Increased level of H-ferritin and its imbalance with L-ferritin, in bone marrow and liver of patients with adult onset Still's disease, developing macrophage activation syndrome, correlate with the severity of the disease

Abstract

In this paper, we aimed to evaluate the levels of ferritin enriched in H subunits (H-ferritin) and ferritin enriched in L subunits (L-ferritin) and the cells expressing these 2 molecules, in the bone marrow (BM) and liver biopsies obtained from adult onset Still's disease (AOSD) patients who developed macrophage activation syndrome (MAS), and correlating these data with the severity of the disease. Twenty-one patients with MAS-associated AOSD underwent BM biopsy and among them, 9 patients with hepatomegaly and elevated liver enzymes underwent liver biopsy. All the samples were stained by both immunohistochemistry and immunofluorescence. A statistical analysis was performed to estimate the possible correlation among both H-ferritin and L-ferritin tissue expression and the clinical picture of the disease. Furthermore, the same analysis was performed to evaluate the possible correlation among the number of CD68/H-ferritin or CD68/L-ferritin positive cells and the clinical picture. Both immunohistochemical and immunofluorescence analysis demonstrated an increased tissue H-ferritin expression, in the BM and liver samples of our patients. This increased expression correlated with the severity of the disease. An inflammatory infiltrate, enriched in CD68 macrophages, expressing H-ferritin was observed in both the BM and the liver samples of our patients. Furthermore, we observed, that this increased number of CD68/H-ferritin positive cells significantly correlated with the severity of clinical picture and this specific BM infiltrate correlated with the mortality rate, reported in our cohort. Our data showed an imbalance between the levels of H- and L-ferritin in different organs of patients with MAS-associated AOSD and the evidence of a strong infiltrate of CD68/H-ferritin positive cells in the same organs. Furthermore, a strong correlation among both the tissue H-ferritin and the CD68/H-ferritin positive cells and the clinical picture was observed.

H-ferritin and CD68+/H-ferritin+ monocytes/macrophages are increased in the skin of adult-onset Still's disease patients and correlate with the multi-visceral involvement of the disease

“…This result may confirm previous reports showing that the persistence of skin lesions correlates with the degree of systemic activity, and although the majority of papers discussing these persistent AOSD‐related skin lesions are case reports or small series, some authors found a significant correlation of AOSD activity with a poor outcome . With regard to the increased H‐ferritin expression in skin lesions, we found a strong correlation between this expression and a more severe disease, paralleling previous studies regarding different target organs of AOSD .…”

Adult-onset Still’s disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers

“…Further, 60–80% of AOSD patients experience a macular or maculopapular evanescent salmon-pink skin rash associated with the fever spiking [38–41]; some patients, those with a usually more severe outcome, may experience this skin involvement for many weeks [7, 42]. Similar to previous studies [22, 24], a strong increase of inflammatory markers as well as of serum ferritin levels were observed herein [43, 44], confirming the systemic nature of the disease. Although it has been proposed that AOSD might be included within the so called “Hyperferritinemic Syndrome”, a common umbrella gathering different diseases in which the increased circulating ferritin levels might not only reflect an acute phase response but be directly involved in inflammation [25], our study did not find any correlation between the levels of this molecule and the patient outcomes.…”

“…Our patients showed peripheral cytopenias associated with high levels of both inflammatory markers and serum ferritin. All these patients were treated with a steroid pulse therapy [43, 45, 46]. Of note, it has been proposed that AOSD and MAS may be part of the same disease spectrum, in which AOSD should be considered the milder form [14], and the occurrence of MAS might be misdiagnosed due to the immunosuppressive treatments used to control an AOSD flare [14, 15].…”

Limited diagnostic value of procalcitonin in early diagnosis of adult onset Still’s disease

“…Reduced suppressive function of ferritin enriched in H subunits may predispose to inflammatory processes. An imbalance between the concentrations of ferritin enriched in H subunits and ferritin enriched in L subunits in bone marrow and liver biopsies correlates with the severity of disease [8]. The elevated concentrations of alpha-globulin observed in our patient were caused by increased concentrations of acute phase reactants, and are commonly seen in inflammatory conditions [3].…”