COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

No abstract

We aimed to investigate the frequency of rheumatic diseases in patients suffering from autoimmune thyroid diseases (ATD). Sixty-five patients (56 F, 9 M), who were followed by diagnosis of ATD, were questioned and examined for the presence of rheumatic disease. Basic laboratory tests and antithyroid antibodies, antinuclear antibody and rheumatoid factor (RF) levels were also measured by appropriate methods. Various rheumatic diseases were detected in 40 (62%) of patients with ATD. The most frequent rheumatic conditions were fibromyalgia, recurrent aphthous stomatitis, osteoarthritis, keratoconjunctivitis sicca and xerostomia and carpal tunnel syndrome which were detected in 20 (31%), 13 (20%), 10 (15%), 9 (14%) and 8 (12%) of patients, respectively. Autoimmune diseases, except Sjogren's syndrome, which were detected in ten patients with ATD, are as follows-vitiligo: two; autoimmune hepatitis: two; oral lichen planus: one, ulcerative colitis: one, inflammatory arthritis in four patients (two of them had rheumatoid arthritis, one had psoriasis and psoriatic arthritis and one had mixed collagen tissue disease). RF was positive in two patients, one of them had rheumatoid arthritis and FANA was positive in six (9%) patients; all of them had hypothyroidism. The frequency of rheumatic diseases seems to be higher in patients suffering from ATD. Initial evaluation and a regular checking for rheumatic diseases in patients suffering from ATD were recommended.

ERA patients had more symmetric joint involvement than PA; laboratory markers could be also an alternative where there is high RF and anti-CCP positivity with antibody levels among the ERA patients. Finally, the demographic features can be used as differentiating factors; ERA was seen predominantly among females aged 40-59 years which refers to young adults.