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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ~80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)–risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92–1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.

OBJECTIVE: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

BACKGROUND Despite enormous clinical improvements, due to better management strategies and the availability of biologicals, immune-mediated inflammatory diseases (IMIDs) still have a significant impact on patients’ lives. To further reduce disease burden, provider- as well as patient-reported outcomes (PROs) should be taken into account during treatment and follow-up. Web-based collection of these outcomes generates valuable repeated measurements, which could be used (1) in daily clinical practice for patient-centered care, including shared decision-making; (2) for research purposes; and (3) as an essential step toward the implementation of value-based health care (VBHC). Our ultimate goal is that our health care delivery system is completely aligned with the principles of VBHC. For aforementioned reasons, we implemented the IMID registry. OBJECTIVE The IMID registry is a digital system for routine outcome measurement that mainly includes PROs to improve care for patients with IMIDs. METHODS The IMID registry is a longitudinal observational prospective cohort study within the departments of rheumatology, gastroenterology, dermatology, immunology, clinical pharmacy, and outpatient pharmacy of the Erasmus MC, the Netherlands. Patients with the following diseases are eligible for inclusion: inflammatory arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, uveitis, Behçet disease, sarcoidosis, and systemic vasculitis. Generic and disease-specific (patient-reported) outcomes, including adherence to medication, side effects, quality of life, work productivity, disease damage, and activity, are collected from patients and providers at fixed intervals before and during outpatient clinic visits. Data are collected and visualized through a data capture system, which is linked directly to the patients’ electronic health record, which not only facilitates a more holistic care approach, but also helps with shared decision-making. RESULTS The IMID registry is an ongoing cohort with no end date. Inclusion started in April 2018. From start until September 2022, a total of 1417 patients have been included from the participating departments. The mean age at inclusion was 46 (SD 16) years, and 56% of the patient population is female. The average percentage of filled out questionnaires at baseline is 84%, which drops to 72% after 1 year of follow-up. This decline may be due to the fact that the outcomes are not always discussed during the outpatient clinic visit or because the questionnaires were sometimes forgotten to set out. The registry is also used for research purposes and 92% of the patients with IMIDs gave informed consent to use their data for that. CONCLUSIONS The IMID registry is a web-based digital system that collects provider- and PROs. The collected outcomes are used to improve care for the individual patient with an IMID and facilitate shared decision-making, and they are also used for research purposes. The measurement of these outcomes is an essential step toward the implementation of VBHC. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/43230

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Autosomal recessive mutations in RAB27A are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous RAB27A c.551G > A p.(R184Q) variant. We aimed to evaluate the contribution of the identified RAB27A variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8+ T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8+ T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells.

Background IgG4-related disease (IgG4-RD) is an immune-mediated, systemic, fibroinflammatory disease. IgG4-RD may manifest in almost every part of the human body. Here, we describe 3 patients with a skull base manifestation of IgG4-RD that mimicked malignancy. Case Description Patient 1, a 73-year-old male, presented with a mass in the left nasopharynx and clivus. Patient 2, a 73-year-old male, presented with a mass in the left petrous bone and clivus with involvement of the left jaw joint. Patient 3, a 50-year-old male, presented with a lytic lesion of the clivus and sphenoid bone. All patients complained of headache and hearing loss. Serum IgG4 was normal, and imaging did not show systemic manifestation. Histology established the diagnosis of IgG4-RD. Two patients were treated successfully with prednisolone, hydroxychloroquine, and radiotherapy. One patient is monitored without treatment. Conclusions The described cases emphasize the broad clinical spectrum of IgG4-RD. The diagnostic workup may be challenging, and serum IgG4 may be normal, as demonstrated in these cases. Careful histopathologic examination of the tissues remains essential. Timely diagnosis of IgG4-RD is important to prevent secondary organ damage in patients with active disease.

Purpose: To compare quantitative optical coherence tomography angiography (OCT-A) measurements of the parafoveal microvasculature in retinal capillary plexuses among Behҫet uveitis (BU) patients, non-ocular Behҫet's disease (NOBD) patients, and healthy volunteers (HVs). Methods: Sixty-eight subjects were enrolled in this prospective observational cross-sectional study. OCT-A imaging was performed using the Heidelberg Engineering Spectralis OCT. A custom algorithm was developed to calculate the vessel density (VD) in three retinal vascular layers: deep capillary plexus, intermediate capillary plexus, and superficial vascular plexus. The foveal avascular zone (FAZ) and acircularity index were calculated for the whole retinal vascular complex. Results: We analyzed one eye from 21 BU patients (age, 51 ± 10 years), 23 NOBD patients (age, 48 ± 14 years), and 22 HVs (age, 44 ± 13 years). One-way multivariate analysis of covariance showed a statistically significant difference in VD among the three groups when combining the layers after controlling for scan quality (P < 0.001). The VD was lowest in the BU group and highest in the HV group in all layers. The FAZ area was also statistically significant different among the groups (P < 0.005), with the largest FAZ areas in BU patients and smallest FAZ areas in the HV group. However, no statistically significant difference was found for the acircularity index. Conclusions: The parafoveal microvasculature is affected not only in BU patients but also in NOBD patients. Most deviations in the retinal microcirculation in Behҫet patients were found in the deeper layers of the retina by using the quantitative VD measurement.

