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Contains fulltext : 251784.pdf (Publisher’s version ) (Closed access) BACKGROUND: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. METHODS: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. FINDINGS: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. INTERPRETATION: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. FUNDING: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

Contains fulltext : 251906.pdf (Publisher’s version ) (Open Access) BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.

Objectives Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. Methods Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry. Results ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. Conclusions Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Background Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. Methods First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. Results The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. Conclusion These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

IntroductionCorticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone.Methods and analysisIn this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18–75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4–8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements.Ethics and disseminationThis study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals.Trial registration numberClinicalTrials.gov (Identifier: NCT04733144), and in the Dutch trial registry (NL9138).

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.Funding: ZonMw (The Netherlands Organization for Health Research and Development).

Introduction Post-operative delirium (POD) is associated with increased morbidity and mortality rates in older patients. Neuroinflammation, the activation of the intrinsic immune system of the brain, seems to be one of the mechanisms behind the development of POD. The aim of this study was to explore the association between the perioperative inflammatory response and the development of POD in a cohort of older oncological patients in need for surgery. Methods In this prospective cohort study, patients 65 years and older in need for oncologic surgery were included. Inflammatory markers C-reactive protein (CRP), interleukin-1 beta (IL-1β), IL-6, IL10 and Neutrophil gelatinase-associated lipocalin (NGAL) were measured in plasma samples pre- and post-operatively. Delirium Observation Screening Scale (DOS) was used as screening instrument for POD in the first week after surgery. In case of positive screening, diagnosis of POD was assessed by a clinician. Results Between 2010 and 2016, plasma samples of 311 patients with median age of 72 years (range 65–89) were collected. A total of 38 (12%) patients developed POD in the first week after surgery. The perioperative increase in plasma levels of IL-10 and NGAL were associated with POD in multivariate logistic regression analysis (OR 1.33 [1.09–1.63] P = 0.005 and OR 1.30 [1.03–1.64], P = 0.026, respectively). The biomarkers CRP, IL-1β and IL-6 were not significantly associated with POD. Conclusions Increased surgery-evoked inflammatory responses of IL-10 and NGAL are associated with the development of POD in older oncological patients. The outcomes of this study contribute to understanding the aetiology of neuroinflammation and the development of POD.

The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.

BACKGROUND: Accurate prognostic biomarkers would substantially improve surgical planning and decisions making yet no studies have been reported exploring the inflammatory response in surgically treated older patients with cancer. The aim of this study was to explore inflammatory biomarkers as potential prognostic factors for postoperative complications within 30 days in older patients with cancer.METHOD: Patients 65 years and older undergoing surgery for removal of a solid malignant tumour were included in an observational cohort study. All complications occurring up to 30 days postoperatively were documented prospectively. Inflammatory markers were measured in plasma samples pre- and postoperatively: C-reactive protein (CRP), Interleukin-1 beta (IL-1β), IL-6, IL-10, IL-12, and Tumour necrosis factor-alpha (TNF-α). Associations between inflammatory markers and postoperative complications were explored using logistic regression analysis.RESULTS: Between July 2010 and April 2014, plasma samples of 224 patients were collected. Median age was 72 (65-89) years and 116 (51.8%) patients were female. Approximately half of the patients developed postoperative complications (49.6%) of whom 62 patients (55.9%) developed >1 complication. An independent prognostic effect was observed for the inflammatory biomarkers IL-6 and IL-10 for the occurrence of postoperative complications.CONCLUSION: The perioperative inflammatory response is associated with complications, independently from patient and surgical factors which are also associated with outcome. Research is warranted towards further exploration of the perioperative inflammatory response with the aim to improve perioperative care and outcome, and might help to improve surgical planning and decision making for older patients with cancer.

Background: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. Objective: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. Methods: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. Results: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. Conclusion: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation. (J Allergy Clin Immunol 2022;149:432-9.)

Objectives To determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production. Methods BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures. Results BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells. Conclusion We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.

Purpose of ReviewThe onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization ofStaphylococcus aureuswith ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular.Recent FindingsNasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships.SummaryThe microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis.

