Porto-sinusoidal vascular disorder and nephrotic-range proteinuria due to venous vasculitis in Behçet's disease.

Behçet's disease (BD) is an autoinflammatory disease with multifactorial and polygenic etiology, potentially involving arteries and veins of any size resulting in variable vessel vasculitis. We report a case of an Iranian male who presented with porto-sinusoidal vascular disorder due to venous vasculitis as initial manifestation of BD. Despite immunosuppression, anticoagulation and venous recanalization, he subsequently developed severe nephrotic-range proteinuria mimicking a primary renal disease which was completely and immediately ameliorated by stenting of the vena cava. This demonstrates that the proteinuria was caused by increased intraglomerular pressure due to venous outflow obstruction as a consequence of venous vasculitis. To our knowledge, this is the first report of massive proteinuria caused by venous obstruction of the caval vein in the context of BD. Altogether, this case demonstrates the extensive spectrum of vascular disease in BD.

Long-term data on efficacy and safety of adalimumab in Behçet's disease.

INTRODUCTION: Behçet's disease (BD) is a systemic, inflammatory disorder affecting multiple organ systems, frequently treated with TNF-α blocking agents, as infliximab and adalimumab. Insights about long-term use of adalimumab are lacking. Therefore, we conducted a study into the long-term efficacy and safety of adalimumab in BD. METHODS: A retrospective cohort study from patients with BD treated with adalimumab in the Erasmus Medical Center was performed. Patients included were at least 18 years of age, diagnosed according to ISG criteria, and uninterruptedly used adalimumab for at least 36 months. RESULTS: In a population of 39 BD patients using adalimumab, 29 patients persisted treatment >36 months (range 37-206 months). Indications for treatment were uveitis (n = 15) 51.7%, mucocutaneous involvement (n = 9) 31%, arthritis (n = 2) 6.9%, intestinal disease (n = 3) 10.3%. Overall, adalimumab decreased the occurrence of flares from 0.64 to 0.17 flares per year and BCVA improved subsequently. Also, a steady decline in BDCAF is reported over the course of at least 5 years. Subsequently, 79% was able to reduce their use of immunosuppressive agents aside from adalimumab. Adverse effects were reported in, (n = 15) 51.7% of which (n = 13) 86.6% were infectious complications. Two of those required inpatient hospital care. CONCLUSION: Our study illustrates durable long-term efficacy of adalimumab treatment in patients with BD. In our patient cohort long-term adalimumab treatment is safe, with a low incidence of serious adverse events.

Adult orbital xanthogranuloma: long-term follow-up of treated cases.

BACKGROUND: Adult orbital xanthogranulomatous disease (AOXGD) is a group of rare disorders. Four subtypes are identified: adult-onset xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD). Therapy options vary and little is known about the long-term effect of the treatment. In this study, we will describe the clinical behaviour, effect of treatment, and long-term outcome in a consecutive series of patients with AOXGD. METHODS: This is a descriptive, retrospective study with a long follow-up term of 21 patients with histologically proven AOXGD, treated between 1989 and 2021 in the Rotterdam Eye Hospital and Erasmus MC University Medical Center. RESULTS: Twenty-one patients with histologically proven AOXGD were included. The follow-up ranged from 2-260 months (median of 67 months). Six of the nine patients with AOX were treated with surgery alone, with recurrence in two. Three received systemic therapy, with recurrence in one. All four patients with AAPOX received systemic treatment, the disease recurred in two. Two patients with NBX were treated with surgery alone, with recurrence in one. Four required additional therapy with recurrence in two. Both patients with ECD required systemic therapy. CONCLUSIONS: Recognition of AOXGD is important, in particular, because of the potential severe systemic locations in the different subtypes. Surgical excision might be a sufficient therapy for patients with AOX. Patients with AAPOX, NBX, and ECD warrant systemic therapy. Currently, there is no conclusive evidence for a superior treatment strategy, but further studies are necessary to investigate treatment options.

Immunopathogenesis of Behçet's disease and treatment modalities.