Contains fulltext : 232941.pdf (Publisher’s version ) (Open Access) Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage-, dendritic cell-, or monocyte-differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist-assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis-affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim-Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell-of-origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.

Background/aimsThe diagnostic properties of conventional diagnostic tests (ACE and chest radiography) for sarcoidosis-associated uveitis are not ideal. The diagnostic value of lymphopaenia for sarcoidosis-associated uveitis is investigated.MethodsA retrospective study of 191 consecutive patients with a first uveitis episode visiting the ophthalmology department (Erasmus Medical Center, Rotterdam, The Netherlands). Receiver operating characteristics (ROC) analysis was performed and compared with known ROC values from literature of conventional diagnostic tests for sarcoidosis-associated uveitis. An ideal cut-off was determined for lymphopaenia by calculation of the highest Youden index.ResultsOut of all patients with first uveitis attack, 32/191 or 17% were subsequently diagnosed with biopsy-proven or radiological diagnosis of sarcoidosis. Lymphopaenia (9/L) was significantly more often observed in patients with sarcoidosis-associated uveitis compared with patients with non-sarcoidosis-associated uveitis (p9/L. Lymphopaenia resulted in a 12.0 (95% CI 4.7 to 30.5 fold risk for having sarcoidosis, corrected for sex, race and age at onset of uveitis in patients with a first uveitis attack.ConclusionLymphopaenia is a non-invasive and useful marker for diagnosing sarcoidosis-associated uveitis.

In this both narrative and systematic review, we explore the role of TNF-α in the immunopathogenesis of Behçet’s disease (BD) and the effect of treatment with TNF-α blockers. BD is an auto-inflammatory disease, characterized by recurrent painful oral ulcerations. The pathogenesis of BD is not yet elucidated; it is assumed that TNF-α may play a key role. In the narrative review, we report an increased production of TNF-α, which may be stimulated via TLR-signaling, or triggered by increased levels of IL-1β and IFN-γ. The abundance of TNF-α is found in both serum and in sites of inflammation. This increased presence of TNF-α stimulates T-cell development toward pro-inflammatory subsets, such as Th17 and Th22 cells. Treatment directed against the surplus of TNF-α is investigated in the systematic review, performed according to the PRISMA guideline. We searched the Pubmed and Cochrane database, including comparative studies only. After including 11 studies, we report a beneficial effect of treatment with TNF-α blockers on the various manifestations of BD. In conclusion, the pivotal role of TNF-α in the immunopathogenesis of BD is reflected in both the evidence of their pro-inflammatory effects in BD and in the evidence of the positive effect of treatment on the course of disease in BD.

Summary TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.

Background: In Behcet’s disease (BD), an auto-inflammatory vasculitis, an unbalanced gut microbiota can contribute to pro-inflammatory reactions. In separate studies, distinct pro- and anti-inflammatory bacteria associated with BD have been identified. Methods: To establish disease-associated determinants, we performed gut microbiome profiling in BD patients from the Netherlands (n = 19) and Italy (n = 13), matched healthy controls (HC) from the Netherlands (n = 17) and Italy (n = 15) and oral microbiome profiling in Dutch BD patients (n = 18) and HC (n = 15) by 16S rRNA gene sequencing. In addition, we used fecal IgA-SEQ analysis to identify specific IgA coated bacterial taxa in Dutch BD patients (n = 13) and HC (n = 8). Results: In BD stool samples alpha-diversity was conserved, whereas beta-diversity analysis showed no clustering based on disease, but a significant segregation by country of origin. Yet, a significant decrease of unclassified Barnesiellaceae and Lachnospira genera was associated with BD patients compared to HC. Subdivided by country, the Italian cohort displays a significant decrease of unclassified Barnesiellaceae and Lachnospira genera, in the Dutch cohort this decrease is only a trend. Increased IgA-coating of Bifidobacterium spp., Dorea spp. and Ruminococcus bromii species was found in stool from BD patients. Moreover, oral Dutch BD microbiome displayed increased abundance of Spirochaetaceae and Dethiosulfovibrionaceae families. Conclusions: BD patients show decreased fecal abundance of Barnesiellaceae and Lachnospira and increased oral abundance of Spirochaetaceae and Dethiosulfovibrionaceae. In addition, increased fecal IgA coating of Bifidobacterium, Ruminococcus bromii and Dorea may reflect retention of anti-inflammatory species and neutralization of pathosymbionts in BD, respectively. Additional studies are warranted to relate intestinal microbes with the significance of ethnicity, diet, medication and response with distinct pro- and inflammatory pathways in BD patients.

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50–60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAFV600E transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAFV600E protein are not presented by HLA class I molecules. Given that the BRAFV600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.

