Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis

Adult onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Systemic onset juvenile idiopathic arthritis (SoJIA) is the preferred nomenclature of Still’s disease. Strong association with so-called macrophage activation syndrome (MAS) may provide a clue to the understanding of the distinctive pathogenetic features of SoJIA. MAS is a severe, potentially life-threatening complication characterized by the excessive activation of well-differentiated macrophages. It is more appropriately named autoimmune disease associated reactive hemophagocytic lymphohistiocytosis (ReHLH), a subset of a histiocytic disorder: class II histiocytosis hemophagocytic lymphohistiocytosis (HLH). The relation of SoJIA with HLH is still under debate. We propose that MAS, HLH, SoJIA, and AOSD are indeed the same disease, in different clinical presentations that may be classified based on severity and laboratory findings, but with essentially the same physiopathogenesis. We propose that the case described by Hong & Lee (Rheumatol Int 2008) was actually an AOSD-associated MAS/RHS/ReHLH fulminant disease.     

Kikuchi's disease with hemophagocytic lymphohistiocytosis: A case report and literature review

Introduction:Kikuchi''s disease (KD) is a rare form of necrotizing lymphadenitis that rarely occurs in association with hemophagocytic lymphohistiocytosis (HLH) in children.Patient concerns:We report the case of a 4-year-5-month-old boy who suffered from fever, cervical lymphadenopathy, pancytopenia, hypertriglyceridemia, splenomegaly, low NK cell activity.Diagnoses:A diagnosis of KD with HLH was made based on the results of biopsy of cervical lymph node and HLH-2004 trial guidelines.Interventions:The patient was treated with corticosteroids, cyclosporine, etoposide, continuous hemodiafiltration (HDF), and plasma exchange (PE).Outcomes:He showed a complete response to therapy, and his condition gradually improved. He was discharged on day 45 after admission due to his good recovery status.Conclusion:HLH can be associated with KD, especially in childhood, and may have an aggressive clinical course. Continuous HDF and PE and chemotherapy should be reserved for those patients who fail to respond to IVIG and corticosteroids.     

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.     

Mutations of the hemophagocytic lymphohistiocytosis–associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis

The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13‐4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH‐associated genes in patients with systemic JIA have not been reported. We report the case of an 8‐year‐old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.     

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.     

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.     

Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis

The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13-4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH-associated genes in patients with systemic JIA have not been reported. We report the case of an 8-year-old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.     

The Obligate Anaerobic Faecal Flora of Patients with Crohn's Disease and Their First-Degree Relatives

The obligate anaerobic faecal floras of patients with Crohn's disease, their first-degree relatives, and healthy control subjects were compared. The flora of Crohn's patients contained more anaerobic gram-positive coccoid rods and gram-negative rods than that of healthy subjects; on this basis patients and healthy subjects formed two clusters with minor overlap. Nine of 26 children of Crohn's patients were also included within the Crohn's disease cluster. During 5 to 7 years of follow-up study 3 of them presented with remitting abdominal pain, diarrhoea, or weight loss, and in 1 of them Crohn's disease was diagnosed; none of the 17 children with a normal flora showed symptoms possibly due to Crohn's disease. It is concluded that the abnormal flora may be indigenous to subjects predisposed to Crohn's disease, suggesting a direct or indirect relationship between the abnormal faecal flora and Crohn's 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.     

Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases

Macrophage activation syndrome (MAS) belongs to secondary hemophagocytic lymphohistiocytosis (HLH) syndrome. It is usually associated with rheumatic diseases. We retrospectively reviewed our hospital's medical records of 102 HLH/MAS patients from the past 20 years. Demographics, clinical data, treatment, and outcomes were analyzed. Among 102 patients, eight patients with underlying juvenile systemic lupus erythematous (two patients), mixed connective tissue disease (one patient), primary anti-phospholipid syndrome (one patient), and systemic type juvenile rheumatoid arthritis (sJRA; four patients) with 13 episodes of MAS were studied. Clinical manifestations of MAS included fever (100 %), hepatosplenomegaly (77 %), lymphadenopathy (38 %), skin rash (62 %), and neurological involvement (31 %). Laboratory features included leukopenia (54 %), anemia (46 %), thrombocytopenia (77 %), jaundice (27 %), hypofibrinogenemia (40 %), decreased erythrocyte sedimentation rate (67 %), and elevated liver enzymes (77 %), lactate dehydrogenase (100 %), ferritin (88 %), triglycerides (91 %), C-reactive protein (85 %), plasma D-dimer (50 %), and hemophagocytosis in bone marrow (83 %). The Epstein-Barr virus and adenovirus infection triggered MAS in two patients with sJRA. Methylprednisolone pulse therapy was effective in two out of three patients, and high-dose intravenous immunoglobulin (IVIG) was effective in two out of six patients. Patients with sJRA responded well to corticosteroids and cyclosporine. Complications included opportunistic infection with Pneumocystis jiroveci, multiple organ failure, and intensive care unit myopathy. The mortality rate was one out of eight (12.5 %). Our results showed that MAS could be fatal and complicate various pediatric autoimmune diseases. It generally has a good response to corticosteroids and IVIG. Prompt recognition and timely treatment can result in good outcomes.     

Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review

The serum-soluble interleukin-2 receptor (sIL-2r) level is considered an important diagnostic test and disease marker in hemophagocytic syndromes/hemophagocytic lymphohistiocytosis (HPS/HLH). However, this cytokine receptor is rarely measured in clinical practice and has been excluded from recent diagnostic/classification criteria such as the HScore and macrophage activation syndrome (MAS) 16. We performed a systematic scoping review of 64 articles (1975–2016) examining the clinical utility of sIL-2r in HPS/HLH. Twenty-two articles describe sIL-2r as a sensitive diagnostic marker for HLH, but only three distinct datasets actually address sensitivity. The original HLH-2004 Guidelines reported sensitivity of 93% and specificity of 100% for sIL-2r ≥ 2400, based on a pediatric dataset (n = 152) which is published for the first time in this review. Two pediatric studies reported sensitivity of 89% for sIL-2r ≥ 2400 in diagnosis of MAS complicating juvenile idiopathic arthritis (JIA) (n = 27) and 88% for secondary HLH in acute liver failure (n = 9). Twenty articles described sIL-2r as a dynamic marker of disease activity that falls with response to treatment, and 15 described high initial sIL-2r levels >10,000 U/mL as a poor prognostic marker. The ability of sIL-2r to distinguish between subtypes of HPS/HLH was inconsistent. This review confirms the importance of soluble IL-2r as a diagnostic and disease marker in HPS/HLH, but also reveals the need for more primary data about its performance characteristics, particularly in adults. More emphasis should be made in including this simple, inexpensive test in clinical practice and studies of HPS/HLH.     

Prevalence of and Predictive Factor for Abdominal Aortic Calcification in Thai Chronic Kidney Disease Patients

Presence and severity of cardiovascular calcifications strongly predict cardiovascular morbidity and mortality in patients with CKD. This multicenter, cross‐sectional study primarily aimed to determine prevalence of abdominal aortic calcification (AAC) detected by plain lateral abdominal radiograph, and secondarily aimed to assess predictive factors for AAC. Patients (N = 1500), aged 18–70 years, with CKD stages 3–5D for ≥3 months prior to evaluation, were enrolled at 24 study centers in Thailand; 54.3% were non‐dialysis patients. The prevalence of AAC was 70.6% and 70.8% in non‐dialysis and dialysis patients, respectively. Patient's advanced age and widening pulse pressure were identified as predictive factors for AAC ≥ 5 in non‐dialysis patients, while patient's age, history of coronary heart disease or diabetes, longer dialysis vintage, and increasing corrected serum calcium or high‐sensitivity C‐reactive protein were identified as such in dialysis patients. With additional regression having covariates in binary, corrected serum calcium ≥9.5 mg/dL gave an OR 1.974 (95% CI: 1.324–2.943) for AAC ≥ 5 among the dialysis patients. AAC in diabetes subgroup (N = 692) was additionally evaluated and found that it was prevalent at 84.7% with increased phosphorus as predictive factor (OR, 1.178; 95% CI: 1.032–1.344) and 1,25 (OH)₂ vitamin D as protective factor (OR, 0.983; 95% CI, 0.970–0.996). The prevalence of AAC in the Thai CKD population is lower than that reported in the literature, and yet the burden is prominent in patients coexisting with diabetes. Variable relationships identified in this study may guide preventive measures against cardiovascular complications in CKD patients.     

