Retinal microangiopathy and rapidly fatal cerebral edema in a patient with adult-onset Still's disease and concurrent macrophage activation syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a complex inflammatory disease with multiple diagnostic and therapeutic pitfalls. The congenital form, referred to as familial hemophagocytic lymphohistiocytosis (FHL), is often associated with cerebromeningeal involvement, whereas neurological complications are not characteristic of the adult form of secondary HLH (sHLH). Here we report the case of a 20-year-old woman with adult-onset Still's disease (AOSD), retinal microangiopathy and concurrent macrophage activation syndrome (MAS), in the context of sHLH. Following treatment with etanercept, ibuprofen, methylprednisolone, and phenylbutazone for 3 weeks, MAS deteriorated and fatal cerebral edema occurred within only 24 h. The clinical signs and neuropathological findings are discussed with special emphasis on possible relationships between the aggravation of MAS and therapeutic interventions for AOSD. In conclusion, even the slightest sign of mental decline in a patient with AOSD must be considered central nervous system MAS which can be rapidly fatal.     

A Recurrent Case of Adult-onset Still's Disease with Concurrent Acalculous Cholecystitis and Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis Successfully Treated with Combination Immunosuppressive Therapy

We herein report the case of 21-year-old female diagnosed with adult-onset Still''s disease (AOSD) three years earlier who presented with fever and right upper abdominal pain. She was diagnosed with acute acalculous cholecystitis (AAC) based on hepatic dysfunction, elevated C-reactive protein, and gallbladder wall thickening on abdominal ultrasound. Based on the presence of pancytopenia, hyperferritinemia, and hemophagocytosis by a bone marrow examination, she was diagnosed with macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) which was refractory to glucocorticoid pulse therapy. The combination of intravenous cyclosporine A with glucocorticoids was able to successfully control the disease activity of AOSD-related AAC and MAS/HLH.     

Adult onset Still’s disease: a study of 14 cases

We studied the clinical profile, laboratory parameters, disease course, and outcomes of patients with adult onset Still’s disease (AOSD). A retrospective analysis of adult patients with Still’s disease diagnosed from 2000 to 2004 was carried out. Their clinical features and laboratory findings at presentation, disease course, and outcomes were analyzed. Data of 14 patients with Still’s disease were analyzed. The age at disease onset ranged from 16 to 59 years with a mean of 29.85, the male to female ratio being 9:5. The mean duration of illness from onset of symptoms to presentation was 14.5 months (range). The most common clinical manifestations were fever (n = 14), articular symptoms (n = 14), rash (n = 8), weight loss (n = 12), and sore throat (n = 5). Elevated ESR was present in all patients with a mean of 98.3 mm at 1 h. Hepatic enzymes were elevated in seven patients at disease onset. The mean duration of follow up was 19.14 months (range). Three patients progressed to chronic arthropathy. Cyclosporine led to dramatic recovery in five patients. Macrophage activation syndrome (MAS) was present in two patients, one after sulfasalazine therapy. One patient with MAS died. Still’s disease, although uncommon, has characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of fever of unknown origin. Nonsteroidal anti-inflammatory drugs, steroids, and methotrexate may not be always effective, and cyclosporine is an effective drug in resistant cases. Sulfasalazine should be avoided in cases of AOSD.     

Adult onset Still’s disease flared with pericardial effusion

Adult onset Still’s disease (AOSD) is characterized by spiking fevers, arthritis, rash, and involvement of multiple organs, and can be classified as self-limited, intermittent, and chronic disease groups. Cardiac manifestations include pericarditis and myocarditis. The case of this disease flared only with pericardial effusion is not reported. We describe a patient with adult onset Still’s disease who was flared with pericardial effusion without other AOSD-associated symptoms, and propose that pericardial effusion should be included as a feature of flare in the intermittent disease group of adult onset Still’s disease.     

Benefit and a possible risk of tocilizumab therapy for adult-onset Still’s disease accompanied by macrophage-activation syndrome

We report a 57-year-old female case of intractable adult-onset Still’s disease (AOSD). Initial high-dose prednisolone therapy was ineffective, and macrophage-activation syndrome (MAS) manifested after one session of additional tocilizumab therapy. After successful treatment for MAS with lipo-dexamethasone and cyclosporin, tocilizumab therapy aided in the rapid reduction of the therapeutic steroid dose. Tocilizumab may be useful for maintenance therapy for AOSD, although its efficacy is unclear for the highly active phase of the disease.     

Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages

Macrophage activation syndrome (MAS) is a rare and potentially fatal disorder, thought to result from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. The term MAS designates a clinicopathologic entity that occurs in different hemophagocytic syndromes (HSs). Primary hemophagocytic lymphohistiocytosis (HLH) is recognized to have an immunogenetic basis, but in the secondary HS (also referred to as secondary HLH), the cause is unknown. The pathogenesis of the accelerated disease phase typical of MAS remains incompletely understood. This report describes the immunohistochemical findings on liver tissues from 5 children, each of whom presented with MAS in the context of a different type of HS. The data provide direct evidence for the involvement of activated CD8(+) lymphocytes through the production of interferon-gamma and of macrophages through hemophagocytosis and production of interleukin 6 and tumor necrosis factor-alpha, and underscore the view that MAS in different HSs share a common effector pathway.     

Glucocorticoid and cyclosporine refractory adult onset Still’s disease successfully treated with tocilizumab

We report a 29-year-old Japanese woman with disseminated intravascular coagulation (DIC) and adult onset Still’s disease (AOSD). Her disease was refractory to high-dose glucocorticoids, two courses of steroid pulse therapy, and addition of cyclosporine (3.5 mg/kg/day). The serum interleukin-6 level was markedly elevated. Therefore, we administered an anti-interleukin-6 receptor antibody (tocilizumab, 8 mg/kg fortnightly), which dramatically improved her symptoms and the levels of acute-phase proteins. In addition, rapid tapering of the glucocorticoid dose was possible. Four months later, she was maintained on tocilizumab infusion once a month with low-dose steroid therapy. Cyclosporine is one of the first-line immunosuppressants for AOSD, especially when associated with DIC, hepatic failure, or hemophagocytic syndrome. In patients with cyclosporine-resistant AOSD, tocilizumab may be another useful option.     

Macrophage activation syndrome and cytokine-directed therapies

Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.     

A rare trigger for macrophage activation syndrome

Macrophage activation syndrome (MAS) is a disorder characterized by increased activation of mononuclear cells leading to phagocytosis of blood cell precursors in the bone marrow. We describe a case of MAS triggered by disseminated histoplasmosis occurring in a patient with Still’s disease on long-term treatment with adalimumab.     

Macrophage activation syndrome II/II

Macrophage activation syndrome (MAS) is a rare systemic disorder which results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. Primary haemophagocytic lymphohistiocytosis (HLH) is recognized as having a genetic basis, but the secondary haemophagocytic syndrome (HS), also referred to as MAS, occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), adult onset Still's disease and other disorders. In this second of the two part series, the clinical features and management are described.     

Etanercept as a rescue agent in patient with adult onset Still’s disease complicated with congestive heart failure

Adult onset Still’s disease (AOSD) is an uncommon disorder of unknown cause. The clinical symptoms of AOSD are a spiking fever, a typical rash, arthralgia or arthritis, sore throat, lymphadenopathy, and splenomegaly. Pleuropulmonary and cardiac involvement are rare. We report a patient with a two-year history of AOSD with myocarditis refractory to cyclosporine and glucocorticoid. Significant congestive heart failure due to left ventricle dysfunction and hyperferritinemia developed during the hospital course. After therapy with etanercept, the patient’s clinical manifestations recovered and she regained normal left ventricular systolic function.     

Onset of adult-onset Still’s disease following influenza vaccination

We describe that case of a 61-year-old woman who developed high spiking fever, sore throat, polyarthralgia, and salmon pink evanescent rash following influenza vaccination. A diagnosis of adult-onset Still’s disease (AOSD) was made based on clinical and laboratory findings. Methylprednisolone pulse therapy followed by oral prednisolone resulted in a favorable outcome. This is the second published case in which a causal relationship between vaccination and onset of AOSD is suggested. Bystander activation would appear to play an important role in inducing the immune reaction.     