Purpose: To report on the prevalence and clinical implications of positive QuantiFERON-Gold (QFT-G) test results in the diagnostic evaluation of a large cohort of consecutive patients with uveitis in the Netherlands. Design: Retrospective cross-sectional study. Methods: This study included 710 consecutive patients who all underwent evaluation for uveitis including QFT-G testing. The ocular features, comorbidity, and abnormalities in diagnostic imaging and laboratory tests were registered for QFT-G–positive patients with uveitis. Results: Of all patients, 13% (92/710) were positive for QFT-G. Previously treated tuberculosis (TB) was documented in 2 patients. Of all 92 QFT-G–positive patients, culture-proven active TB was observed in 1 case. The proportion of patients with uveitis of unknown etiology was higher in QFT-G–positive than in the QFT-G–negative patients (54/92, 59% vs 238/618, 39%; P = .0004). The uveitis features of QFT-G–positive patients were mainly nonspecific. Of all QFT-G–positive patients with uveitis, 17 patients had chest imaging changes suggesting either TB or sarcoidosis. Twenty-nine QFT-G–positive patients with otherwise unexplained uveitis completed antituberculous therapy (29/710; 4% of all included patients) with beneficial effect in most cases. Conclusion: The QFT-G tested positive in 13% of patients with uveitis in the Netherlands, whereas only sporadic patients had a documented previous or active TB infection. The proportion of patients with unexplained uveitis was higher in QFT-G–positive patients. Though the association between uveitis and a positive QFT-G test might be coincidental, the majority of treated QFT-G–positive patients with otherwise unexplained severe uveitis cause had a beneficial response to antituberculous therapy.

Background: Hemofagocytic lymfohistiocytosis (HLH) is a rare and often overlooked clinical manifestation of an aberrant hyper inflammatory immune response leading to a fatal cytokine storm(1). Diagnostic criteria according to The HLH Study Group of the Histiocyte Society include fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia, low/or absent NK activity, increased soluble CD-25 levels and hemophagocytosis(2). Prompt recognition and differentiation from severe sepsis is essential to improve the outcome. HLH reflects a disbalanced immune system in response to infectious, malignancy, or autoinflammatory/autoimmune mediated triggers(1). The latter group of patients are regarded as having Macrophage Activation Syndrome (MAS-HLH)() In adults MAS-HLH comprises 12.5% of all HLH causing triggers(4). The most frequent immunological disorders associated with adult HLH-MAS are systemic lupus erythematosus and adult onset Still’s disease, but every other immunological disorder can be involved(4, 5). Treatment: Treatment of adults HLH patients requires swift recognition and an experienced team of specialists that are acquainted with the critical factors influencing the balance between co-morbidity, cytokine storm induced septic-like symptoms and toxicity of chemo-immunotherapy(6). In general, adult patients do not tolerate doses of etoposide that are given in (HLH-94 based) chemo-immunotherapy schedules that have been shown effective in children(7,8). Dose and frequency modifications of etoposide may avoid prolonged neutropenia, infectious complications or hepatic toxicity. The same precautions account for adults patients with MAS-HLH in which treatment differs from the HLH schedules. A step up approach depending on clinical features and severity is warranted(9, 10). High doses of corticosteroids are recognized as first-line treatment(9, 10). In patients with MAS-HLH and SLE steroids, cyclophosphamide or etoposide are given (10). Cyclosporine can be added in patients with insufficient immediate response(9). The cytokine blocking agent anakinra (anti-IL-1β) given in high doses is emerging as an alternative or additional treatment of adult MAS-HLH(11, 12, 13). Another promising cytokine blocker is anti-IL-6 (tocilizumab). Etoposide at a reduced dose can be initiated in patients with severe non-responsive and active disease or CNS-involvement(10). Conclusion: Awareness of the clinical emergency MAS-HLH in patients with autoinflammatory/autoimmune mediated disorders is essential for timely recognition and potential life-saving treatment. The management of MASH-HLH in adults requires a team of dedicated specialists with experience in the treatment of critically ill patients with immunological disorders and anticipation on its rapidly changing and deteriorating nature. References: [1] Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233-46 [2] Henter JI, Horne A, Arico M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131 [3] Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology (Oxford). 2019;58(1):5-17. [4] Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383:1503-1516 [5] Fukaya S, Yasuda S, Hashimoto T, et al. Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases: analysis of 30 cases. Rheumatology (Oxford) 2008;47: 1686–91 [6] Halyabar O, Chang MH, Schoettler ML, et al. Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Pediatr Rheumatol Online J. 2019;17:7 [7] La Rosee P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program. 2015;2015:190-196 [8] Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6:1508-1517 [9] Kumar B, Aleem S, Saleh H, Petts J, Ballas ZK. A Personalized Diagnostic and Treatment Approach for Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Adults. J Clin Immunol. 2017;37:638-643 [10] Gavand PE, Serio I, Arnaud L, et al. Clinical spectrum and therapeutic management of systemic lupus erythematosus-associated macrophage activation syndrome: A study of 103 episodes in 89 adult patients. Autoimmun Rev. 2017;16:743-749 [11] Wohlfarth P, Agis H, Gualdoni GA, et al. Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis. J Intensive Care Med. 2017:885066617711386 [12] Schulert GS, Minoia F, Bohnsack J, et al. Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken). 2018;70:409-419 [13] Zhou S, Qiao J, Bai J, Wu Y, Fang H. Biological therapy of traditional therapy-resistant adult-onset Still”s disease: an evidence-based review. Ther Clin Risk Manag. 2018;14:167-171 Disclosure of Interests: None declared

Chromobacterium violaceum is a rare cause of infection in immunocompromised patients in the tropics with a spectrum of disease manifestations, including severe disease. Early identification of this micro-organism is essential for appropriate management. We present a case of C. violaceum septicaemia in a patient with chronic granulomatous disease.