Objectives To investigate whether there is a direct relation between expanded proportions of Th17 effector memory (ThEM17) cells and regulatory B cells (Bregs) in peripheral blood of granulomatosis with polyangiitis (GPA) patients. Methods Frequencies of Bregs and ThEM17 cells, as well as ThEM1 cells, were determined by flow cytometry in blood samples from 42 GPA patients in remission and 18 matched healthy controls (HCs). The Breg frequency was defined as CD24hiCD38hiCD19+ cells. ThEM17 cells were defined as CCR6+CXCR3-CCR4+ cells and ThEM1 cells as CCR6-CXCR3+CCR4- cells within the CD3+CD4+CD45RO+CCR7- population. In addition, CD3+CD4+ Th cells from 9 GPA patients were co-cultured in vitro with either total B cells or a Breg-depleted B cell fraction. Cultured cells were stimulated with Staphylococcus Enterotoxin B (SEB) and CpG-oligodeoxynucleotides (CpG-ODN). Th17- (IL-17+) and Th1 cell (IFNγ+) frequencies were determined at baseline and day 5 upon restimulation with phorbol myristate acetate (PMA) and Ca-I. Results A decreased Breg frequency was found in treated GPA patients, whereas an increased ThEM17 cell frequency was observed in treated and untreated GPA patients compared with HCs. Additionally, a decreased ThEM1 cell frequency was seen in untreated GPA patients compared with HCs. In untreated GPA patients circulating Breg frequencies correlated negatively with ThEM17 cells (r = −0.533; P = 0.007) and positively with ThEM1 cells (r = −0.473; P = 0.015). The co-culture experiments revealed a significant increase in the frequency of IL-17+ Th cells in Breg-depleted samples (median: 3%; range: 1–7.5%) compared with Breg-undepleted samples (P = 0.002; undepleted samples median: 2.1%; range: 0.9–6.4%), whereas no difference in the frequency of IFNγ+ Th cells in Breg-depleted cultures was observed (undepleted median: 11.8%; range: 2.8–21% vs Breg-depleted median: 12.2%; range: 2.6–17.6%). Conclusion Bregs modulate ThEM17 responses in GPA patients. Future studies should elaborate on clinical and therapeutical implications of the Breg-Th17 interaction in GPA patients.

Objectives. We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis.Methods. Patients diagnosed with ANCA-associated vasculitis (n=241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of GR haplotypes and the HSD11B1 genotype.Results. Carriers of haplotype 4 (ER22/23EK + 9 beta+Tthlll1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (Bcll) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes.Conclusion. Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis.

BACKGROUND: Azathioprine hypersensitivity syndrome is a rare complication of azathioprine therapy. Its symptoms resemble infection or relapse of inflammatory disease, hindering correct diagnosis. Current literature is limited to sporadic case reports and reviews.OBJECTIVE: To estimate the incidence of azathioprine hypersensitivity syndrome and describe its characteristics in the context of an observational cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Also, to facilitate early recognition and awareness among clinicians.METHODS: Within a cohort of 290 patients with ANCA-associated vasculitis receiving azathioprine maintenance therapy, frequency of azathioprine hypersensitivity was described and characteristics were compared between hypersensitive and non-hypersensitive patients. Clinical picture, laboratory abnormalities, and concurrent medication of patients with azathioprine hypersensitivity were described.RESULTS: Of 290 patients, 25 (9%) experienced azathioprine hypersensitivity after a median of 14 (interquartile range [IQR] 12-18) days. Frequent symptoms were fever (100%), malaise (60%), arthralgia (36%), and rash (32%). All patients used prednisolone (median 10 mg/day, IQR 9.4-16.3 mg/day) at the time of the hypersensitivity reaction. Most patients had a rise in C-reactive protein (CRP), leukocyte counts, and neutrophil counts, but no eosinophilia. Thiopurine S-methyltransferase (TPMT) activity was significantly lower in hypersensitive patients (median 74.4 [IQR 58.0-80.1] nmol/gHb/L) compared with controls (median 81.4 [71.9-90.5] nmol/gHb/L), P = .01. Hypersensitive patients had a higher risk of relapse (hazard ratio 2.2, 95% confidence interval 1.2-4.2; P=.01).CONCLUSIONS: Azathioprine hypersensitivity syndrome is strikingly common in ANCA-associated vasculitis, might be associated with reduced TPMT activity, is accompanied by an increase in neutrophil counts, and may occur even during concomitant prednisolone therapy. Proper recognition may prevent unnecessary hospital procedures and damage to the patient. (C) 2018 American Academy of Allergy, Asthma & Immunology

