Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363(14):1303–12.

    Article  CAS  PubMed  Google Scholar 

  121. van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, Cardiel MH, Cohen S, Nash P, Song YW, Tegzová D, Wyman BT, Gruben D, Benda B, Wallenstein G, Krishnaswami S, Zwillich SH, Bradley JD, Connell CA, ORAL Scan Investigators. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559–70.

    Article  PubMed  CAS  Google Scholar 

  122. Donahue KE, Gartlehner G, Jonas DE, Lux LJ, Thieda P, Jonas BL, Hansen RA, Morgan LC, Lohr KN. Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 2008;148(2):124–34.

    Article  PubMed  Google Scholar 

  123. Ding CZ, Yao Y, Feng XB, Fang Y, Zhao C, Wang Y. Clinical analysis of Chinese patients with rheumatoid arthritis treated with leflunomide and methotrexate combined with different dosages of glucocorticoid. Curr Ther Res Clin Exp. 2012;73(4–5):123–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137(9):726–33.

    Article  CAS  PubMed  Google Scholar 

  125. Kremer J, Genovese M, Cannon GW, Caldwell J, Cush J, Furst DE, Luggen M, Keystone E, Bathon J, Kavanaugh A, Ruderman E, Coleman P, Curtis D, Kopp E, Kantor S, Weisman M, Waltuck J, Lindsley HB, Markenson J, Crawford B, Fernando I, Simpson K, Strand V. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol. 2004;31(8):1521–31.

    CAS  PubMed  Google Scholar 

  126. Weinblatt ME, Kremer JM, Coblyn JS, Maier AL, Helfgott SM, Morrell M, Byrne VM, Kaymakcian MV, Strand V. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum. 1999;42(7):1322–8.

    Article  CAS  PubMed  Google Scholar 

  127. Bird P, Griffiths H, Tymms K, Nicholls D, Roberts L, Arnold M, Burnet S, de Jager J, Scott J, Zochling J, Littlejohn G. The SMILE study—safety of methotrexate in combination with leflunomide in rheumatoid arthritis. J Rheumatol. 2013;40(3):228–35.

    Article  CAS  PubMed  Google Scholar 

  128. Hill RL, Topliss DJ, Purcell PM. Pancytopenia associated with leflunomide and methotrexate. Ann Pharmacother. 2003;37(1):149.

    Article  PubMed  Google Scholar 

  129. Toth P, Bernd R. Severe leukopenia in a rheumatoid arthritis patient treated with a methotrexate/leflunomide combination. Rev Bras Reumatol. 2014;54(2):152–4.

    Article  PubMed  Google Scholar 

  130. Nagashima M, Matsuoka T, Saitoh K, Koyama T, Kikuchi O, Yoshino S. Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with low-dose methotrexate, sulfasalazine, and bucillamine in 1,358 Japanese patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24(3):260–7.

    CAS  PubMed  Google Scholar 

  131. Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol. 1997;36(10):1082–8.

    Article  CAS  PubMed  Google Scholar 

  132. O’Dell J, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ, Garwood V, Maloley P, Klassen LW, Wees S, Klein H, Moore GF. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med. 1996;334:1287–91.

    Article  PubMed  Google Scholar 

  133. Scott DL, Ibrahim F, Farewell V, O’Keeffe AG, Ma M, Walker D, Heslin M, Patel A, Kingsley G. Randomised controlled trial of tumour necrosis factor inhibitors against combination intensive therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews. Health Technol Assess. 2014;18(66):i–xxiv (1–164).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van Riel P. When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? Ann Rheum Dis. 2005;64(1):44–51.

    Article  CAS  PubMed  Google Scholar 

  135. Marchesoni A, Arreghini M, Panni B, Battafarano N, Uziel L. Life-threatening reversible bone marrow toxicity in a rheumatoid arthritis patient switched from leflunomide to infliximab. Rheumatology (Oxford). 2003;42:193–4.

    Article  CAS  Google Scholar 

  136. Anstey A, Lennard L, Mayou SC, Kirby JD. Pancytopenia related to azathioprine—an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med. 1992;85(12):752–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Woodland J, Chaput de Saintonge DM, Evans SJ, Sharman VL, Currey HL. Azathioprine in rheumatoid arthritis: double-blind study of full versus half doses versus placebo. Ann Rheum Dis. 1981;40(4):355–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zazgornik J, Kopsa H, Schmidt P, Pils P, Kuschan K, Deutsch E. Increased danger of bone marrow damage in simultaneous azathioprine–allopurinol therapy. Int J Clin Pharmacol Ther Toxicol. 1981;19(3):96–7.