Background Activation of the type I interferon (IFN) system has been found in large subsets of patients with systemic autoimmune diseases. This is usually assessed with a laborious quantification of IFN-stimulated genes. An easier and cheap biomarker would facilitate implementation of type I IFN measurements in diagnostic laboratories. Previously, we described Myxovirus resistance protein 1 enzyme immunoassay (MxA-EIA) for systemic evaluation of type I IFN activity in primary Sjogren’s syndrome [1]. Objectives To assess the applicability of the MxA-EIA to detect systemic type I IFN activation in patients with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Methods Whole blood intracellular MxA protein levels were measured in SLE (discovery cohort: n=25; replication cohort retrieved from the CHILL-NL study [2]: n=102), SSc (n=28) and healthy controls (HC) using the MxA-EIA. IFN scores were determined from whole blood gene expression of interferon-stimulated genes IFI44, IFI44L, IFIT1, IFIT3, and MxA by RT-PCR. Results MxA levels were significantly elevated in patients with SLE and SSc compared to HC and highly correlated to IFN scores (rs=0.735 to rs=0.854, p≤0.003). MxA-EIA robustly discriminated (AUC=0.938 to AUC=0.991, p≤0.007) between low and high type I IFN activity in SLE and SSc patients with a specificity of 100% and a sensitivity of 87.5 to 94.7%. Patients with autoantibodies against SM, RNP, SSA/Ro, or SSB/La antigens showed higher MxA levels and IFN scores compared to patients without these antibodies. Conclusion Intracellular MxA is an easy applicable and clinically relevant biomarker for systemic type I IFN bioactivity in SLE and SSc. MxA-EIA could be used to identify patients eligible for IFN-targeting treatments and potentially to monitor treatment responses. References [1] Maria NI, Brkic Z, Waris M, van Helden-Meeuwsen CG, Heezen K, van de Merwe JP, van Daele PL, Dalm VA, Drexhage HA, Versnel MA. MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjogren’s syndrome. Ann Rheum Dis 2014;73:1052-9. [2] Groot N, Shaikhani D, Teng YKO, de Leeuw K, Bijl M, Dolhain R, Zirkzee E, Fritsch-Stork R, Bultink IEM, Kamphuis S. Long-term clinical outcomes in a cohort of adults with childhood-onset Systemic Lupus Erythematosus. Arthritis Rheumatol 2018; doi: 10.1002/art.40697. Acknowledgement The research for this manuscript was (partly) performed within the framework of the Academic Centers for Rare Immunological Diseases and Inflammunity, and the Erasmus Postgraduate School Molecular Medicine. Disclosure of Interests Erika Huijser: None declared, C.G. van Helden-Meeuwsen: None declared, Noortje Groot: None declared, Iris LA Bodewes: None declared, M. Javad Wahadat: None declared, Marco WJ Schreurs: None declared, Paul LA van Daele: None declared, Virgil ASH Dalm: None declared, Jan van Laar: None declared, P Martin van Hagen: None declared, Matti Waris: None declared, Sylvia Kamphuis: None declared, Marjan Versnel Grant/research support from: MAV received financial support from Domainex.

Background: Knowledge about COVID-19 infections is expanding, although knowledge about the disease course and antibody formation in patients with an auto-immune disease or immunodeficiency is not fully unraveled yet. It could be hypothesized that immunodeficient patients, due to immunosuppressive drugs or their disease, have a more severe disease course due to their immunocompromised state. However, it could also be hypothesized that some of the immunosuppressive drugs protect against a hyperinflammatory state. Methods: We collected data on the incidence of COVID-19, disease course and SARS-CoV-2 antibody formation in COVID-19 positive patients in a cohort of patients (n ​= ​4497) known at the Clinical Immunology outpatient clinic in a tertiary care hospital in the Netherlands. Results: In the first six months of the pandemic, 16 patients were identified with COVID-19, 14 by nasal swab PCR, and 2 patients by SARS-CoV-2 antibodies. Eight patients were admitted to the hospital. SARS-CoV-2 antibodies were measured in 8 patients and were detectable in all, including one patient on B-cell ablative therapy and one patient with Common Variable Immunodeficiency Disorder. Conclusion: This study indicates that the disease course differs among immunocompromised patients, independently of (dis)continuation of immunosuppressive drugs. Antibody production for SARS-CoV-2 in immunocompromised patients was shown. More research needs to be conducted to confirm these observations and guidelines regarding (dis)continuation of immunosuppressive drugs in COVID-19 positive immunocompromised patients should be developed.

BACKGROUND: The soluble interleukin 2 receptor (sIL-2R) has been proposed as a marker of disease activity in patients with sarcoidosis. However, no studies have evaluated whether serum sIL-2R measurement is of use in establishing the diagnosis of sarcoidosis in patients who are suspected of sarcoidosis among other diseases. METHODS: A cohort study was conducted, consisting of new patients who visited the immunology outpatient clinic and whose serum sIL-2R levels were available before a definitive diagnosis was established between February 2011 and February 2016. All patients underwent standard diagnostic testing for sarcoidosis (e.g. laboratory tests, radiographic and/or nuclear imaging and/or affected site biopsy). This resulted either in the diagnosis of sarcoidosis or the exclusion of sarcoidosis with the diagnosis of another disease. Results of sIL-2R and angiotensin-converting enzyme (ACE) levels, radiographic and nuclear imaging and histology results were collected and definitive diagnoses were recorded. Sensitivity, specificity, the concordance statistic from the receiver operating characteristic curve and Youden's Index were calculated to assess the performance of sIL-2R in the diagnosis of sarcoidosis and were compared to ACE, currently one of the most used diagnostic biomarkers in the diagnosis of sarcoidosis. RESULTS: In total 983 patients were screened for inclusion, of which 189 patients met the inclusion criteria. A total of 101 patients were diagnosed with sarcoidosis after diagnostic workup, of whom 79 were biopsy-proven. In 88 patients a diagnosis other than sarcoidosis was made. The sensitivity and specificity of serum soluble interleukin 2 receptor levels to detect sarcoidosis were 88% and 85%. The sensitivity and specificity of ACE were 62% and 76%. Receiver operating characteristic curve analysis revealed that sIL-2R receptor is superior to ACE (p

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAF(V600E) driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAF(V600E) can be a source of neoantigens capable of eliciting effective antitumor CD8(+) T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8(+) T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8(+) T cell density in n = 101 LCH-lesions, with BRAF(V600E) mutated lesions displaying significantly lower CD8(+) T cell:CD1a(+) LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8(+) T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAF(V600E) protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAF(V600E) derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAF(V600E) expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAF(V600E) transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAF(V600E) protein are not presented by HLA class I molecules. Given that the BRAF(V600E) mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

The TNF-blocker adalimumab can be effective in Behçet's disease (BD), a multisystem auto-inflammatory disorder. Unfortunately, the therapeutic efficacy of TNF-blockers can be hampered by the formation of anti-drug antibodies. We present an observational study of adalimumab in refractory BD with measurement of anti-drug antibodies.The effect of fortnightly 40mg adalimumab in nine patients with therapy refractory mucocutaneous, non-ocular or organ threatening BD was studied up to 60 months. Primary endpoint was a decrease in disease activity, measured by the BD Current Activity Form (BDCAF) within 6 months. Secondary endpoints included serum cytokines and the long-term formation of anti-adalimumab antibodies.BDCAF improved significantly in all nine patients from 5.4 (SD=1.4) to 2.4 (SD=1.4) (p=0.007) within one month up to 6 months and after prolonged follow up of 5 years. All patients could either taper or stop concomitant therapy. Symptoms of mucocutaneous lesions, erythema nodosum and joint involvement decreased or disappeared. Serum TNF-alpha levels were elevates in five patients and decreased upon treatment (p=0.017). Adalimumab was save and none of the patients experienced therapy failure or antibodies against adalimumab.We present an observational study on patients with BD treated with adalimumab and provide a basis for long-term use in refractory mucocutaneous BD. These findings show that adalimumab can safely be administered yielding sustainable clinical effects in refractory BD patients with mucocutaneous disease without formation of anti-adalimumab antibodies, even after long follow up.

Purpose To relate erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) values to different uveitis entisties. Methods A retrospective study of patients with a first episode of active uveitis visiting the Erasmus University Medical Center, uveitis clinic, Rotterdam, the Netherlands, was performed. Levels of ESR and CRP were determined within 2 weeks and 1 week after onset of uveitis, respectively. Uveitis had to be of unknown origin at that moment. The specific etiologic groups were related to ESR and CRP values. Results The majority of patients with uveitis had ESR and/or CRP values within the normal limits and no association of ESR and/or CRP with the specific cause of uveitis was observed. However, elevation of ESR ≥ 60 mm/h and/or CRP ≥ 60 mg/L was mostly seen in patients with systemic immune-mediated diseases (8/59, 14% of all with immune-mediated diseases) or systemic infectious causes (7/38, 18% of all infectious uveitis). Patients with ocular toxoplasmosis typically exhibited normal ESR and CRP (9/11, 82%) while patients with endogenous endophthalmitis had elevated ESR and/or CRP in 6/7, 86%. Sarcoidosis-associated uveitis showed predominantly elevated ESR (13/24, 54%; range 20–59 mm/h in 11/13, 85%). Human immunodeficiency virus–positive patients had more often elevated ESR values when compared to the remainder of patients (9/11, 82% vs. 64/163, 39%, 18%, P = 0.009). The cause of uveitis was established in 19/20 (95%) of patients with ESR ≥ 60 mm/h and/or CRP ≥ 60 mg/L. Conclusions The majority of patients with first attack of uveitis had ESR and CRP within the normal limits. Elevated levels of ESR and CRP reflected systemic involvement and high levels of both values were associated with established uveitis cause. Electronic supplementary material The online version of this article (10.1007/s00417-018-4174-7) contains supplementary material, which is available to authorized users.

Human herpes virus 8 (HHV-8)-associated secondary hemophagocytic lymphohistiocytosis is a rare but critical immuno-hematological entity in immunocompetent patients. Establishing a diagnosis is challenging as is the monitoring of disease activity and therapeutic effects. We report a case of a HHV-8-associated hemophagocytic lymphohistiocytosis in a HIV-negative adult patient with multicentric Castleman's disease. As a novel finding, we report the use of certain inflammatory parameters, primarily interleukin-10 combined with viral load monitoring of the causative infectious agent in this case HHV-8 to monitor the clinical course of the hemophagocytic lymphohistiocytosis in the setting of bacterial septic complications.