INTRODUCTION: Behçet's disease (BD) is an auto-inflammatory disease, primarily characterized by recurrent painful mucocutaneous ulcerations. METHODS: A literature search was performed to write a narrative review into the pathogenesis and current treatment options of BD. RESULTS: The pathogenesis of BD remains to be elucidated, but is considered a genetically primed disease in which an external trigger causes immune activation resulting in inflammatory symptoms. GWAS data show an association between multiple genetic polymorphisms (HLA-B51, ERAP1, IL10 and IL23R-IL12RB2) and increased susceptibility to BD. Bacteria as streptococci, an unbalanced microbiome or molecular mimicry trigger the inflammation in BD. Increased production or responsiveness of pro-inflammatory components of the innate immune response (TLR, neutrophils, NK-cells or γδ T-cells) to these triggers may be a crucial step in the pathogenesis of BD. Additionally to an increased autoinflammatory response there is evidence of a dysregulated adaptive immune system, with a disturbed Th1/Th2 balance, expansion of Th17 cells and possibly a decrease in regulatory T cells, resulting in a surplus in pro-inflammatory cytokines. The inflammation causes a typical clinical phenotype including orogenital ulcerations, uveitis and skin lesions. Treatment is aimed at the aberrations found in the innate (neutrophils and γδ-T cells) and adaptive immune system (TNF-α, INF-γ, IL-1), directed at organ involvement and individualized based on patient characteristics. CONCLUSION: We presented an extensive review into the pathogenesis and treatment options of BD.

HLH caused by an HSV-2 infection: a case report and review of the literature.

Haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory condition that can be triggered by infections, malignancies, or auto-immune diseases. Here, we present a patient with rapidly progressive HLH triggered by a herpes simplex virus type 2 (HSV-2) primary infection. The patient was successfully treated with intravenous high-dose acyclovir, immunoglobulins, and dexamethasone. This is the first report of HSV-2-associated HLH in an immunocompetent adult patient.

Are Patients at Risk for Recurrent Disease Activity After Switching From Remicade® to Remsima®? An Observational Study.

Background: Since the late '90s, infliximab (Remicade®) is being used successfully to treat patients with several non-infectious immune mediated inflammatory diseases (IMIDs). In recent years, infliximab biosimilars, including Remsima® were introduced in clinical practice. Aim: To investigate the interchangeability of Remicade® (originator infliximab) and its biosimilar Remsima® in patients with rare immune-mediated inflammatory diseases (IMIDs). Methods: This two-phased prospective open label observational study was designed to monitor the transition from Remicade® to Remsima® in patients with rare IMIDs. All included patients were followed during the first 2 years. The primary endpoint was the demonstration of non-difference in quality of life and therapeutic efficacy, as measured by parameters including a safety monitoring program, physicians perception of disease activity (PPDA) and patient self-reported outcomes (PSROs). Secondary outcomes included routine blood analysis, pre-infusion serum drug concentration values and anti-drug antibody formation. Results: Forty eight patients treated with Remicade® were switched to Remsima® in June-July 2016 and subsequently monitored during the first 2 years. The group consisted of patients with sarcoidosis (n = 17), Behçet's disease (n = 12), non-infectious uveitis (n = 11), and other diagnoses (n = 8). There were no significant differences in PPDA, PSROs, clinical and laboratory assessments and pre-infusion serum drug concentrations between the groups. De novo anti-drug antibodies were observed in two patients. Seven patients with sarcoidosis and five with another diagnosis developed a significant disease relapse (n = 7) or adverse events (n = 5) within 2 years; 10 of these patients discontinued Remsima® treatment, one withdrew from the study and one received additional corticosteroid therapy. Conclusions: We observed no significant differences in PSROs, PPDA and laboratory parameters after treatment was switched from Remicade® to Remsima®. However, disease relapse or serious events were observed in 12 out of 48 patients when treatment was switched from Remicade® to Remsima®. The choice to switch anti-TNF alpha biologics in patients with rare IMIDs, particularly in sarcoidosis, requires well-considered decision-making and accurate monitoring due to a possibly higher incidence of disease worsening.

Current insights in the pathogenesis of scleritis.

Scleritis is a sight-threatening inflammation characterized by severe pain and redness of the eye. It can cause blindness by severe complications like scleral and corneal necrosis, keratitis, and uveitis. The pathogenesis of scleritis is largely unknown due to a combination of the rarity of the disease, the little available human tissue-based research material, and the lack of animal models. The immune system is assumed to play a crucial role in the pathogenesis of scleritis. Multiple clues indicate probable antigenic stimuli in scleritis, and the involvement of matrix metalloproteinases in the destruction of scleral tissue. In this article we review the current insights into the pathogenesis of scleritis, and we suggest new hypotheses by implementing knowledge of systemic autoimmune disease pathogenesis. Understanding the pathogenesis of scleritis is crucial to improve the clinical management, as well as to find novel treatment modalities.