    CAS  PubMed  Google Scholar 

  139. Mikuls TR, MacLean CH, Olivieri J, Patino F, Allison JJ, Farrar JT, Bilker WB, Saag KG. Quality of care indicators for gout management. Arthritis Rheum. 2004;50(3):937–43.

    Article  PubMed  Google Scholar 

  140. Raman G, Sharman V, Lee H. Azathioprine and allopurinol: a potentially dangerous combination. J Intern Med. 1990;228:69–71.

    Article  Google Scholar 

  141. Govani SM, Higgins PD. Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD. J Crohns Colitis. 2010;4(4):444–9.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Zhang XW, Li C, Ma XX, Zhao JX, An Y, Liu S, Li Y, Li ZG. Short-interval lower-dose intravenous cyclophosphamide as induction and maintenance therapy for lupus nephritis: a prospective observational study. Clin Rheumatol. 2014;33(7):939–45.

    Article  CAS  PubMed  Google Scholar 

  143. Calgüneri M, Ozbalkan Z, Ozturk MA, Apras S, Ertenli AI, Kiraz S. Intensified, intermittent, low-dose intravenous cyclophosphamide together with oral alternate-day steroid therapy in lupus nephritis (long-term outcome). Clin Rheumatol. 2006;25(6):782–8.

    Article  PubMed  Google Scholar 

  144. Yee CS, Gordon C, Dostal C, Petera P, Dadoniene J, Griffiths B, Rozman B, Isenberg DA, Sturfelt G, Nived O, Turney JH, Venalis A, Adu D, Smolen JS, Emery P. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis. 2004;63(5):525–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Martin F, Lauwerys B, Lefèbvre C, Devogelaer JP, Houssiau FA. Side-effects of intravenous cyclophosphamide pulse therapy. Lupus. 1997;6(3):254–7.

    Article  CAS  PubMed  Google Scholar 

  146. Katsifis GE, Tzioufas AG, Vlachoyiannopoulos PG, Voulgarelis M, Moutsopoulos HM, Ioannidis JP. Risk of myelotoxicity with intravenous cyclophosphamide in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2002;41(7):780–6.

    Article  CAS  PubMed  Google Scholar 

  147. Moore RA, Derry S. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Res Ther. 2006;8(6):R182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Subedi A, Magder LS, Petri M. Effect of mycophenolate mofetil on the white blood cell count and the frequency of infection in systemic lupus erythematosus. Rheumatol Int. 2015;35(10):1687–92.

    Article  CAS  PubMed  Google Scholar 

  149. Feng L, Deng J, Huo DM, Wu QY, Liao YH. Mycophenolate mofetil versus azathioprine as maintenance therapy for lupus nephritis: a meta-analysis. Nephrology (Carlton). 2013;18(2):104–10.

    Article  CAS  PubMed  Google Scholar 

  150. Kamanamool N, McEvoy M, Attia J, Ingsathit A, Ngamjanyaporn P, Thakkinstian A. Efficacy and adverse events of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: systematic review and meta-analysis. Medicine (Baltimore). 2010;89(4):227–35.

    Article  CAS  PubMed  Google Scholar 

  151. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343(16):1156–62.

    Article  CAS  PubMed  Google Scholar 

  152. Schiff M, Beaulieu A, Scott DL, Rashford M. Mycophenolate mofetil in the treatment of adults with advanced rheumatoid arthritis: three 24-week, randomized, double-blind, placebo- or ciclosporin-controlled trials. Clin Drug Investig. 2010;30(9):613–24.

    Article  CAS  PubMed  Google Scholar 

  153. Kawai S, Yamamoto K. Safety of tacrolimus, an immunosuppressive agent, in the treatment of rheumatoid arthritis in elderly patients. Rheumatology (Oxford). 2006;45(4):441–4.

    Article  CAS  PubMed  Google Scholar 

  154. Park EY, Lee SG, Park EK, Koo DW, Park JH, Kim GT, Tag HS, Kim HO, Suh YS. Drug survival and the associated predictors in South Korean patients with rheumatoid arthritis receiving tacrolimus. Korean J Intern Med. 2016. doi:10.3904/kjim.2015.385.

    Google Scholar 

  155. Lee WS, Lee SI, Lee MS, Kim SI, Lee SS, Yoo WH. Efficacy and safety of low-dose tacrolimus dose tacrolimus for active rheumatoid arthritis with an inadequate response to methotrexate. Korean J Intern Med. 2016. doi:10.3904/kjim.2015.066.

    Google Scholar 

  156. Dutta S, Ahmad Y. The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2011;3(6):283–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kitahama M, Okamoto H, Koseki Y, Inoue E, Kaneko H, Taniguchi A, Momohara S, Yamanaka H. Efficacy and safety of tacrolimus in 101 consecutive patients with rheumatoid arthritis. Mod Rheumatol. 2010;20(5):478–85.

    Article  CAS  PubMed  Google Scholar 

  158. Hannah J, Casian A, D’Cruz D. Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun Rev. 2016;15(1):93–101.

    Article  CAS  PubMed  Google Scholar 

  159. De Rycke A, Dierickx D, Kuypers DR. Tacrolimus-induced neutropenia in renal transplant recipients. Clin J Am Soc Nephrol. 2011;6(3):690–4.

    Article  PubMed  Google Scholar 

  160. Drosos A. Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alternatives? Drugs Aging. 2003;20(10):723–36.

    Article  CAS  PubMed  Google Scholar 

  161. Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist. 2000;5(3):224–37.

    Article  CAS  PubMed  Google Scholar 

  162. Duthie E. Physiology of aging: relevance to symptom perceptions and treatment tolerance. In: Balducci L, Lyman GH, Ershler WB, editors. Comprehensive geriatric oncology. London: Harwood Academic Publishers; 1998. p. 247–62.

    Google Scholar 

  163. Balducci L, Hardy CL, Lyman GH. Hemopoietic reserve in the older cancer patient: clinical and economic considerations. Cancer Control. 2000;7(6):539–47.

    CAS  PubMed  Google Scholar 

  164. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ. Innate immunity and aging. Exp Gerontol. 2008;43(8):718–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chatta GS, Price TH, Allen RC, Dale DC. Effects of in vivo recombinant methionyl human granulocyte colony–stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers. Blood. 1994;84(9):2923–9.

    CAS  PubMed  Google Scholar 

  166. Bagnara GP, Bonsi L, Strippoli P, Bonifazi F, Tonelli R, D’Addato S, Paganelli R, Scala E, Fagiolo U, Monti D, Cossarizza A, Bonafé M, Franceschi C. Hemopoiesis in healthy old people and centenarians: well-maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol A Biol Sci Med Sci. 2000;55(2):B61–6 (discussion B67–70).

    Article  CAS  PubMed  Google Scholar 

  167. Povsic TJ, Zhou J, Adams SD, Bolognesi MP, Attarian DE, Peterson ED. Aging is not associated with bone marrow-resident progenitor cell depletion. J Gerontol A Biol Sci Med Sci. 2010;65(10):1042–50.

    Article  PubMed  CAS  Google Scholar 

  168. Nesher G, Moore TL. Rheumatoid arthritis in the aged. Incidence and optimal management. Drugs Aging. 1993;3(6):487–501.

    Article  CAS  PubMed  Google Scholar 

  169. Rasch EK, Hirsch R, Paulose-Ram R, Hochberg MC. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States: effect of different methods of case classification. Arthritis Rheum. 2003;48(4):917–26.

    Article  PubMed  Google Scholar 

  170. Doran MF, Pond GR, Crowson CS, O’Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum. 2002;46(3):625–31.

    Article  PubMed  Google Scholar 

  171. Negoescu A, Ostör AJ. Early recognition improves prognosis in elderly onset RA. Practitioner. 2014;258(1767):11–4.

    PubMed  Google Scholar 

  172. Carli L, Tani C, Vagnani S, Signorini V, Mosca M. Leukopenia, lymphopenia, and neutropenia in systemic lupus erythematosus: prevalence and clinical impact—a systematic literature review. Semin Arthritis Rheum. 2015;45(2):190–4.

    Article  PubMed  Google Scholar 

  173. Nossent JC, Swaak AJ. Prevalence and significance of haematological abnormalities in patients with systemic lupus erythematosus. Q J Med. 1991;80(291):605–12.

    CAS  PubMed  Google Scholar 

  174. Kurien BT, Newland J, Paczkowski C, et al. Association of neutropenia in systemic lupus erythematosus (SLE) with anti-Ro and binding of an immunologically cross-reactive neutrophil membrane antigen. Clin Exp Immunol. 2000;120:209–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Fayyaz A, Igoe A, Kurien BT, Danda D, James JA, Stafford HA, Scofield RH. Haematological manifestations of lupus. Lupus Sci Med. 2015;2(1):e000078.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Kaplan MJ. Neutrophils in the pathogenesis and manifestations of SLE. Nat Rev Rheumatol. 2011;7(12):691–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Somers EC, Marder W, Cagnoli P, Lewis EE, DeGuire P, Gordon C, Helmick CG, Wang L, Wing JJ, Dhar JP, Leisen J, Shaltis D, McCune WJ. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan lupus epidemiology and surveillance program. Arthritis Rheumatol. 2014;66(2):369–78.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Markusse HM, Oudkerk M, Vroom TM, Breedveld FC. Primary Sjögren’s syndrome: clinical spectrum and mode of presentation based on an analysis of 50 patients selected from a department of rheumatology. Neth J Med. 1992;40(3–4):125–34.

    CAS  PubMed  Google Scholar 

  179. Baldini C, Pepe P, Quartuccio L, Priori R, Bartoloni E, Alunno A, Gattamelata A, Maset M, Modesti M, Tavoni A, De Vita S, Gerli R, Valesini G, Bombardieri S. Primary Sjogren’s syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford). 2014;53(5):839–44.

    Article  PubMed  Google Scholar 

  180. Grayson PC, Sloan JM, Niles JL, Monach PA, Merkel PA. Antineutrophil cytoplasmic antibodies, autoimmune neutropenia, and vasculitis. Semin Arthritis Rheum. 2011;41(3):424–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pamuk ON, Pamuk GE, Usta U, Cakir N. Hemophagocytic syndrome in one patient with adult-onset Still’s disease: presentation with febrile neutropenia. Clin Rheumatol. 2007;26(5):797–800.

    Article  PubMed  Google Scholar 

  182. Hirshberg B, Muszkat M, Schlesinger O, Rubinow A. Safety of low dose methotrexate in elderly patients with rheumatoid arthritis. Postgrad Med J. 2000;76(902):787–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Bologna C, Viu P, Jorgensen C, Sany J. Effect of age on the efficacy and tolerance of methotrexate in rheumatoid arthritis. Br J Rheumatol. 1996;35:453–7.

    Article  CAS  PubMed  Google Scholar 

  184. Bathon JM, Fleischmann RM, Van der Heijde D, Tesser JR, Peloso PM, Chon Y, White B. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol. 2006;33(2):234–43.

    CAS  PubMed  Google Scholar 

  185. Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359(9313):1173–7.

    Article  CAS  PubMed  Google Scholar 

  186. van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther. 2006;8(5):R151.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, Todd C. Risk factors for falls in adults with rheumatoid arthritis: a prospective study. Arthritis Care Res (Hoboken). 2013;65(8):1251–8.

    Article  PubMed  PubMed Central  Google Scholar 

  188. van Schaardenburg D, Breedveld FC. Elderly-onset rheumatoid arthritis. Semin Arthritis Rheum. 1994;23(6):367–78.

    Article  PubMed  Google Scholar 

  189. Innala L, Berglin E, Möller B, Ljung L, Smedby T, Södergren A, Magnusson S, Rantapää-Dahlqvist S, Wållberg-Jonsson S. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2014;16(2):R94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Fraenkel L, Rabidou N, Dhar R. Are rheumatologists’ treatment decisions influenced by patients’ age? Rheumatology. 2006;45:1555–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Carli C, Ehlin AGC, Klareskog L, Lindblad S, Montgomery SM. Trends in disease modifying antirheumatic drug prescription in early rheumatoid arthritis are influenced more by hospital setting than patient or disease characteristics. Ann Rheum Dis. 2006;65:1102–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Katada H, Yukawa N, Urushihara H, Tanaka S, Mimori T, Kawakami K. Prescription patterns and trends in anti-rheumatic drug use based on a large-scale claims database in Japan. Clin Rheumatol. 2015;34(5):949–56.

    Article  PubMed  Google Scholar 

  193. Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood. 2014;124(8):1251–8.

    Article  CAS  PubMed  Google Scholar 

  194. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013;50(3):198–206.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Bux J, Chapman J. Report on the second international granulocyte serology workshop. Transfusion. 1997;37(9):977–83.

    Article  CAS  PubMed  Google Scholar 

  196. Estcourt LJ, Stanworth S, Doree C, Blanco P, Hopewell S, Trivella M, Massey E. Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2015;6:CD005341.

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    Su-Ann Yeoh

  2. Rheumatology Department, Queen Alexandra Hospital, Portsmouth, PO6 3LY, UK

    Christine Fox & Richard Hull

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Correspondence to Christine Fox.

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Su-Ann Yeoh, Christine Fox, and Richard Hull have no conflicts of interest that are relevant to the content of this article. No funding was received for the preparation of this article.

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Yeoh, SA., Fox, C. & Hull, R. Neutropenia in the Elderly: A Rheumatology Perspective. Drugs Aging 33, 585–601 (2016). https://doi.org/10.1007/s40266-016-0383-0

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