Background Cryopyrin-associated periodic syndrome (CAPS) is a rare disease. Knowledge on the quality of life (QoL) and the disease’s societal impact is limited. Canakinumab is used in increasing frequency for the treatment of CAPS. Methods Observational study in Dutch CAPS patients. Patients completed questionnaires regarding treatment with canakinumab at baseline and retrospectively. Quality of life was assessed using the EQ-5D-5L in adults and CHQ-PF50 in children. Impact on work and school was assessed. Caregivers' quality of life was assessed using the CarerQol. Results Mean quality of life scores during treatment with canakinumab were 0.769 (EQ-5D-5L), 51.1 (CHQ-P) and 57–1 (CHQ-M). Most patients experienced problems on the pain/discomfort dimension. Higher disease activity and the presence of complications negatively influenced QoL. Half of the patients with a paid job reported absenteeism from work due to CAPS, for an average of 8.7 days in a 4-week period. All schoolgoing patients (N = 5) reported absence from school due to CAPS, for an average of 2.9 days. Caregivers reported gaining a lot fulfillment from providing care for their family members. Conclusion QoL during treatment is lower than in the general Dutch population. CAPS leads to productivity loss and absenteeism from school, and impacts the quality of life in informal caregivers. Electronic supplementary material The online version of this article (10.1186/s13023-018-0799-1) contains supplementary material, which is available to authorized users.

Purpose Sarcoidosis is a multisystem granulomatous disorder, most frequently involving the lungs, skin, or eyes. Somatostatin receptor scintigraphy (SRS) can visualize sarcoid granulomas through binding of a radionuclide-coupled somatostatin analog to somatostatin receptors that are expressed in sarcoidosis. Uptake and patterns on SRS were studied and correlated to clinical and conventional findings. Patients and Methods Data of 218 SRSs undertaken for the analysis of potential sarcoidosis were studied. These scintigraphies were retrospectively studied on intensity uptake degrees and localization of sarcoidosis-associated lesions, and compared with conventional radiological techniques (chest x-ray and CT). Results In all but 1 of the 175 evaluable patients, SRS demonstrated uptake. In patients with thoracic sarcoidosis-associated lesions, SRS improved the yield of visualization of chest x-ray in 20 (36%) and CT in 7 (32%) of histologically unproven patients, and in 31 (30%) and 8 (14%) of the histologically proven patients, respectively. Mediastinal lesions together with either eye, salivary glands, clavicular, or hilar localizations were most frequent demonstrated on SRS and constituted characteristic patterns. Exclusive extrapulmonary disease was found in 6% of the patients. Conclusions Somatostatin receptor scintigraphy enhances the yield of investigations in sarcoidosis patients and therefore provides a useful and sensitive imaging technique to monitor organ involvement and therapeutic efficacy in patients with sarcoidosis.

Importance New and improved diagnostic tests for sarcoidosis-associated uveitis are needed because the currently available laboratory diagnostic biomarkers (eg, lysozyme and angiotensin-converting enzyme [ACE]) are lacking in high sensitivity and specificity. Objective To compare the value of soluble interleukin 2 receptor (sIL-2R) with ACE as diagnostic biomarkers of sarcoidosis in patients with uveitis. Design, Setting, and Participants A cross-sectional retrospective study was conducted using data collected from 249 consecutive patients with uveitis at the Erasmus University Medical Center uveitis outpatient clinic, Rotterdam, the Netherlands, from April 3, 2013, through November 25, 2015. Measurements of sIL-2R and ACE in serum samples and data extraction from patient files were conducted from December 2016 through February 2017, and analysis from April to May 2017. Main Outcomes and Measures Serum levels of sIL-2R and ACE and chest radiographic findings were assessed. Receiver operating characteristics analysis was used to determine the probability that individual tests correctly identified patients with sarcoidosis. The Youden Index was used to determine the optimal cutoff points for serum sIL-2R and ACE levels to define sarcoidosis in patients with uveitis. Results Data were analyzed from 249 patients with uveitis who had their serum sIL-2R and ACE levels determined and underwent chest radiography. Mean (SD) age at the time of sampling was 51 (16) years, 161 patients (64.7%) were women, and 191 (76.7%) were white. Although patients with sarcoidosis-associated uveitis had the highest mean (SD) serum sIL-2R (6047 [2533] pg/mL) and ACE (61 [38] U/L) levels, elevated serum sIL-2R levels were also found in patients with HLA-B27–associated (4460 [2465] pg/mL) and varicella-zoster virus–associated (5386 [1778] pg/mL) uveitis. Serum sIL-2R and ACE levels were significantly correlated (Pearson correlation coefficient, 0.205;P = .001, 2-sided), but no association was found between uveitis activity and sIL-2R (Spearman rank correlation coefficient [ρ], 0.070,P = .27) nor uveitis activity and ACE (ρ, −0.071;P = .27). The highest Youden index for sIL-2R alone was 0.45, corresponding to an optimal cutoff of 4000 pg/mL and providing 81% (95% CI, 74%-89%) sensitivity and 64% (95% CI, 56%-72%) specificity alone but combined with chest radiography yielded 92% sensitivity and 58% specificity. Chest radiography combined with sIL-2R at a cutoff of 6000 pg/mL resulted in 77% sensitivity and 73% specificity. Combined chest radiography and serum ACE levels at the standard cutoff of 68 U/L resulted in 70% sensitivity and 79% specificity. Conclusions and Relevance This cross-sectional study demonstrates that sIL-2R is a useful marker for diagnosing sarcoidosis in patients with uveitis and has slightly better diagnostic value than ACE.

