HSS Journal ®

, Volume 14, Issue 2, pp 214–221 | Cite as

Adult-Onset Still’s Disease and Macrophage-Activating Syndrome Progressing to Lymphoma

A Clinical Pathology Conference Held by the Division of Rheumatology at Hospital for Special Surgery
  • Bella Mehta
  • Shanthini Kasturi
  • Julie Teruya-Feldstein
  • Steven Horwitz
  • Anne R. Bass
  • Doruk Erkan
Clinical Pathology Conference

Clinical Presentation

A 66-year-old man with adult-onset Still’s disease (AOSD) and macrophage-activation syndrome (MAS) presented with four weeks of progressive fatigue and weakness. Past history was notable for gout and a deep vein thrombosis provoked after a long flight, and there was no family history of autoimmune conditions or malignancy. Two and a half years prior, he developed anemia, thrombocytopenia, hypoalbuminemia, and hyperferritinemia, followed by fatigue, weight loss, fever, and night sweats. He had no rash, arthritis, arthralgias, or pleuritic chest pain.

On physical examination, he had splenomegaly with mild lymphadenopathy. The patient underwent an extensive workup including malignancy screening, in which cross-sectional imaging confirmed splenomegaly and scattered lymphadenopathy. Bone marrow biopsy was hypercellular, with normal cell lines and no hemophagocytosis. Left inguinal lymph node biopsy showed reactive hyperplasia, suggestive of Castleman’s disease-like...


macrophage-activating syndrome adult-onset Still’s disease hemophagocytic lymphohistiocytosis lymphoma 


Compliance with Ethical Standards

Conflict of Interest

Bella Mehta, MD, Shanthini Kasturi, MD, MS, Julie Teruya-Feldstein, MD, and Anne R. Bass, MD, declare that they have no conflicts of interest. Steven Horwitz, MD, reports receiving grants and personal fees from Celgene, Millennium/Takeda Oncology, Kyowa Hakko Kirin, Seattle Genetics, Forty Seven, and Infinity/Verastem; personal fees from HUYA Bioscience International, Bristol-Myers Squibb, and Mundipharma; and grants from Spectrum Pharmaceuticals, ADC Therapeutics, and Aileron Therapeutics, outside the submitted work. Doruk Erkan, MD, MPH, reports receiving grants from the Lupus Clinical Trial Consortium, the National Heart, Lung, and Blood Institute, HSS Medical Education Academy, EMD Serono, and Xencor; grants and personal fees from GlaxoSmithKline; and personal fees from Ablynx, outside the submitted work.

Human/Animal Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013.

Informed Consent

Informed consent was waived from all patients for being included in this study.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.