Successful father-to-son stem cell transplantation in a child with hemophagocytic lymphohistiocytosis using a reduced-intensity conditioning regimen

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder, usually lethal without allogeneic stem cell transplantation (SCT). MATERIALS AND METHODS: We report a 9-month-old boy, the first child of consanguineous parents, diagnosed with HLH and neurological involvement demonstrated by magnetic resonance imaging (MRI), who received an allogeneic SCT from his HLA genetically matched father. Transplant was performed after a reduced-intensity conditioning (RIC) regimen consisting of cyclophosphamide, fludarabine, and melphalan. Graft vs. host disease (GVHD) prophylaxis included cyclosporine a and methotrexate. RESULTS: An absolute neutrophil count of 0.5 x 10(9)/L was documented on day +20 and a platelet count >20 x 10(9)/L was shown by day 33. Full donor chimerism was showed on day +175. A follow-up brain MRI was reported normal. Twenty months after SCT, the child shows no evidence of HLH or GVHD activity, and has a normal psychomotor development. CONCLUSION: Given the reduced toxicity of SCT with RIC, it could represent an attractive transplant method for children with HLH, in whom myeloablation plays no role in disease eradication, and in whom mixed chimerism may be enough to cure the disease.     

Sickle cell crisis associated with hemophagocytic lymphohistiocytosis

Sickle-beta(+) (beta(+)) thalassemia is a double heterozygous genetic disorder characterized by both a qualitative and quantitative abnormality. We present a case of an African American male who was first diagnosed with sickle cell disease (SCD) at the age 23 years when he presented with generalized bone pain, fever, and hepatosplenomegaly. Laboratory findings included thrombocytopenia, microcytic anemia, and markedly elevated ferritin. He was subsequently diagnosed with a sickle-beta thalassemia hemoglobinopathy. Findings in the bone marrow aspirate and biopsy were consistent with hemophagocytic lymphohistiocytosis (HLH). HLH resolved with the resolution of sickle cell bone pain crisis without use of immunosuppressive therapy. To the best of our knowledge this is the first documented case of HLH associated with sickle cell bone pain crisis.     

腰椎侧位X线片评估维持性血液透析患者腹主动脉钙化的研究

目的:探讨腰椎侧位X线片评估维持性血液透析患者腹主动脉钙化(AAC)的意义,分析AAC与心血管疾病发生的关系。方法:选择34例维持性血液透析(MHD)患者,检测肝、肾功能和电解质等指标;利用腰椎侧位X线片评估AAC积分。分析AAC的发生率、分布特点和严重程度;比较钙化组与非钙化组患者心血管疾病(CVD)发生情况;以受试者操作特征曲线(ROC曲线)下面积评价AAC积分对诊断MHD患者发生CVD的特异性。结果:34例MHD患者中,28例发生AAC(占82.4%);钙化发生率从腰椎L1向L4逐渐增高(P0.05),且钙化程度逐步加重(P0.05)。与非钙化组比较,钙化组患者CVD的发生率显著增高(71.4%vs 33.3%,P0.05);发生CVD患者的AAC积分显著高于未发生CVD的患者(P0.05);AAC积分显示发生CVD的ROC曲线下面积为0.738。结论:MHD的AAC的发生率较高,钙化程度由L1向L4逐步加重;AAC积分可用于预测MHD发生CVD的可能性。     

Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, syndrome of excessive and ineffective activation of the immune system. The majority of the reported data on HLH is from pediatric patients and lacks specificity. This makes HLH diagnosis challenging especially in adults where HLH is triggered by many conditions and can resemble many disease entities. Elevated ferritin is one of the diagnostic criteria for HLH. We determined the conditions associated with elevated ferritin at our medical center to assess how specific ferritin is for predicting HLH. We retrospectively reviewed all ferritin results >10,000 μg/L in pediatric and adult patients. The most common condition associated with elevated ferritin was hematologic malignancy in adults (25.7%) and HLH in pediatric patients (48.9%). HLH was diagnosed in 14.2% of adults and 48.9% of children with ferritin >10,000 µg/L. Hyperferritinemia occurs in a variety of conditions and is not specific for adult or pediatric HLH. Common causes of elevated ferritin should be considered before entertaining the possibility of HLH, especially in adult patients.     

Successful Therapy Using Pasireotide Long-acting Release for Cushing's Disease Merged with Biochemical Acromegaly

It is quite rare that Cushing''s disease shows acromegaly, and no pharmacotherapy has yet been discussed. A 21-year-old woman was diagnosed with Cushing''s disease and underwent trans-sphenoidal surgery. Five years later, she was diagnosed with recurrent Cushing''s disease and biochemical acromegaly because of elevated levels of serum growth hormone (GH), plasma insulin-like growth factor-1, plasma adrenocorticotropic hormone (ACTH), and the 24-hour urinary excretion of free cortisol. After treatment initiation with pasireotide-long-acting release (LAR), both the ACTH and GH declined. Our case is the first to show the efficacy of pasireotide-LAR in controlling both Cushing''s disease and acromegaly.     

Hemophagocytic Lymphohistiocytosis in the Elderly

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of massive, dysregulated cytokine release and secondary multiorgan failure and is associated with high mortality. Primary HLH occurs predominately in infants and young children with a genetic predisposition. Acquired HLH is less well characterized and usually occurs in younger adults in the setting of severe inflammation triggered by infection or malignancy. Little is known about the disease in elderly. We report 3 patients >50 years old who presented with multiorgan failure and shock without an identifiable source and were ultimately diagnosed with acquired HLH. We performed a literature review of HLH in adults >50 years of age and identified an additional 68 cases. Mean age was 62 years, with male predominance. Most cases were triggered by infection (49%) followed by malignancy (27%). Nineteen patients were treated with the HLH-94 protocol, 11 received corticosteroids and the remainder received non-HLH specific interventions. Overall mortality was 62%.     

Clinical Appearance at Diagnosis of Ulcerative Colitis and Crohn's Disease in a Regional Patient Group

A regional patient group comprising 783 patients with ulcerative colitis (UC) and 185 patients with Crohn's disease (CD) diagnosed during the period 1960 to 1978 was analysed in accordance with clinical appearance at diagnosis. Of the UC patients, 16% showed total colonic involvement, 41% substantial colonic involvement, and 41% rectal affection only. The disease extent was positively correlated to the degree of activity but not to the age or sex of the patients. 70% of the patients were in moderately or very active stage of disease, 28% in slightly active stage, and 2% inactive at the time of diagnosis. 43% of the patients had experienced weight loss, 27% fever, and 53% abdominal pains in their initial attack of the disease. Immunological manifestations were present in 13%. Of the CD patients 31% had small-bowel localization only, 28% large bowel only, 36% ileocolonic affection, and 5% other combinations. Patients with ileal involvement were significantly younger than patients with colonic involvement. There was no sex difference in accordance with the localization of Crohn's disease. 71% of the patients were in moderately or very active stage of disease and 29% in low activity at diagnosis. The intestinal symptoms were independent of the sex and age of the patients, whereas abdominal pains were present significantly more frequently in younger age groups. In all, 76% of the patients experienced abdominal pains, 34% fever, and 54% weight loss. Immunological symptoms from joints, skin, or eyes were present in 12% of the patients.     

Acute acalculous cholecystitis as the initial manifestation of systemic lupus erythematous: A case report

Rationale:Acute acalculous cholecystitis (AAC) is an extremely rare manifestation of systemic lupus erythematous (SLE). In previous reports, most of the patients were already diagnosed cases of SLE upon confirmation of AAC.Patient concerns:A 24-year-old female who initially presented with fever and acute right upper quadrant abdominal pain. She had no medical history.Diagnoses:Abdominal ultrasonography and computed tomography (CT) showed gallbladder thickening with pericholecystic edema without gallstones or sludge, demonstrating acalculous cholecystitis. She revealed discoid rash on the both shin. Laboratory tests revealed pancytopenia. The titer of antinuclear antibody (ANA) was 1:1280. Anti-dsDNA antibody, anti-phospholipid antibody, anti-Sm antibody test, and proteinuria in 24 hours were positive. Both C3 and C4 were low. Echocardiography and chest CT showed pericardial effusion and pleural effusion. Using the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria, the score was 31. We thought AAC of this case that was one of the initial manifestations of SLE.Interventions:The patient was treated with high-dose prednisolone (1 mg/kg) and hydroxychloroquine 400 mg.Outcomes:After 4 days of administration of high-dose corticosteroid therapy, symptoms rapidly improved. After 35 days of the treatment, her symptoms and disease activity of SLE were markedly improved.Lessons:Although AAC being the initial manifestation of SLE is very rare, prompt diagnosis and management with corticosteroids precluded surgical intervention. Physicians need to be cognizant of AAC as a disease flare and as a rare initial manifestation of SLE.