Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study.

BACKGROUND: Bile salt export pump (ABCB11) deficiency [Progressive familial intrahepatic cholestasis (PFIC2)] is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. Surgical biliary diversion or pharmacological [ileal bile acid transporter inhibitor (IBATi)] approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome. METHODS: This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed. RESULTS: Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis. CONCLUSION: Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi.

Diagnosing Acute Cellular Rejection after Paediatric Liver Transplantation-Is There Room for Interleukin Profiles?

BACKGROUND: The current gold standard to diagnose T-cell-mediated acute rejection (TCMR) requires liver histology. Using data from the ChilSFree study on immune response after paediatric liver transplantation (pLT), we aimed to assess whether soluble cytokines can serve as an alternative diagnostic tool in children suspected to have TCMR. METHODS: A total of n = 53 blood samples obtained on the day of or up to 3 days before liver biopsy performed for suspected TCMR at median 18 days (range 7-427) after pLT in n = 50 children (38% female, age at pLT 1.8 (0.5-17.5) years) were analysed for circulating cytokine levels using Luminex-based Multiplex technology. Diagnostic accuracy of cytokine concentrations was assessed using a multivariable model based on elastic net regression and gradient boosting machine analysis. RESULTS: TCMR was present in 68% of biopsies. There was strong evidence that patients with TCMR had increased levels of soluble CXCL8, CXCL9, CXCL10, IL-16, IL-18, HGF, CCL4, MIF, SCGF-ß, and HGF before biopsy. There was some evidence for increased levels of sCD25, ICAM-1, IL-6, IL-3, and CCL11. Diagnostic value of both single cytokine levels and a combination of cytokines and clinical markers was poor, with AUROCs not exceeding 0.7. CONCLUSION: Patients with TCMR showed raised levels of cytokines and chemokines reflective of T-cell activation and chemotaxis. Despite giving insight into the mechanisms of TCMR, the diagnostic value of soluble cytokines for the confirmation of TCMR in a clinical scenario of suspected TCMR is poor.

Peripheral neuropathy in antineutrophil cytoplasmic antibody-associated vasculitides: Insights from the DCVAS study.

OBJECTIVE: Reported prevalence of vasculitic neuropathy (VN) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is highly variable, and associations with other organ manifestations have not been studied systematically while accounting for diagnostic certainty of VN. METHODS: Data of all patients with AAV within the Diagnostic and Classification criteria for primary systemic VASculitis study were analyzed cross-sectionally. VN was categorized as definite (histology proven), probable (multiple mononeuropathy or nerve biopsy consistent with vasculitis), or possible (all others). Associations with other organ manifestations were compared in patients with and without VN. RESULTS: Nine hundred fifty-five patients (mean age 57 years, range 18-91 years, 51% female) were identified. Of these, 572 had granulomatosis with polyangiitis (GPA), 218 microscopic polyangiitis (MPA), and 165 eosinophilic granulomatosis with polyangiitis (EGPA). The prevalence of VN was 65% in EGPA, 23% in MPA, and 19% in GPA. Nerve biopsy was performed in 32/269 (12%) patients, demonstrating definite vasculitis in 17/32 (53%) of patients. VN was associated with myeloperoxidase-ANCA positivity (p = 0.004) and skin (p < 0.001), musculoskeletal, (p < 0.001) and cardiovascular (p = 0.005) involvement. Patients with VN were less likely to have renal (p < 0.001), eye (p < 0.001), and gastrointestinal (p = 0.023) involvement. CONCLUSIONS: Our study provides comprehensive insights into the prevalence and organ associations of VN in a large, systematically collected AAV cohort. VN is most commonly associated with skin, musculoskeletal, and cardiovascular manifestations. In routine clinical practice, diagnosis of VN is infrequently confirmed by the gold standard of nerve biopsy but rather supported by the clinical setting of active systemic AAV.

Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis.