  1. 1.
    Aeberli D, Oertle S, Mauron H, Reichenbach S, Jordi B, Villiger PM. Inhibition of the TNF-pathway: use of infliximab and etanercept as remission-inducing agents in cases of therapy-resistant chronic inflammatory disorders. Swiss Med Wkly. 2002;132(29–30):414–422.PubMedGoogle Scholar
  2. 2.
    Arlet JB, Le TH, Marinho A, Amoura Z, Wechsler B, Papo T, et al. Reactive haemophagocytic syndrome in adult-onset Still’s disease: a report of six patients and a review of the literature. Ann Rheum Dis. 2006;65(12):1596–1601.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Atteritano M, David A, Bagnato G, Beninati C, Frisina A, Iaria C, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1414–1424.PubMedGoogle Scholar
  4. 4.
    Balamuth NJ, Nichols KE, Paessler M, Teachey DT. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29(8):569–573.CrossRefPubMedGoogle Scholar
  5. 5.
    Balwierz W, Czogala M, Czepko E. [Anaplastic large cell lymphoma associated with hemophagocytic lymphohistiocytosis: a case report and review of the literature]. Przegl Lek. 2010;67(6):436–438.PubMedGoogle Scholar
  6. 6.
    Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest. 2011;121(6):2264–2277.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Belyea B, Hinson A, Moran C, Hwang E, Heath J, Barfield R. Spontaneous resolution of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2010;55(4):754–756.CrossRefPubMedGoogle Scholar
  8. 8.
    Bosman G, Langemeijer SM, Hebeda KM, Raemaekers JM, Pickkers P, van der Velden WJ. The role of rituximab in a case of EBV-related lymphoproliferative disease presenting with haemophagocytosis. Neth J Med. 2009;67(8):364–365.PubMedGoogle Scholar
  9. 9.
    Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol. 2011;17(1):23–27.CrossRefPubMedGoogle Scholar
  10. 10.
    Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–382.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Coca A, Bundy KW, Marston B, Huggins J, Looney RJ. Macrophage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol. 2009;132(1):10–18.CrossRefPubMedGoogle Scholar
  12. 12.
    Davi S, Consolaro A, Guseinova D, Pistorio A, Ruperto N, Martini A, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011;38(4):764–768.Google Scholar
  13. 13.
    De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–2395.Google Scholar
  14. 14.
    Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 2003;49(5):633–639.Google Scholar
  15. 15.
    Durand M, Troyanov Y, Laflamme P, Gregoire G. Macrophage activation syndrome treated with anakinra. J Rheumatol. 2010;37(4):879–880.Google Scholar
  16. 16.
    Falini B, Pileri S, De Solas I, Martelli MF, Mason DY, Delsol G, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood. 1990;75(2):434–44.PubMedGoogle Scholar
  17. 17.
    Felix FH, Leal LK, Fontenele JB. Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis. Rheumatol Int. 2009;29(8):973–974.Google Scholar
  18. 18.
    Fernandes F, Eloy C, Carimo A, Pinto P, Graves S, Simoes J, et al. Simultaneous presentation of Kaposi sarcoma and HHV8-associated large B-cell lymphoma in the same lymph node: a rare diagnosis in an HIV-negative patient. Am J Case Rep. 2013;14:263–266.Google Scholar
  19. 19.
    Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(8):1006–12.Google Scholar
  20. 20.
    Fox CP, Shannon-Lowe C, Gothard P, Kishore B, Neilson J, O’Connor N, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis. 2010;51(1):66–69.Google Scholar
  21. 21.
    George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69–86.Google Scholar
  22. 22.
    George TI, Jeng M, Berquist W, Cherry AM, Link MP, Arber DA. Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature. Pediatr Blood Cancer. 2005;44(3):270–276.Google Scholar
  23. 23.
    Goel S, Polski JM, Imran H. Sensitivity and specificity of bone marrow hemophagocytosis in hemophagocytic lymphohistiocytosis. Ann Clin Lab Sci. 2012;42(1):21–25.Google Scholar
  24. 24.
    Gupta A, Tyrrell P, Valani R, Benseler S, Weitzman S, Abdelhaleem M. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;51(3):402–404.Google Scholar
  25. 25.