Simple SummaryOlder patients can have an increased expression of inflammatory cytokines due to ageing of the immune system. It is likely that older cancer patients with a low-grade inflammatory state are more at risk for an exaggerated inflammatory response to surgery and for poor outcome after surgery. The aim of this study was to examine whether preoperative inflammatory markers could be a predictor of overall survival in older patients undergoing oncologic surgery. In this prospective cohort study, a plasma level of C-reactive protein (CRP) >= 10 mg/L was a predictor of inferior three-year overall survival after oncologic surgery in older cancer patients, and also for the specific group of older patients with a colorectal tumor. Measuring preoperative plasma level of CRP might be useful in risk stratification for poor outcome after surgery in older cancer patients.Oncologic surgery results in substantially higher morbidity and mortality rates in older patients compared to younger patients, yet little is known about the relation between the preoperative inflammatory state and postoperative outcome in the specific group of older cancer patients. The aim of this study was to examine whether preoperative inflammatory markers could be a predictor of overall survival in older patients undergoing elective surgery for a solid malignant tumor. Patients 65 years and older undergoing surgery for a solid malignant tumor were included in a prospective cohort study. Inflammatory markers C-reactive protein (CRP), interleukin-1 beta (IL-1 beta), IL-6, IL10, IL-12 and tumor necrosis factor-alpha (TNF-alpha) were measured in plasma samples preoperatively. The main outcome was overall survival three years after surgery. Between 2010 and 2016, 328 patients with a median age of 71.5 years (range 65-89) were included. A significantly higher mortality rate three years after surgery, was found in patients with high preoperative plasma levels of CRP and IL-6 (p = 0.013 and p = 0.046, respectively). In multivariate analysis, corrected for variables such as age, disease stage, frailty, comorbidities, type of surgery and complications, a preoperative plasma level of CRP >= 10 mg/L was an independent prognostic factor for inferior overall survival three years after surgery (multivariate hazard ratio 1.50, 95% confidence interval 1.04-2.16, p = 0.031). Also, for the specific group of patients with colorectal cancer, a preoperative plasma level of CRP >= 10 mg/L was a prognostic factor for inferior survival three years after surgery (multivariate hazard ratio 2.40, 95% confidence interval 1.20-4.81, p = 0.014). Preoperative elevated plasma level of CRP is an independent unfavorable prognostic factor for overall survival three years after oncologic surgery. This gives more insight into the relationship between inflammation and survival in older cancer patients, and might contribute to risk stratification for poor outcome after surgery in older cancer patients.

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.

Introduction: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidis-ciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. Methods: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. Results: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. Conclusion: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

We read with great interest the article ‘Addressing immune-related adverse events of cancer immunotherapy: how prepared are rheumatologists?’ by Kostine et al .1 The introduction of immune checkpoint inhibitor (ICI) therapy has been a major breakthrough in the management of metastatic cancer. On the downside, ICI therapy may induce unwanted autoimmune effects, the so-called immune-related adverse effects (irAEs). Various irAEs have been described that resemble a regular rheumatic disease, including polymyalgia rheumatica (ICI-PMR).2 3 The authors report that rheumatologists may lack confidence in diagnosing irAEs. Therefore, recommendations for the diagnosis of rheumatic irAEs are needed. Based on our experience with ICI-PMR, we propose that imaging could be an important part of such recommendations. We investigated six consecutive patients with ICI-PMR by ultrasonography, and five of these patients also by [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan. Five patients fulfilled the provisional American College of Rheumatology/European League Against Rheumatism classification criteria for PMR.4 A normal C-reactive protein level in the absence of an erythrocyte sedimentation rate (ESR) test precluded PMR classification in one patient. However, this patient fulfilled both the clinical and ultrasound criteria for PMR,4 and showed findings suggestive of PMR on the FDG-PET/CT scan.5 The median age was 73 years (range 59–83; online supplementary table 1). Patients received anti-programmed cell death protein 1 (PD-1) treatment, that …

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels, affecting primarily the lungs and kidneys. Both animal and human studies show that the balance between inflammatory- and regulatory T- and B cells determines the AAV disease pathogenesis. Recent evidence shows malfunctioning of the regulatory lymphocyte compartment in AAV. In this review we summarize the immune regulatory properties of both T- and B cells in patients with AAV and discuss how aberrations herein might contribute to the disease pathogenesis.

Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases.

Background:ANCA associated vasculitis (AAV) is a complex, rare systemic autoimmune disease with an estimated prevalence of 5-18 patients per 100.000 individuals worldwide. Managing a low prevalent disease can be challenging which is reflected in clinical practice variation.Objectives:This study investigated clinical practice variation of the care for AAV patients in the Netherlands.Methods:In a nationwide online survey, AAV patients were selected from academic and non-academic centers. Within centers, patients were eligible when they had a confirmed diagnosis of microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) or eosinophilic granulomatosis with polyangiitis (eGPA) according to the treating physician. There were no exclusion criteria. In each center a comparable number of patients was included. Data capture encompassed a wide set of variables on diagnosis, management and outcomes.Results:From December 2018 to November 2019, 230 AAV patients were recruited in 6 non-academic and 3 academic hospitals (120 vs 110 patients respectively). Differences in clinical diagnoses (GPA, MPA and eGPA) were observed between non-academic and academic centers (p=0.05), which was mainly caused by a higher number of MPA patients in non-academic centers. The year of diagnosis was comparable (median 2013 [2009-2016], p=0.150). The median follow up since diagnosis was 4.8 years [1.8-9.6] with a median in-hospital time-to-diagnosis of 13 days [2-50]. Patients were diagnosed at a mean age of 63 years (±11.18) in non-academic centers and 53 years (±16.92) in academic centers (pConclusion:The present study highlights important practice variation in the management of AAV between academic and non-academic hospitals in the Netherlands. A high proportion of patients is treated with oral cyclophosphamide as induction therapy while rituximab is increasingly used in academic centers. Rates of mortality, infections and malignancies were not different. Altogether, this study raises awareness into the variation of management for AAV patients and allows the identification of areas for improvement of clinical care for Dutch AAV patients.Disclosure of Interests:Ebru Dirikgil: None declared, Abraham Rutgers: None declared, Sander Tas: None declared, Cornelis A. Verburgh: None declared, Darius Soonawala: None declared, A. Elisabeth Hak: None declared, Hilde H.F. Remmelts: None declared, Daphne IJpelaar: None declared, Gozewijn D. Laverman: None declared, Jacob M. van Laar Grant/research support from: MSD, Genentech, Consultant of: MSD, Roche, Pfizer, Eli Lilly, BMS, H.J. Bernelot Moens: None declared, Peter Verhoeven: None declared, Willem Jan W. Bos: None declared, Y.K. Onno Teng Grant/research support from: GSK, Consultant of: GSK, Aurinia Pharmaceuticals, Novartis

Although the use of extracorporeal life support (ECLS) treatment is increasing rapidly, its use in immunocompromised patients is still under debate as infections are a main predictor of poor outcome during ECLS therapy. Predicting the prognosis for a specific type of immunocompromised patient is challenging and is depending on the underlying disease and the amount of accumulated organ damage that has occurred.

The formation of neutrophil extracellular traps induced by antineutrophil cytoplasmic autoantibodies has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis. Kraaij et al. now provide evidence that excessive neutrophil extracellular trap formation in vitro induced by sera from patients with antineutrophil cytoplasmic autoantibody-associated vasculitis is associated with active disease but is not dependent on the presence of antineutrophil cytoplasmic autoantibodies.

Human CD4+FoxP3+T-cells are heterogeneous in function and include not only suppressive cells (Tregs), but also effector cells that transiently express FoxP3 upon activation. Previous studies in Granulomatosis with Polyangiitis (GPA-)patients have demonstrated an increase in FoxP3+T-cells with impaired suppressive capacity and an increase in Th17 cells. We hypothesized that the increase in FoxP3+T-cells results from an increase in non-suppressive effector-like cells. The frequency of circulating CD4+FoxP3+T-cell subsets were determined by flow cytometry in 46 GPA-patients in remission and 22 matched healthy controls (HCs). Expression levels of FoxP3 and CD45RO were used to distinguish between CD45RO−FoxP3low resting Tregs (rTreg), CD45RO+FoxP3high activated Tregs (aTreg) and CD45RO+FoxP3low proinflammatory non-suppressive T-cells (nonTreg). Intracellular expression of IFNγ, IL-17, and IL-21 was compared within these subsets. We found a significant increase in the frequency of nonTreg cells in GPA-patients as compared with HCs. Importantly, within the nonTreg subset, antineutrophil cytoplasmic autoantibody (ANCA-)positive patients demonstrated a significantly higher percentage of IL-17+ and IL-21+ cells when compared with ANCA-negative patients and HCs. Moreover, expanded nonTregs from ANCA-positive patients induced excessive proliferation of responder cells in vitro and exhibited higher IL-21 production. Production of IL-17 and IL-21 in non-suppressive FoxP3+T-cells may point toward a pathogenic role in ANCA formation.

Background: Granulomatosis with polyangiitis (GPA) patients are prone to disease relapses. We aimed to determine whether GPA patients at risk for relapse can be identified by differences in B cell subset frequencies. Methods: Eighty-five GPA patients were monitored for a median period of 3.1 years (range: 0.1–6.3). Circulating B cell subset frequencies were analyzed by flow cytometry determining the expression of CD19, CD38, and CD27. B cell subset frequencies at the time of inclusion of future-relapsing (F-R) and non-relapsing (N-R) patients were compared and related to relapse-free survival. Additionally, CD27+CD38hi B cells were assessed in urine and kidney biopsies from active anti-neutrophil cytoplasmic autoantibody-associated vasculitides (AAV) patients with renal involvement. Results: Within 1.6 years, 30% of patients experienced a relapse. The CD27+CD38hi B cell frequency at the time of inclusion was increased in F-R (median: 2.39%) compared to N-R patients (median: 1.03%; p = 0.0025) and a trend was found compared with the HCs (median: 1.33%; p = 0.08). This increased CD27+CD38hi B cell frequency at inclusion was correlated to decreased relapse-free survival in GPA patients. In addition, 74.7% of patients with an increased CD27+CD38hi B cell frequency (≥2.39%) relapsed during follow-up compared to 19.7% of patients with a CD27+CD38hi B cell frequency of