The tarsal plate manifestation of IgG4-related disease.

PURPOSE: To describe a clinical case of bilateral biopsy-proven IgG4-related disease confined to the tarsal plate. METHOD: Interventional case report. RESULTS: A 58-year-old woman presented with a tarsal swelling in the lateral part of the upper eyelids, with focal ulceration and mucus. Histology revealed fibrotic inflammation with increased IgG4-positive plasma cells fulfilling the criteria of IgG4-related disease (IgG4-RD). Serum IgG4 levels were increased, and pathological fluorodeoxyglucose uptake at positron emission tomography/CT scanning was restricted to the upper eyelids. After treatment with oral and topical prednisone, the tarsal lesions markedly regressed. CONCLUSIONS: Periorbital IgG4-RD may be confined to the tarsal plate. Treatment with systemic and topical steroids may induce significant regression.

The treatment outcomes in IgG4-related disease.

INTRODUCTION: IgG4-related disease (IgG4-RD) is an emerging systemic inflammatory disease involving nearly all organs eventually leading to fibrosis. Prompt and adequate treatment to prevent irreversible organ damage is therefore pivotal. To evaluate the treatment outcomes, we studied a well-defined cohort of patients with IgG4-RD. METHOD: 32 patients with histologically confirmed IgG4-RD diagnosed between 1999 and April 2017 were included and reviewed for demographic and clinical characteristics. The response to treatment with glucocorticoids, disease modifying antirheumatic drugs, rituximab and other therapeutic interventions were evaluated. RESULTS: Glucocorticoids as well as rituximab appeared successful therapeutic drugs leading to clinical remission (complete or partial remission) in all patients. Recurrences, however, were frequently seen (62% versus 100%, respectively). Diseases modifying antirheumatic drugs (DMARDs), including azathioprine, methotrexate and mycophenolate mofetil were effective in less than half of the cases. A minority of patients was treated with alternative treatments including hydroxychloroquine, thalidomide and infliximab which all appeared effective. Surgical intervention and radiotherapy in local disease seemed to induce clinical remission and were associated with low recurrence rates. CONCLUSION: Glucocorticoids and rituximab induce substantial responses as well as primary surgical intervention and radiotherapy, while the efficacy of DMARDs is limited. Based on the few data available, hydroxychloroquine, infliximab and thalidomide may be promising treatment options for second or third line strategies.

Needs, Perceptions and Education in Sarcoidosis: A Live Interactive Survey of Patients and Partners.

OBJECTIVES: Sarcoidosis is a chronic, multisystem disease with often a major impact on quality of life. Information on unmet needs of patients and their partners is lacking. We assessed needs and perceptions of sarcoidosis patients and their partners. METHODS: During patient information meetings in 2015 and 2017 in the Erasmus University Medical Center, we interviewed patients and partners using interactive voting boxes. Patients responded anonymously to 17 questions. Answers were projected directly on the screen in the room. RESULTS: 210 patients and 132 partners participated. Sarcoidosis has a subjective significant impact on lives of both patients and partners. The vast majority of patients and partners feel regularly misunderstood because of the general unawareness of sarcoidosis. Many patients and partners experience anxiety. Three-quarters of patients would like to see more attention and support for their psychological problems. Additionally, more supportive care for partners of sarcoidosis patients is warranted. Interactive interviewing was considered educational (91%) and pleasant (84%). DISCUSSION: This study improves awareness of needs and perceptions of patients with sarcoidosis and their partners. Sarcoidosis leads to anxiety and psychological distress and impairs well-being of patients and their partners. Attention for psychological support, better disease education, and more supportive care for partners is warranted.