Granulomas in sarcoidosis express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented.

It remains unclear whether atopy is associated with the occurrence of sarcoidosis or affects its severity. The purpose of this study was to compare the lifetime prevalence of atopic eczema, asthma, and hay fever in sarcoidosis patients with controls and to assess whether atopy influences the severity of sarcoidosis. The prevalence of atopic disorders assessed with a validated postal questionnaire in sarcoidosis patients with pulmonary, uveitis, and cutaneous sarcoidosis was compared with that of their domestic partners in a case-control study. The serological parameters, the pulmonary function tests, and the high-resolution computed tomography (HRCT) scans of atopic and nonatopic sarcoidosis patients were compared in a nested cohort. Multivariate logistic regression models were used to calculate the odds ratios (ORs) and the 95% confidence intervals (CIs). Two hundred twenty-five sarcoidosis patients and 177 controls were included. The prevalences of atopic eczema, asthma, and hay fever were comparable between patients and controls (12.4% versus 12.4%, 5.3% versus 5.6%, and 16.9% versus 15.8%, respectively). After adjusting for gender and ethnicity, those with sarcoidosis and a history of atopic eczema were significantly less likely to have uveitis (OR, 0.30; 95% CI, 0.13-0.71). Within the sarcoidosis cohort, the distributions of serological markers, the lung function tests, and the HRCT scans were similar between atopic and nonatopic patients. Atopy is not associated with the occurrence of sarcoidosis, but atopic eczema may decrease the likelihood of eye involvement. Copyright

Renal acid-base homeostasis is a complex process, effectuated by bicarbonate reabsorption and acid secretion. Impairment of urinary acidification is called renal tubular acidosis (RTA). Distal renal tubular acidosis (dRTA) is the most common form of the RTA syndromes. Multiple pathophysiologic mechanisms, each associated with various etiologies, can lead to dRTA. The most important consequence of dRTA is (recurrent) nephrolithiasis. The diagnosis is based on a urinary acidification test. Potassium citrate is the treatment of choice.

Aims Carotid contrast-enhanced ultrasound (CEUS) was recently proposed for the evaluation of large-vessel vasculitides (LVV), particularly to assess vascularization within the vessel wall. The aim of this pilot study was to evaluate the potential of carotid colour Doppler ultrasound (CDUS) and CEUS in patients with LVV. Methods and results This prospective study included seven patients (mean age 48 +/- 14 years, all females) with established LVV (Takayasu arteritis or giant cell arteritis). All patients underwent CDUS and CEUS (14 carotid arteries). Intima-media thickness, lumen diameter, Doppler velocities, vessel wall thickening, and lesion thickness were assessed. CEUS was used to improve visualization of the lumen-to-vessel wall border, and to visualize carotid wall vascularization. Four (57%) patients [7 (50%) carotid arteries] exhibited lesions, and the average lesion thickness was 2.0 +/- 0.5 mm. According to the Doppler peak systolic velocity, 5 (35%) carotid arteries had a = 70% stenosis. The contrast agent improved the image quality and the definition of the lumen-to-vascular wall border. Carotid wall vascularization was observed in 5 (71%) patients [9 (64%) carotid arteries]. Five (36%) carotid arteries had mild-to-moderate vascularization, and 4 (29%) had severe wall vascularization. Conclusion Carotid CDUS allows the assessment of anatomical features of LVV, including vessel wall thickening and degree of stenosis. Carotid CEUS improves the visualization of the lumen border, and allows dynamic assessment of carotid wall vascularization, which is a potential marker of disease activity in patients with LVV.

Objectives Behcet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy. Methods B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied. Results Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+ memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+ IgA+ B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+ IgM+ IgD+ B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+ B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls. Conclusion We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.

_SIR,_ IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease that can affect almost every organ. Indeed, previous unexplained conditions have now been reclassified as primarily IgG4-RD and may imitate many inflammatory, infectious and malignant disorders often leading to a delay in diagnosis or incorrect diagnosis. Nasal manifestation of IgG4-RD, mostly of the paranasal sinuses, has previously been described in case reports, but it can also manifest as a primary or secondary nasal disease such as chronic sinusitis and paranasal sinusitis with dacryoadenitis. Since IgG4-RD localized in the nasal or orbital region remarkably resembles limited granulomatosis with polyangiitis (GPA), IgG4-RD could be an alternative diagnosis in ANCA negative limited GPA. After revising the diagnosis to IgG4-RD in patient 1, we re-evaluated two other ANCA negative patients from a funded database with similar clinical features and could alter the diagnosis into IgG4-RD. The histomorphological features matching IgG4-RD and absence of evident features of GPA were the reasons for immunohistochemical analysis in these cases leading to the diagnosis of IgG4-RD. [...]

