Very low density lipoprotein, chylomicron, and lipoprotein (a) are more useful to detect the development of macrophage activation syndrome in adult-onset still's disease as compared with cytokines and triglyceride

Hemophagocytic lymphocytosis (HLH) is a rare and severe inflammatory disorder, resulting in excessive cytokine production, and enhanced immune system activation. A special form of HLH in rheumatic diseases is called macrophage activation syndrome (MAS). MAS is a life-threatening complication observed in adult onset Still's disease (AOSD) 1. Elevation of serum triglyceride (TG), ferritin, and cytokines have been suggested as biochemical markers for the development of MAS 2, 3. We have studied cytokines and lipoprotein fractions by a newly developed anion-exchange high-performance liquid chromatography in a patient with AOSD and MAS 4. A 39-year-old man was referred to our hospital due to prolonged fever and arthralgia for 2 weeks on August 14, 2012. Physical examination and computed tomography revealed salmon-pink rash and hepatosplenomegaly. Laboratory data on admission showed significantly elevated serum levels of ferritin (3,876 ng/ml; normal, 20–250 ng/ml), aspartate aminotransferase (AST, 245 IU/l; normal, 10–40 IU/l), alanine aminotransferase (ALT, 159 IU/l; normal, 5–40 IU/l), C-reactive protein (CRP, 14.06 mg/dl; normal, < 0.3 mg/dl), with leukocytosis (17,600/µl) and neutrophilia (15,664/µl). This presentation and the negativity for rheumatoid factor and antinuclear antibodies favored a diagnosis of AOSD. At this time, serum TG was 221 mg/dl and platelets were 45.3 × 104/µl. Prednisolone (30 mg/day) was started on August 17, however, serum ferritin increased to 41,020 ng/ml and platelets decreased to 14.9 × 104/µl, indicating the development of MAS on August 20. We used methylprednisolone (1,000 mg/day) from August 20 to 22, and prednisolone, 100 mg/day, from August 23 to 28, 90 mg/day from August 29 to 31, and 80 mg/day from September 1 to 3. A single dose of tocilizumab (560 mg/day) was administered on August 28. This therapy ameliorated his MAS. Serum ferritin levels were significantly and positively correlated with blood levels of AST (r = 0.90, P < 0.01 by the Spearman rank correlation test), ALT (r = 0.93, P < 0.01), lactate dehydrogenase (r = 0.95, P < 0.01), and were negatively correlated with platelets counts (r = −0.88, P < 0.05), supporting the usefulness of ferritin for the maker of development of MAS 3. However, cytokines like interleukin (IL)−18, IL-12, IL-6, tumor necrosis factor-α, and CRP did not show the same behavior as ferritin. MAS is a highly inflammatory disorder, which may inactivate lipoprotein lipase 5, resulting in increase of TG-rich lipoprotein such as very-low density-lipoprotein (VLDL) and chylomicron (CM). Lipoprotein (a) has been suggested to be associated with inflammation 6. Elevation of lipoprotein (a) may also reflect highly inflammatory state of MAS. Changes in each lipoprotein during the development of MAS are shown in Fig. 1. Serum VLDL (r = 0.81, P < 0.05), CM (r = 0.84, P < 0.05) and lipoprotein (a) (r = 0.81, P < 0.05) levels were significantly and positively correlated with serum ferritin levels during the development of MAS. Other lipoprotein levels and serum TG were not correlated with serum ferritin levels. In summary, VLDL, CM, and lipoprotein (a) were more useful to detect the development of MAS in AOSD as compared with cytokines and TG. Hidekatsu Yanai1 Sumie Moriyama1 Yuji Hirowatari2 Hiroshi Kaneko3 1Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan; 2 Bioscience Division, Tosoh Corporation, Kanagawa, Japan; 3 Department of Rheumatology, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan