Reactive hemophagocytic syndrome in a patient with adult-onset Still disease
Authors: Geneviève Gavigan, Jennifer Beecker
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: A healthy 37-year-old woman presented with a 2-week history of fever, arthralgias affecting knees and wrists, and an evanescent rash. The rash presented every day and favored the trunk, extremities, and face (Fig 1, A). Clinically, she had erythematous macules and papules scattered over her trunk, neck, and extremities, which exhibited the Koebner phenomenon. There was no evidence of pharyngitis, cervical lymphadenopathy, hepatosplenomegaly, pleuritis, or pericarditis on physical examination. Blood work was significant for a white blood count (WBC) of 17.6 (normal: 3.5 to 10.5 × 109/L) with more than 80% neutrophils, C-reactive protein was 167 (normal: <10 mg/L), erythrocyte sedimentation rate was 71 (normal: 0 to 10 mm/hr), and ferritin was 4422 (normal: 11 to 307 μg/L). An infectious workup was noncontributory and an autoimmune screen was negative.Adult-onset Still disease (AOSD) was diagnosed, and the patient was treated conservatively with ibuprofen, in that she declined prednisone. Her condition rapidly deteriorated, and she was admitted to the intensive care unit with hypotension, disseminated intravascular coagulation, and multiorgan failure. She was treated with methylprednisolone and intravenous immunoglobulin. As her status declined, bone marrow biopsy and aspirate findings were consistent with the suspected of diagnosis of reactive hemophagocytic syndrome (RHS). She died within days.AOSD is an uncommon, poorly understood inflammatory process, characterized by 4 cardinal symptoms: spiking fever ≥39°C, arthralgias or arthritis, evanescent rash, and elevated WBC (≥10,000 cells/mm3) with 80% neutrophils or more.1Fautrel B. Adult-onset Still disease.Best Pract Res Clin Rheumatol. 2008; 22: 773-792Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Rash is present in 77% to 100% of cases and is an important diagnostic clue.1Fautrel B. Adult-onset Still disease.Best Pract Res Clin Rheumatol. 2008; 22: 773-792Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Classically, the rash is asymptomatic and composed of evanescent salmon-pink colored macules or papules, with maximal intensity during fever spikes.1Fautrel B. Adult-onset Still disease.Best Pract Res Clin Rheumatol. 2008; 22: 773-792Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar The trunk and extremities are most commonly involved; yet the rash has a predilection for sites of pressure, such as areas of tight clothing, which was exemplified in our patient. Light trauma may trigger the rash, demonstrating the Koebner phenomenon (Fig 1, B).2Efthimiou P. Paik P.K. Bielory L. Diagnosis and management of adult onset Still's disease.Ann Rheum Dis. 2006; 65: 564-572Crossref PubMed Scopus (284) Google Scholar Ferritin is often significantly elevated, and may correlate with disease activity.2Efthimiou P. Paik P.K. Bielory L. Diagnosis and management of adult onset Still's disease.Ann Rheum Dis. 2006; 65: 564-572Crossref PubMed Scopus (284) Google Scholar Importantly, AOSD can culminate in RHS in 12% to 15% of cases.3Arlet J.B. Le T.H. Marinho A. Amoura Z. Wechsler B. Papo T. Piette J.C. 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: 1596-1601Crossref PubMed Scopus (175) Google Scholar, 4Hot A. Toh M.L. Coppéré B. Perard L. Madoux M.H. Mausservey C. et al.Reactive hemophagocytic syndrome in adult-onset Still’s disease: clinical features and long-term outcome: a case control study of 8 patients.Medicine. 2010; 89: 37-46Crossref PubMed Scopus (76) Google Scholar RHS is a life-threatening complication of rheumatic diseases characterized by fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, rash, and increased proliferation of benign histiocytes in the bone marrow. High ferritin and liver function tests are often present. RHS may also develop in patients with systemic lupus erythematosus, lymphoma, or serious infections.3Arlet J.B. Le T.H. Marinho A. Amoura Z. Wechsler B. Papo T. Piette J.C. 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: 1596-1601Crossref PubMed Scopus (175) Google Scholar, 4Hot A. Toh M.L. Coppéré B. Perard L. Madoux M.H. Mausservey C. et al.Reactive hemophagocytic syndrome in adult-onset Still’s disease: clinical features and long-term outcome: a case control study of 8 patients.Medicine. 2010; 89: 37-46Crossref PubMed Scopus (76) Google ScholarThere is limited literature on RHS, and although there is evidence that early treatment of RHS may improve prognosis,5Emmenegger U. Frey U. Reimers A. Fux C. Semela D. Cottagnoud P. et al.Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes.Am J Hematol. 2001; 68: 4-10Crossref PubMed Scopus (120) Google Scholar there is no specific data to support or refute that early aggressive treatment in AOSD would prevent development of RHS. Intuitively, though, it follows that disease control might bestow a more favorable outcome. Interestingly, in 2 of the case series, RHS developed in only 1 of 14 patients (combined) during AOSD remission. Immunosuppressants were not routinely used before the onset of RHS in either series (2 of 8 and 2 of 6).3Arlet J.B. Le T.H. Marinho A. Amoura Z. Wechsler B. Papo T. Piette J.C. 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: 1596-1601Crossref PubMed Scopus (175) Google Scholar, 4Hot A. Toh M.L. Coppéré B. Perard L. Madoux M.H. Mausservey C. et al.Reactive hemophagocytic syndrome in adult-onset Still’s disease: clinical features and long-term outcome: a case control study of 8 patients.Medicine. 