    Hagihara M, Inoue M, Hua J, Iwaki Y. Lymphocyte-depleted Hodgkin lymphoma complicating hemophagocytic lymphohistiocytosis as an initial manifestation: a case report and review of the literature. Intern Med. 2012;51(21):3067–3072.Google Scholar
  26. 26.
    Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–2922.Google Scholar
  27. 27.
    Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–131.Google Scholar
  28. 28.
    Ho C, Yao X, Tian L, Li FY, Podoltsev N, Xu ML. Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability. Am J Clin Pathol. 2014;141(1):62–71.Google Scholar
  29. 29.
    Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. J Pediatr Hematol Oncol. 2011;33(1):35–39.Google Scholar
  30. 30.
    Imashuku S, Kuriyama K, Teramura T, Ishii E, Kinugawa N, Kato M, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19(10):2665–2673.Google Scholar
  31. 31.
    Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother. 2001;2(9):1437–1448.Google Scholar
  32. 32.
    Jaffe ES, Costa J, Fauci AS, Cossman J, Tsokos M. Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med. 1983;75(5):741–749.Google Scholar
  33. 33.
    Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program.2013;2013:605–611.Google Scholar
  34. 34.
    Jordan MB, Filipovich AH. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step. Bone Marrow Transplant. 2008;42(7):433–437.Google Scholar
  35. 35.
    Kaplan LD. Human herpesvirus-8: Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma. Hematology Am Soc Hematol Educ Program. 2013;2013:103–108.Google Scholar
  36. 36.
    Kelesidis T, Humphries R, Terashita D, Eshaghian S, Territo MC, Said J, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Los Angeles County. J Med Virol. 2012;84(5):777–785.Google Scholar
  37. 37.
    Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008;4(11):615–620.Google Scholar
  38. 38.
    Kirino Y, Takeno M, Iwasaki M, Ueda A, Ohno S, Shirai A, et al. Increased serum HO-1 in hemophagocytic syndrome and adult-onset Still’s disease: use in the differential diagnosis of hyperferritinemia. Arthritis Res Ther. 2005;7(3):R616–24.Google Scholar
  39. 39.
    Kumakura S, Murakawa Y. Clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome in adults. Arthritis Rheumatol. 2014;66(8):2297–307.Google Scholar
  40. 40.
    Mahlaoui N, Ouachee-Chardin M, de Saint Basile G, Neven B, Picard C, Blanche S, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120(3):e622–628.Google Scholar
  41. 41.
    Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–109.Google Scholar
  42. 42.
    Matsumoto Y, Naniwa D, Banno S, Sugiura Y. The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apher. 1998;2(4):300–304.Google Scholar
  43. 43.
    Meeths M, Chiang SC, Wood SM, Entesarian M, Schlums H, Bang B, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood. 2011;118(22):5783–93.Google Scholar
  44. 44.
    Moradinejad MH, Ziaee V. The incidence of macrophage activation syndrome in children with rheumatic disorders. Minerva Pediatr. 2011;63(6):459–66.Google Scholar
  45. 45.
    Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63(2):545–555.Google Scholar
  46. 46.
    Osugi Y, Hara J, Tagawa S, Takai K, Hosoi G, Matsuda Y, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89(11):4100–3.Google Scholar
  47. 47.
    Park KH, Yu HS, Jung SI, Shin DH, Shin JH. Acute human immunodeficiency virus syndrome presenting with hemophagocytic lymphohistiocytosis. Yonsei Med J. 2008;49(2):325–328.Google Scholar
  48. 48.
    Parvaneh N, Filipovich AH, Borkhardt A. Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases. Br J  Haematol. 2013;162(5):573–586.Google Scholar
  49. 49.
    Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom AA. Etanercept in the treatment of macrophage activation syndrome. J Rheumatol. 2001;28(9):2120–2124.Google Scholar
  50. 50.
    Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2003;30(2):401–403.Google Scholar
  51. 51.
    Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults. Chest. 2011;140(4):933–938.Google Scholar
  52. 52.
    Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005;146(5):598–604.Google Scholar