Hemophagocytic syndrome in one patient with adult-onset Still’s disease

Macrophage activation syndrome (MAS) is an important complication seen in systemic for juvenile rheumatoid arthritis; until now, it has been reported in only a few cases of adult-onset Still’s disease (AOSD). Here, we shall present a 50-year-old female patient who was using steroids and antimalarial drugs for AOSD, and who developed MAS during follow-up. The patient presented with febrile neutropenia, and the neutropenic period lasted for 15 days. The examination of bone marrow aspiration smears demonstrated increased macrophages and findings of hemophagocytosis. Flow cytometric analysis of peripheral blood showed decreased natural killer cells. The patient developed neurologic findings during this period, and during the recovery of neutropenia, she had icterus and liver function test abnormalities. The patient was given granulocyte colony-stimulating factor during neutropenic period, and her neutropenia improved after the administration of high-dose steroids. Our patient was the first AOSD patient who presented with febrile neutropenia during the course of her disease and who was diagnosed to have MAS.     

Hemophagocytic Lymphohistiocytosis: Clinical Analysis of 103 Adult Patients

To investigate the clinical features of adult patients with hemophagocytic lymphohistiocytosis (HLH) and to explore possible risk factors for death, we retrospectively reviewed the medical records of 103 adult HLH patients hospitalized from 1997 to 2012. We analyzed the underlying diseases, clinical characteristics, 1aboratory findings, outcomes, and prognostic factors. The most common cause of HLH was hematologic malignancies (n = 49), followed by infectious diseases (n = 24) and autoimmune disorders (n = 14); 24 cases were of unknown etiology. Eight patients had a combination of underlying diseases. HLH was clinically characterized by high fever (96.1%), splenomegaly (79.6%), hepatomegaly (65.0%), lymphadenopathy (53.4%), proteinuria (31.1%), skin rash (25.2%), gastrointestinal hemorrhage (14.6%), disseminated intravascular coagulation (13.6%), increased creatinine (7.8%), and central nervous system involvement (12.6%) including altered mental status (9.7%) and cranial hemorrhage (2.9%). Laboratory abnormalities included cytopenia (99.0%), serum ferritin >500 ug/L (98.4%), liver dysfunction (98.1%), hypertriglyceridemia (88.5%), hemophagocytosis in bone marrow smear (87.4%), and hypofibrinogenemia (60.9%).In addition to the treatment they received for the underlying causes, patients received therapy for HLH consisting of corticosteroids, immunosuppressive drugs, and intravenous immunoglobulin. Twenty-six patients (25.2%) recovered after treatment, and 19 of them achieved long-term remission during follow-up. Seventy-seven patients (74.8%) died because of tumor, sepsis, multiple organ failure, or HLH-related organ hemorrhage and coagulopathy. The deceased patients were more likely to be older at disease onset, male, and to present with splenomegaly and thrombocytopenia, compared to the survivors. Treatment for the underlying diseases combined with corticosteroids, immunosuppressive agents, and immunoglobulin therapy may improve the prognosis of HLH. More attention should be paid to high-risk patients to prevent the development of serious complications associated with HLH.Key words/Abbreviations: hemophagocytic lymphohistiocytosis, lymphoma, autoimmune diseases, clinical manifestation, prognosis, risk factor, AOSD = adult-onset Still disease, CNS = central nervous system, DIC = disseminated intravascular coagulation, CMV = cytomegalovirus, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IVIg = intravenous immunoglobulin, MAS = macrophage-activation syndrome, NK = natural killer, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus     

Different Articular Outcomes of Still’s Disease in Chinese Children and Adults

The clinical manifestations, treatment and course, and articular outcomes of 24 children with juvenile-onset Still’s disease (JOSD) and 21 adults with adult-onset Still’s disease (AOSD) were compared retrospectively. There was no significant difference in the initial clinical and laboratory manifestations except that more adults presented with a sore throat (81% vs 46%, p = 0.03). Although serum ferritin was almost always elevated in both diseases, adults had significantly higher serum ferritin concentrations compared with those of children. Steroid treatment was required in 71% of children and 52% of adults, while disease-modifying antirheumatic drugs were used in 42% of children and 24% of adults during the course. Chronic arthritis (>6 months) occurred in comparable proportions of patients with JOSD and AOSD (46% vs 38%, p = 0.82), irrespective of the disease pattern (monocyclic or polycyclic). However, severe deforming arthritis with marked functional limitation occurred only in JOSD, particularly with polyarthritis at disease onset (more than five affected joints). In contrast, AOSD patients with chronic arthritis had a favourable functional outcome at the end of the follow-up. Our study suggested different articular outcomes of Still’s disease in Chinese children and adults. Received: 19 April 1999 / Accepted: 6 August 1999     

A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years

Interleukin-6 overproduction is pathologically involved in adult onset Still’s disease (AOSD). We successfully treated a man with refractory AOSD utilizing tocilizumab. Tocilizumab was discontinued after 15 doses due to intestinal bleeding, but the efficacy was sustained over 21 months. Tocilizumab was readministered safely upon recurrence and showed similar efficacy over 6 years. Corticosteroid and NSAIDs could be discontinued and intestinal bleeding was no more observed. Tocilizumab can be a therapeutic option for AOSD.     

Acute hepatitis in adult Still’s disease during corticosteroid treatment successfully treated with anakinra

Adult onset Still’s disease (AOSD) is a well-recognized clinical disorder characterized by involvement of various organs, including liver. However, acute hepatitis or hepatic failure is extremely rare, and most of the reported cases occurred during treatment with hepatotoxic drugs. Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Experimental and clinical data support a central role for IL-1Ra in fulminant hepatic failure. We report the case of a patient with AOSD complicated with acute hepatitis during treatment with corticosteroids, which was dramatically improved with anakinra.     

Clinical characteristics and follow-up analysis of adult-onset Still’s disease complicated by hemophagocytic lymphohistiocytosis

We evaluated clinical characteristics and prognosis for adult-onset Still’s disease (AOSD) complicated by hemophagocytic lymphohistiocytosis (HLH). We retrospectively identified cases of AOSD with (n?=?10) and without (n?=?305) HLH complications. We reviewed their medical records, completed follow-up through outpatient clinic and telephone interviews, and analyzed their clinical symptoms, signs, laboratory test results, treatments, and prognosis. More AOSD patients with HLH developed hepatomegaly, bleeding, serositis, and neurologic symptoms than those without HLH, and they more commonly presented with leukopenia, thrombocytopenia, severe anemia, severe liver function abnormalities, decreased fibrinogen, elevated immunoglobulin, and bone marrow hemophagocytosis. The ten patients with AOSD complicated by HLH were treated with high-dose steroids or pulse steroid therapy, and eight of them also received cytotoxic drugs, while biological agents showed poor response. Follow-up results indicated that AOSD patients overall had good prognosis, while those with HLH showed worse prognosis, including higher relapse and readmission rates and increased mortality. In patients with AOSD, unexplained decreased blood cells, severe liver dysfunction, and/or hemophagocytosis in the bone marrow should be considered as signs of HLH complication. Patients with AOSD complicated by HLH have worse prognosis and higher relapse rates compared to AOSD patients without HLH complications. Thus, these patients should undergo frequent and careful follow-up.     

Bilateral low lobar atelectasis in a young woman with adult-onset Still’s disease

Adult-onset Still’s disease (AOSD) is an uncommon inflammatory condition of unknown origin and pathogenesis. Pulmonary manifestations are rare and include pleuritis and transient radiological infiltrations. We report a case of a young woman with AOSD who developed unusual respiratory symptoms, with bilateral lower lobar atelectasis and restrictive syndrome and reviewed the literature on it. We illustrate the difficulties in diagnosis of atypical pulmonary defect with unusual radiological aspects and discuss causality relationship between lung abnormalities and Still’s disease.     

成人斯蒂尔病与巨噬细胞活化综合征关联性的临床分析

目的 探讨成人斯蒂尔病(AOSD)与巨噬细胞活化综合征(MAS)的关系.方法 选择AOSD组为78例资料完整的AOSD;MAS组是从26例有组织学证据的噬血细胞综合征的随访治疗中确定11例为风湿免疫疾病相关的噬血细胞综合征.对以上患者的临床表现和实验室资料进行分析.结果 在AOSD组78例中,有9例(占12%)在使用治疗之前可以诊断为MAS,但无噬血组织学依据.在11例有噬血现象的MAS中,AOSD 6例,脂膜炎2例,系统性红斑狼疮、皮肌炎、系统性血管炎各1例.脾脏肿大、白细胞减低、贫血、血小板下降、高甘油三酯是AOSD出现MAS的相关临床指标.结论 AOSD继发MAS的现象比较常见,严重者可以有组织学的噬血表现.AOSD出现脾脏增大、血细胞降低时,需要作MAS的相关检查,包括骨髓检查以及甘油三酯、纤维蛋白原、自然杀伤(NK)细胞活性等,以便及时诊断MAS.