Reactive oxygen species (ROS) are implicated in the aetiology of interstitial lung disease (ILD). We investigated the role of large-scale somatically acquired mutations in mitochondrial DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS-formation and lung fibrosis. Mitochondria were analysed in lung biopsies from 30 patients with idiopathic or connective tissue disease (CTD)-related ILD and 13 controls. In 17 patients we had paired biopsies from upper and lower lobes. Control samples were taken from lung cancer resections without interstitial fibrosis. Malondialdehyde, a marker of ROS-formation, was elevated in ILD-biopsies (p = 0.044). The activity of the mitochondrial respiratory chain (cytochrome c-oxidase/succinate dehydrogenase [COX/SDH]-ratio) was depressed in ILD (median = 0.10,) compared with controls (0.12, p < 0.001), as was the expression of mtDNA-encoded COX-subunit-2 protein normalized for the nucleus-encoded COX-subunit-4 (COX2/COX4-ratio; ILD-median = 0.6; controls = 2.2; p < 0.001). Wild-type mtDNA copies were slightly elevated in ILD (p = 0.088). The common mtDNA deletion was only present at low levels in controls (median = 0%) and at high levels in ILD (median = 17%; p < 0.001). In ILD-lungs with paired biopsies, lower lobes contained more malondialdehyde and mtDNA deletions than upper lobes and had lower COX2/COX4-ratios and COX/SDH-ratios (all p < 0.001). Acquired mtDNA-mutations and consecutive respiratory chain dysfunction may both trigger and perpetuate ROS-formation in ILD.

Do Patients With Skin Psoriasis Show Subclinical Axial Inflammation on Magnetic Resonance Imaging of the Sacroiliac Joints and Entire Spine?

OBJECTIVE: To explore potential subclinical involvement of the axial skeleton by magnetic resonance imaging (MRI) of the sacroiliac (SI) joints and the entire spine in patients with skin psoriasis without clinical evidence of peripheral or axial inflammation. METHODS: Twenty patients with skin psoriasis but no clinical evidence of peripheral or axial inflammation and 22 healthy controls underwent standardized dermatologic and rheumatologic clinical examination and unenhanced 1.5T MRI of the SI joint and the entire spine. Two blinded readers globally assessed the presence or absence of SI joint inflammation simultaneously on T1-weighted and short tau inversion recovery MRI sequences with a confidence estimate. Bone marrow edema, fat metaplasia, erosion, and ankylosis of the SI joint, and vertebral corner inflammatory lesions and fat lesions were recorded using standardized modules. The prevalence of each lesion type was calculated in both groups, averaged across 2 readers. The number of subjects with lesions in the SI joint and spine (≥1, 2, 3, 4, or 5 lesions) as concordantly assessed by both readers was recorded. RESULTS: The median duration of skin psoriasis was 23.0 years, the median age of patients was 48.5 years, and 25.0% of patients and 9.1% of healthy controls were concordantly classified by both readers as having SI joint inflammation (P = 0.23). The prevalence of bone marrow edema and structural lesions was comparable across patients and controls, both on SI joint and spine MRI. CONCLUSION: In this controlled study, patients with skin psoriasis but no clinical arthritis or spondylitis showed limited evidence of concomitant subclinical axial involvement by SI joint and spine MRI. These findings do not support routine screening for subclinical axial inflammation in patients with longstanding skin psoriasis.

Brief Report: Influence of Disease Activity in Rheumatoid Arthritis on Radiographic Progression of Concomitant Interphalangeal Joint Osteoarthritis.

OBJECTIVE: Distal interphalangeal (DIP) joints are commonly considered to be unaffected by rheumatoid arthritis (RA). Despite synovitis and bone marrow edema being associated with radiographic progression in hand osteoarthritis (OA) and hand RA, radiographic courses differ substantially. This study was undertaken to analyze incidence and progression of radiographically evident DIP joint OA in RA patients, in relation to RA activity and patient characteristics. METHODS: In sequential radiographs of 1,988 RA patients in the Swiss Clinical Quality Management in Rheumatic Diseases registry, we evaluated and scored 15,904 DIP joints. Scoring was based on the presence of central erosions and subchondral sclerosis and on the severity of osteophytes and joint space narrowing, according to the modified Kellgren/Lawrence (K/L) grade. The presence of DIP joint OA was defined as ≥1 joint with a K/L grade of ≥2, and progression was defined as an increase in a summed K/L grade. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The median follow-up time was 4.5 years (interquartile range 3.1-7.0), and the mean ± SD age was 56.1 ± 11.1 years. DIP joint OA was present in 60% of patients at baseline. Higher mean age (OR 1.09 [95% CI 1.08-1.10]), female sex (OR 1.37 [95% CI 1.08-1.74]), and higher mean body mass index (OR 1.03 [95% CI 1.00-1.06]) were associated with the presence of DIP joint OA, but neither the presence of anti-citrullinated protein antibodies (ACPAs) (OR 0.72 [95% CI 0.50-1.03]) nor the presence of rheumatoid factor (OR 1.01 [95% CI 0.74-1.38]) were associated with it. Disease Activity Score using the erythrocyte sedimentation rate and metacarpophalangeal (MCP) joint erosions were not associated with DIP joint OA progression. RA disease duration had no relevant effect size associated with DIP joint OA progression (OR 0.97 [95% CI 0.96-0.99]). CONCLUSION: Known risk factors for DIP joint OA were replicated in patients with RA. The observation that RA activity, the presence of ACPA, and MCP joint erosions were not associated with the prevalence or progression of DIP joint OA indicates that there are distinct roles of inflammation in the pathogenesis of RA and DIP joint OA.

Brief Report: Smoking in Systemic Sclerosis: A Longitudinal European Scleroderma Trials and Research Group Study.

OBJECTIVE: Data on the role of tobacco exposure in systemic sclerosis (SSc; scleroderma) severity and progression are scarce. We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations, based on the European Scleroderma Trials and Research group database. METHODS: Adult SSc patients with data on smoking history and a 12-24-month follow-up visit were included. Associations of severity and progression of organ involvement with smoking history and the Comprehensive Smoking Index were assessed using multivariable regression analyses. RESULTS: A total of 3,319 patients were included (mean age 57 years, 85% female); 66% were never smokers, 23% were ex-smokers, and 11% were current smokers. Current smokers had a lower percentage of antitopoisomerase autoantibodies than previous or never smokers (31% versus 40% and 45%, respectively). Never smokers had a higher baseline forced expiratory volume in 1 second/forced vital capacity (FEV1 /FVC) ratio than previous and current smokers (P < 0.001). The FEV1 /FVC ratio declined faster in current smokers than in never smokers (P = 0.05) or ex-smokers (P = 0.01). The baseline modified Rodnan skin thickness score (MRSS) and the MRSS decline were comparable across smoking groups. Although heavy smoking (>25 pack-years) increased the odds of digital ulcers by almost 50%, there was no robust adverse association of smoking with digital ulcer development. CONCLUSION: The known adverse effect of smoking on bronchial airways and alveoli is also observed in SSc patients; however, robust adverse effects of smoking on the progression of SSc-specific pulmonary or cutaneous manifestations were not observed.

Safety of vaccinations in patients with cryopyrin-associated periodic syndromes: a prospective registry based study.

Objectives: Pneumococcal, tetanus and influenza vaccinations are recommended for patients with cryopyrin-associated periodic syndromes (CAPS) when treated with immunosuppressive medication. The aim of this publication is to report the safety of pneumococcal and other vaccinations in CAPS patients. Methods: All CAPS patients followed in the ß-CONFIDENT (Clinical Outcomes and Safety Registry study of Ilaris patients) registry were analysed if they had received a vaccination. The ß-CONFIDENT registry is a global, long-term, prospective, observational registry, capturing and monitoring patients treated with canakinumab. Results: Sixty-eight CAPS patients had received a total of 159 vaccine injections, 107 injections against influenza, 19 pneumococcal vaccinations, 12 against tetanus/diphtheria antigens and 21 other vaccinations. Fourteen per cent of injections had elicited at least one vaccine reaction. All five vaccine-related serious adverse events were associated with pneumococcal vaccination. Vaccine reactions were observed in 70% of pneumococcal vaccinations, compared with 7% in influenza and 17% in tetanus/diphtheria vaccinations. The odds ratios to react to the pneumococcal vaccines compared with influenza and tetanus/diphtheria vaccines were 31.0 (95% CI: 8, 119) and 10.8 (95% CI: 2, 74). Vaccine reactions after pneumococcal vaccinations were more severe and lasted significantly longer (up to 3 weeks) compared with other vaccinations. In two patients, pneumococcal vaccination also elicited symptoms consistent with systemic inflammation due to CAPS reactivation. Conclusion: Pneumococcal vaccines, unlike other vaccines, frequently trigger severe local and systemic inflammation in CAPS patients. Clinicians must balance potential benefits of pneumococcal immunization against safety concerns. The 13-valent pneumococcal conjugate vaccine might be favourable over the polysaccharide vaccine in CAPS patients.

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation - A systematic review of randomized trials, observational studies and case reports.

BACKGROUND: Live vaccines are generally contraindicated on immunosuppressive therapy due to safety concerns. However, data are limited to corroborate this practice. OBJECTIVES: To estimate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) or solid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrow transplantation (BMT). DATA SOURCES: A search was conducted in electronic databases (Cochrane, Pubmed, Embase) and additional literature was identified by targeted searches. ELIGIBILITY CRITERIA: Randomized trials, observational studies and case reports. POPULATION: Patients with IMID or SOT on immunosuppressive treatment and BMT patients <2years after transplantation. INTERVENTION/VACCINATIONS LOOKED AT: Live vaccinations: mumps, measles, rubella (MMR), yellow fever (YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette-Guérin (BCG), smallpox. DATA EXTRACTION: One author performed the data extraction using predefined data fields. It was cross-checked by two other authors. RESULTS: 7305 articles were identified and 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the administration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine strain; in most cases the infection was mild. However, in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dexamethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than 20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancy received the BCG vaccine at the age of three months and developed disseminated BCG infection and died. An immunogenicity assessment was performed in 43 studies. In most cases the patients developed satisfactory seroprotection rates. In the IMID group, YFV and VV demonstrated high seroconversion rates. MTX and tumor necrosis factor inhibitory therapy appeared to reduce immune responses to VV and HZ vaccine, but not to MMR and YF-revaccination. Seroconversion in SOT and BMT patients showed mostly higher rates for rubella than for measles, mumps and varicella. LIMITATIONS: Risk of bias was high in the majority of studies since 39 of them were observational and 17 were case series/case reports. Only eight studies were randomized trials. BMT patient numbers included in this review were low. CONCLUSIONS: Although live vaccinations were safe and sufficiently immunogenic in most studies, some serious reactions and vaccine-related infections were reported in immunosuppressed IMID and SOT patients. Apart from mild vaccine-related infections MMR and VV vaccines were safe when administered less than two years after BMT. IMPLICATIONS OF KEY FINDINGS: Until further data are available, live vaccinations under most immunosuppressive treatments should only be administered after a careful risk benefit assessment of medications and dosages. FUNDING: None.

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA. METHODS: Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors. RESULTS: Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome. CONCLUSIONS: This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therapy.

Biological monitoring and health effects of low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study.

PURPOSE: To examine the value of urinary 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) in a population of workers exposed to N-methyl-2-pyrrolidone (NMP) and to look for health effects of exposure to this organic solvent. METHODS: Airborne NMP was determined according to the NIOSH method. Urinary 5-HNMP and 2-HMSI (after and before next shift) were determined by liquid chromatography with tandem mass spectrometry. Outcomes were effects on lung, kidney, skin and mucous membranes, nervous system, haematopoiesis and liver determined by clinical examination and laboratory measurements. Univariate statistical methods and multiple regressions were used to analyse results. Skin resorption, smoking and other potential confounders were taken into account. RESULTS: Three hundred twenty-seven workers were eligible out of which 207 workers (63%) participated. Ninety-one of these worked with NMP. Occupational exposure to NMP did often not occur daily and ranged from non-detectable to 25.8 mg/m3 (median = 0.18). Urinary 2-HMSI (mg/l; before next shift) was the best biomarker of exposure to NMP, explaining about 70% of the variance, but most likelihood ratios did not allow for ruling exposure in or out, at these low levels of exposure. Creatinine adjustment did not improve the results clearly. No clear and consistent health effects could be associated with NMP exposure. No indication for a bias due to non-participation was found. CONCLUSIONS: Biological monitoring, primarily urinary 2-HMSI (mg/l; before next shift), is of value to estimate exposure to NMP even when exposure is irregular and low. Likelihood ratios of urinary 5-HMNP or 2-HMSI are, however, not quite satisfactory at these low levels. No irritant or other health effects were found.