In a letter describing a patient with renal AA amyloidosis associated with IgG4-related disease, the correspondents report that the treatment of IgG4-related disease may modulate inflammatory effects that could lead to secondary amyloidosis.

Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis.To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease.Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses.Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses.The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.

Background Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with an unclear pathophysiological mechanism affecting different parts of the body. If untreated, the disease can lead to fibrosis and irreversible organ damage. IgG4-RD mostly has been described in adults, hence it is generally unknown among pediatricians. This systematic search of the literature provides an overview of all reports published on IgG4-RD in children in order to create awareness of IgG4-RD in pediatrics and to emphasize the broad clinical presentation of this disease. Methods A systematic literature search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for case reports on IgG4-RD in children. Results Of total 740 articles identified by the search, 22 case reports including 25 cases of IgG4-RD in children were found. The median age of the children was 13 years, of which 64 % were girls. IgG4-related orbital disease (44 %) and autoimmune pancreatitis type 1/IgG4-related pancreatitis (12 %) predominantly occurred. Less frequently, other manifestations as pulmonary manifestation, cholangitis and lymphadenopathy were also found. Almost all cases were histologically proven. Prednisone was the first choice of treatment leading to favorable clinical response in 83 % of the cases. Maintenance therapy with steroid sparing agents was required in 43 % of the cases needing therapy. Rituximab was successful in all 4 cases, whereas, the disease modifying rheumatic drugs (DMARDs) mycophenolate mofetil, azathioprine and methotrexate were effective in almost 50 % of the cases. Conclusion IgG4-RD in children is a generally unknown disease among pediatricians, but several pediatric cases have been described. Prednisone is the first choice of treatment leading to disease remission in the majority of the cases. DMARDs and rituximab are alternative effective steroid sparing agents with more positive evidence for the latter.

We read with great interest the published article by Perugino et al (1) providing an excellent overview on IgG4-related disease (IgG4-RD). However, the authors have not included the value of C-reactive protein (CRP) in IgG4-RD and the potential secondary complications due to this. Herewith, we want to highlight the clinical relevance of elevated CRP in IgG4-RD. This article is protected by copyright. All rights reserved.

Background IgG 4 -related disease (IgG 4 -RD) is a systemic fibroinflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG 4 + plasma cells in tissue are hallmarks of the disease, and IgG 4 -RD is associated with increased IgG 4 serum levels. However, disease pathogenesis is still unclear, and these cellular and molecular parameters are neither sensitive nor specific for the diagnosis of IgG 4 -RD. Objective Here we sought to develop a flow cytometric gating strategy to reliably identify blood IgG 4 + B cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis. Methods Sixteen patients with histologically confirmed IgG 4 -RD, 11 patients with sarcoidosis, and 30 healthy subjects were included for 11-color flow cytometric analysis of peripheral blood for IgG 4 -expressing B cells and T H subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG 4 -expressing B cells, and IgG 4 transcripts were analyzed for somatic hypermutations. Results Cellular and molecular analyses revealed increased numbers of blood IgG 4 + memory B cells in patients with IgG 4 -RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, patients with IgG 4 -RD, but not patients with sarcoidosis, had increased numbers of circulating plasmablasts and CD21 low B cells, as well as T H 2 and regulatory T cells, indicating a common disease pathogenesis in patients with IgG 4 -RD. Conclusion These results provide new insights into the dysregulated IgG 4 response in patients with IgG 4 -RD. A specific "peripheral lymphocyte signature" observed in patients with IgG 4 -RD, could support diagnosis and treatment monitoring.

Background: Systemic mastocytosis (SM) is a rare heterogeneous disease which is characterized by the aberrant proliferation of mast cells. It can be divided into various subtypes with different phenotypes and prognoses. Here, we report on the clinical characteristics of 136 SM patients. Methods: A retrospective cohort study was conducted from January 2009 to September 2014 in a large tertiary centre in The Netherlands. We included all patients who fulfilled WHO criteria for SM. Data were collected from electronic patient files. Results: A total of 124 patients had indolent SM (ISM) (91.2%), 7 had aggressive SM(ASM) (5.1%) and 5 had SM with associated hematological non-mast cell lineage disease (SM-AHNMD) (3.7%). There was no progression from ISM to advanced SM subtypes, but 1 patient with ASM developed chronic myelocytic leukemia 2 years after diagnosis. The average time to diagnosis for the whole population was 8.1 years (range, 0-49 years). The most frequent triggers for work-up-skin involvement, anaphylaxis and osteoporosis-were characterized by an interval to diagnosis of 10.9, 2.9 and 7.5 years, respectively. A total of 32 patients (23.5%) had a serum tryptase levels below the cutoff value of 20 ng/mL at the time of diagnosis, but these patients did not have significant differences in clinical phenotype. Conclusions: SM comprises a wide spectrum of signs and symptoms and its often atypical presentation can delay the establishment of the diagnosis substantially. Skin involvement, anaphylaxis and unexplained osteoporosis should trigger analysis for mastocytosis. A normal serum tryptase does not exclude the diagnosis of SM. (C) 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.