Soluble Interleukin-2 Receptor: A Potential Marker for Monitoring Disease Activity in IgG4-Related Disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition. T-cells play a crucial role in the pathogenesis, and therefore, serum soluble interleukin-2 receptor (sIL-2R) may be a potential biomarker. METHOD: We studied the levels of sIL-2R in 26 histologically proven IgG4-RD patients with available serum sIL-2R and compared them to those in newly diagnosed and untreated sarcoidosis patients (n = 78) and controls (n = 101) and the serum sIL-2R levels in patients after treatment of IgG4-RD (n = 15). The disease activity was measured using the IgG4-Related Disease Responder Index (IgG4-RD RI). RESULTS: Median serum sIL-2R in IgG4-RD patients was 4667 pg/ml compared to 1515 pg/ml in controls (P < 0.001) and 6050 pg/ml in sarcoidosis patients (P = 0.004 compared to IgG4-RD). All IgG4-RD patients had elevated serum sIL-2R levels compared to the reference value of <2500 pg/ml in controls and 85% elevated serum IgG4; however, these did not correlate with each other. Both serum sIL-2R and IgG4 levels declined significantly after treatment (P = 0.001 and P = 0.01, resp.). Before treatment, serum sIL-2R level and IgG4-RD RI did not correlate with each other. However, the decrease in serum sIL-2R upon treatment did correlate significantly (P = 0.04) with the decrease in disease activity assessed by IgG-RD RI. CONCLUSION: Serum sIL-2R is elevated in IgG4-RD reflecting the inflammatory process with enhanced T-cell activation. Furthermore, serum sIL-2R might serve as a potential marker of response to treatment in IgG4-RD.

Infliximab for IgG4-Related Orbital Disease.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition with unclear pathophysiology. It may occur as a single organ disorder, but multiorgan presentation is common and can mimic several conditions. The preferred therapy consists of steroids, but definite maintenance strategy remains unclear. The authors describe a case of a 61-year-old woman, initially diagnosed with idiopathic orbital inflammation refractory to multiple immunosuppressive agents. The disease was complicated with epilepsy, vision loss, and trismus. Treatment with various immunosuppressive agents was unsuccessful. Eventually the patient was effectively treated with infliximab. This is the second case of IgG4-RD treated with a TNF-blocker documented in literature and the first description to demonstrate its superiority over steroid sparing agents. Although speculative, TNF-blockers might exert their effect in IgG4-RD by interfering with the possible overexpressed TNF alpha due to fibrosis in this disease. Treatment with infliximab appears a good alternative for refractory IgG4-RD. However, further studies are required to define the value of infliximab in IgG4-RD.

[Systemic mastocytosis: a heterogeneous disease]. / Systemische mastocytose: een heterogene ziekte.

Systemic mastocytosis (SM) is an acquired myeloproliferative disease, which is caused by an uncontrolled proliferation of aberrant mast cells. SM patients can have very different clinical phenotypes and may therefore initially present to different specialties. Diagnosis is often delayed because many physicians are unfamiliar with this illness. This can lead to substantial morbidity and puts patients at risk of complications such as severe anaphylaxis. Measurement of serum tryptase levels is always a sensible first step in the diagnostic work-up, but a normal serum tryptase does not rule out SM completely, and a bone marrow biopsy is essential for a conclusive diagnosis. Here, we describe two patient cases to illustrate the heterogeneous nature of this disease, and provide an overview of the symptoms, diagnostic work-up and current treatments options for SM.

An inflammatory condition with different faces: immunoglobulin G4-related disease.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with involvement of different organs. The pathophysiological mechanism is unclear, but fibrosis is the hallmark of this disease. Early recognition is critical to avoid irreversible organ damage. Recently improved histological testing boosts the diagnostic yield. We present three cases of patients with IgG4-RD to emphasise the broad clinical presentation of this disease. CASE DESCRIPTIONS: Patient A, a 63-year-old male with bilateral orbital swelling due to IgG4-RD, was shown to suffer from IgG4-RD in a multifocal pattern as demonstrated by PET scanning. Patient B, a 53-year-old male with a long-standing abdominal mass of unknown origin, eventually proved to have IgG4-RD. Patient C was a 32-year-old male admitted with pleural effusion and pericardial tamponade. Histological diagnosis after pericardiectomy confirmed IgG4-RD. DISCUSSION: IgG4-RD has many faces and may mimic other conditions, such as malignancy and infectious diseases. Knowledge of this disease is needed to avoid unnecessary diagnostics and delay in treatment. IgG4- RD may be suspected based on specific clinical findings such as elevated serum IgG4 levels, but the diagnosis can only be established histologically. Although corticosteroids are an effective first choice of therapy, the relapse rate after this treatment remains high. The role of disease-modifying antirheumatic drugs in the treatment of IgG4-RD has not been outlined yet, but there is increasing evidence that rituximab might be an effective second-line therapy. CONCLUSION: IgG4-RD is a disease with many faces requiring early recognition and therapy to avoid permanent damage of the organs.

Behçet's disease, hospital-based prevalence and manifestations in the Rotterdam area.

INTRODUCTION: Behçet's disease is most prevalent in countries along the former Silk Road. Prevalence varies from 70-420 per 100,000 in Turkey, and 13.5-20 and 1-2 per 100,000 in Asia and Western Europe, respectively. Additionally, disease severity and morbidity might be correlated with ethnicity. We studied demography and morbidity in the Dutch cohort of patients with Behçet's disease and compared those with known figures. PATIENTS AND METHODS: The prevalence of Behçet's patients in the Rotterdam area was determined by comparing the total number of patients within the ethnic population with the number of patients diagnosed with Behçet's disease. Patient files of the Erasmus University Medical Centre (Erasmus MC) were reviewed for morbidity figures and compared with existing data. RESULTS: In total 84 Behçet's patients of Dutch, Turkish or Moroccan descent were identified in the Rotterdam area. Prevalence of Behçet's disease differed per ethnicity: 1, 71 and 39 per 100,000 for Dutch-Caucasians, Turks, and Moroccans, respectively. These figures are comparable with occurrence in West Turkey and Morocco. Within the studied Erasmus MC cohort no significant differences in morbidity appeared between the ethnic groups. However, uveitis and pustules were significantly more common in the Erasmus MC cohort as compared with UK, German, Turkish and Moroccan cohorts. DISCUSSION AND CONCLUSIONS: We present the first epidemiological study of Behçet's disease in the Netherlands. The prevalence of Behçet's disease in the studied Dutch region and in countries of ancestry is similar. Morbidity is equally spread, compared with other countries, but uveitis and pustules seem to be more common in the Netherlands.

Treatment of multicentric Castleman’s disease in HIV-1 infected and uninfected patients: a systematic review.

BACKGROUND: Multicentric Castleman's disease (MCD) is frequently associated with human-herpesvirus (HHV)-8, especially in human immunodeficiency virus (HIV)-1 co-infections. The optimal treatment is unclear. This systematic review provides an overview of available evidence on chemotherapeutic and monoclonal antibody therapies directed against CD20, interleukin (IL)6 or IL6 receptor. METHODS: A systematic literature search of Embase, Medline, Web-of-Science, Scopus, PubMed publisher, Cochrane and Google Scholar was conducted for trials and cohort studies on MCD therapy. Baseline characteristics and reported endpoints were summarised and treatment efficacy was assessed by overall mortality rates. RESULTS: 1817 studies were identified providing five trials and 14 cohort studies on 666 patients, including one randomised placebo-controlled trial. Ten studies reported on 450 HIV-1 positive patients. Most HIV-1 positive (99.7%), and 24.4% of HIV-1 negative patients were HHV-8 infected. Study populations and methods varied considerably. The use of rituximab was associated with better treatment responses and survival compared with chemotherapy without rituximab in HHV- associated, predominantly HIV-1 infected, MCD patients. Anti-IL6(receptor) antibodies might be promising second-line or salvage agents, at least in HIV-1 and HHV-8 negative patients. Kaposi sarcoma (re)activation with rituximab and MCD progression to aggressive lymphoma, or haemophagocytic lymphohistiocytosis were important complications. CONCLUSIONS: Optimal MCD treatment for HIV-1 and÷or HHV-8 positive or negative patients remains unclear. The available evidence is of low quality due to study designs, treatment allocation bias, and publication bias. MCD patients remain at risk for developing lymphomas or haemophagocytic lymphohistiocytosis. Rituximab may have survival benefits for HHV-8 associated MCD, but it is related to Kaposi sarcoma exacerbations.

Glucocorticoid sensitivity in Behçet's disease.

OBJECTIVE: Glucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-)inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behçet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity. METHODS: Healthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-α and GR-ß) were measured. RESULTS: Healthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9ß minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals. At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-α/GR-ß mRNA expression levels was significantly lower in BD. CONCLUSIONS: Polymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-ß splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.