2010; 89: 37-46Crossref PubMed Scopus (76) Google Scholar This suggests that RHS may be less likely to develop in patients with controlled AOSD. Taken together, it is important to identify and monitor patients with AOSD for potentially life-threatening sequelae, so that prompt treatment is possible. To the Editor: A healthy 37-year-old woman presented with a 2-week history of fever, arthralgias affecting knees and wrists, and an evanescent rash. The rash presented every day and favored the trunk, extremities, and face (Fig 1, A). Clinically, she had erythematous macules and papules scattered over her trunk, neck, and extremities, which exhibited the Koebner phenomenon. There was no evidence of pharyngitis, cervical lymphadenopathy, hepatosplenomegaly, pleuritis, or pericarditis on physical examination. Blood work was significant for a white blood count (WBC) of 17.6 (normal: 3.5 to 10.5 × 109/L) with more than 80% neutrophils, C-reactive protein was 167 (normal: <10 mg/L), erythrocyte sedimentation rate was 71 (normal: 0 to 10 mm/hr), and ferritin was 4422 (normal: 11 to 307 μg/L). An infectious workup was noncontributory and an autoimmune screen was negative. Adult-onset Still disease (AOSD) was diagnosed, and the patient was treated conservatively with ibuprofen, in that she declined prednisone. Her condition rapidly deteriorated, and she was admitted to the intensive care unit with hypotension, disseminated intravascular coagulation, and multiorgan failure. She was treated with methylprednisolone and intravenous immunoglobulin. As her status declined, bone marrow biopsy and aspirate findings were consistent with the suspected of diagnosis of reactive hemophagocytic syndrome (RHS). She died within days. AOSD is an uncommon, poorly understood inflammatory process, characterized by 4 cardinal symptoms: spiking fever ≥39°C, arthralgias or arthritis, evanescent rash, and elevated WBC (≥10,000 cells/mm3) with 80% neutrophils or more.1Fautrel B. Adult-onset Still disease.Best Pract Res Clin Rheumatol. 2008; 22: 773-792Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Rash is present in 77% to 100% of cases and is an important diagnostic clue.1Fautrel B. Adult-onset Still disease.Best Pract Res Clin Rheumatol. 2008; 22: 773-792Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Classically, the rash is asymptomatic and composed of evanescent salmon-pink colored macules or papules, with maximal intensity during fever spikes.1Fautrel B. Adult-onset Still disease.Best Pract Res Clin Rheumatol. 2008; 22: 773-792Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar The trunk and extremities are most commonly involved; yet the rash has a predilection for sites of pressure, such as areas of tight clothing, which was exemplified in our patient. Light trauma may trigger the rash, demonstrating the Koebner phenomenon (Fig 1, B).2Efthimiou P. Paik P.K. Bielory L. Diagnosis and management of adult onset Still's disease.Ann Rheum Dis. 2006; 65: 564-572Crossref PubMed Scopus (284) Google Scholar Ferritin is often significantly elevated, and may correlate with disease activity.2Efthimiou P. Paik P.K. Bielory L. Diagnosis and management of adult onset Still's disease.Ann Rheum Dis. 2006; 65: 564-572Crossref PubMed Scopus (284) Google Scholar Importantly, AOSD can culminate in RHS in 12% to 15% of cases.3Arlet J.B. Le T.H. Marinho A. Amoura Z. Wechsler B. Papo T. Piette J.C. 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: 1596-1601Crossref PubMed Scopus (175) Google Scholar, 4Hot A. Toh M.L. Coppéré B. Perard L. Madoux M.H. Mausservey C. et al.Reactive hemophagocytic syndrome in adult-onset Still’s disease: clinical features and long-term outcome: a case control study of 8 patients.Medicine. 2010; 89: 37-46Crossref PubMed Scopus (76) Google Scholar RHS is a life-threatening complication of rheumatic diseases characterized by fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, rash, and increased proliferation of benign histiocytes in the bone marrow. High ferritin and liver function tests are often present. RHS may also develop in patients with systemic lupus erythematosus, lymphoma, or serious infections.3Arlet J.B. Le T.H. Marinho A. Amoura Z. Wechsler B. Papo T. Piette J.C. 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: 1596-1601Crossref PubMed Scopus (175) Google Scholar, 4Hot A. Toh M.L. Coppéré B. Perard L. Madoux M.H. Mausservey C. et al.Reactive hemophagocytic syndrome in adult-onset Still’s disease: clinical features and long-term outcome: a case control study of 8 patients.Medicine. 2010; 89: 37-46Crossref PubMed Scopus (76) Google Scholar There is limited literature on RHS, and although there is evidence that early treatment of RHS may improve prognosis,5Emmenegger U. Frey U. Reimers A. Fux C. Semela D. Cottagnoud P. et al.Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes.Am J Hematol. 2001; 68: 4-10Crossref PubMed Scopus (120) Google Scholar there is no specific data to support or refute that early aggressive treatment in AOSD would prevent development of RHS. Intuitively, though, it follows that disease control might bestow a more favorable outcome. Interestingly, in 2 of the case series, RHS developed in only 1 of 14 patients (combined) during AOSD remission. Immunosuppressants were not routinely used before the onset of RHS in either series (2 of 8 and 2 of 6).3Arlet J.B. Le T.H. Marinho A. Amoura Z. Wechsler B. Papo T. Piette J.C. 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: 1596-1601Crossref PubMed Scopus (175) Google Scholar, 4Hot A. Toh M.L. Coppéré B. Perard L. Madoux M.H. Mausservey C. et al.Reactive hemophagocytic syndrome in adult-onset Still’s disease: clinical features and long-term outcome: a case control study of 8 patients.Medicine. 2010; 89: 37-46Crossref PubMed Scopus (76) Google Scholar This suggests that RHS may be less likely to develop in patients with controlled AOSD. Taken together, it is important to identify and monitor patients with AOSD for potentially life-threatening sequelae, so that prompt treatment is possible.