  53. 53.
    Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814–822.Google Scholar
  54. 54.
    Safdar SM, Rehman JU, Samman EM, Bahabri NM. Fatal hemophagocytic syndrome as a manifestation of immune reconstitution syndrome in a patient with acquired immunodeficiency syndrome. Saudi Med J. 2013;34(8):861–864.Google Scholar
  55. 55.
    Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85(5):421–426.Google Scholar
  56. 56.
    Schneider EM, Lorenz I, Muller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood. 2002;100(8):2891–2898.Google Scholar
  57. 57.
    Schulert GS, Grom AA. Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277–292.Google Scholar
  58. 58.
    Shah NN, Harrison N, Stonecypher M, Frank D, Amorosa V, Svoboda J. Extracavitary primary effusion lymphoma initially presenting with hemophagocytic lymphohistocytosis. Clin Lymphoma Myeloma Leuk.2014;14(5):e157–160.Google Scholar
  59. 59.
    Singh S, Samant R, Joshi VR. Adult onset Still’s disease: a study of 14 cases. Clin Rheumatol. 2008;27(1):35–39.Google Scholar
  60. 60.
    Sonke GS, Ludwig I, van Oosten H, Baars JW, Meijer E, Kater AP, et al. Poor outcomes of chronic active Epstein-Barr virus infection and hemophagocytic lymphohistiocytosis in non-Japanese adult patients. Clin Infect Dis. 2008;47(1):105–108.Google Scholar
  61. 61.
    Stern A, Riley R, Buckley L. Worsening of macrophage activation syndrome in a patient with adult onset Still’s disease after initiation of etanercept therapy. J Clin Rheumatol. 2001;7(4):252–256.Google Scholar
  62. 62.
    Sumegi J, Nestheide SV, Barnes MG, Villanueva J, Zhang K, Grom AA, et al. Gene-expression signatures differ between different clinical forms of familial hemophagocytic lymphohistiocytosis. Blood. 2013;121(7):e14–24.Google Scholar
  63. 63.
    Takada H, Ohga S, Mizuno Y, Suminoe A, Matsuzaki A, Ihara K, et al. Oversecretion of IL-18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity. Br J Haematol. 1999;106(1):182–189.Google Scholar
  64. 64.
    Terrell CE, Jordan MB. Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood. 2013;121(26):5184–91.Google Scholar
  65. 65.
    Teruya-Feldstein J, Setsuda J, Yao X, Kingma DW, Straus S, Tosato G, et al. MIP-1alpha expression in tissues from patients with hemophagocytic syndrome. Lab Invest. 1999;79(12):1583–1590.Google Scholar
  66. 66.
    Tristano AG. Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases. Med Sci Monit. 2008;14(3):RA27–36.Google Scholar
  67. 67.
    Tse E, Kwong YL. Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target. Exp Mol Med. 2015;47:e136.Google Scholar
  68. 68.
    Wang Z, Wang Y, Wang J, Feng C, Tian L, Wu L. Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. Int J Hematol. 2009;90(4):501–5.Google Scholar
  69. 69.
    Weaver LK, Behrens EM. Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol. 2014;26(5):562–9.Google Scholar
  70. 70.
    Yamada M, Katano H, Yotsumoto M, Hashimoto H, Muramatsu T, Shiotsuka M, et al. Unique expression pattern of viral proteins in human herpesvirus 8-positive plasmablastic lymphoma: a case report. Int J Clin Exp Pathol. 2014;7(9):6415–6418.Google Scholar
  71. 71.
    Yokota S, Itoh Y, Morio T, Sumitomo N, Daimaru K, Minota S. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with tocilizumab. J Rheumatol. 2015;42(4):712–722. Google Scholar
  72. 72.
    Zeft A, Hollister R, LaFleur B, Sampath P, Soep J, McNally B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol. 2009;15(4):161–164.Google Scholar
  73. 73.
    Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794–8.Google Scholar

Copyright information

© Hospital for Special Surgery 2018

Authors and Affiliations

  • Bella Mehta
    • 1
    • 2
  • Shanthini Kasturi
    • 3
  • Julie Teruya-Feldstein
    • 4
  • Steven Horwitz
    • 5
  • Anne R. Bass
    • 1
    • 2
  • Doruk Erkan
    • 1
    • 2
  1. 1.Hospital for Special SurgeryNew YorkUSA
  2. 2.Weill Cornell MedicineNew YorkUSA
  3. 3.Tufts Medical CenterBostonUSA
  4. 4.Icahn School of MedicineMount Sinai Health SystemNew YorkUSA
  5. 5.Memorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations