MAdCAM-1 does not play a central role in the early pathophysiology of autoimmune hepatitis.

INTRODUCTION: CD4+ T cells are thought to have a central role in the pathogenesis of autoimmune hepatitis (AIH). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs homing of CD4+ T cells in the alimentary tract and is a therapeutic target in inflammatory bowel diseases. Here we assessed MAdCAM-1 expression in AIH and viral hepatitis and related its expression with immune infiltrate analysis and histopathological key features. METHODS: Hepatic portal areas of pretreatment biopsies (n=10) and follow-up biopsies (n=9) of patients with a confirmed diagnosis of AIH were assessed for MAdCAM-1 expression and infiltrate composition using immunohistochemistry and multispectral imaging (Vectra® Polaris™). Controls consisted of biopsies of patients with untreated chronic viral hepatitis B or C (n=22). RESULTS: MAdCAM-1 expression on endothelium was sparsely present in portal fields of two treatment-naïve AIH patients. Three patients showed MAdCAM-1 expression within lymphoid aggregates. No expression of significance (including single-cell expression) was observed in the remaining 6 patients. In contrast, viral hepatitis C biopsies showed endothelial MAdCAM-1 expression in 8 of 13 untreated patients. Densities of both B-cells (CD20+) and CD4+ T-cells (CD3+ CD8-) were increased in AIH and viral hepatitis patients with MAdCAM-1 expression. CONCLUSION: MAdCAM-1 was detected in liver biopsies in a minority of patients with AIH at the time of diagnosis suggesting no central role in its pathophysiology. Lymphoid or reticular MAdCAM-1 pattern expression was associated with more dense infiltrates of both B-cells and CD4+ T-cells, and may be related to the formation of secondary lymphoid follicles.

Real-world management of juvenile autoimmune liver disease.

BACKGROUND AND AIMS: Juvenile autoimmune liver disease (JAILD) includes paediatric forms of autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). Since evidence is scarce, there are currently no evidence-based management guidelines for juvenile AIH. This survey was carried out amongst the paediatric members of the International AIH Group (IAIHG) to describe their practices in the management of JAILD. METHODS: An online survey questionnaire was distributed to members of the IAIHG with active practice (https://www.surveymonkey.de/r/Juvenile_AILD). The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Fifty-eight surveys were sent to the IAIHG members, out of which 43 (74%, 22 countries, four continents) were returned. None reported budesonide as a first-line induction agent for the acute presentation of AIH. Sixteen (37%) routinely perform liver biopsy at three years of biochemical remission. Thirty-five respondents (81%) perform magnetic resonance cholangiography (MRC) at presentation. Ciclosporin is the most widely used second-line agent (number of patients treated = ∼360, 21 centres). Mycophenolate mofetil (n = ∼225, 31 centres), tacrolimus (n = ∼130, 21 centres) and sirolimus (n = ∼5, 3 centres) are less often reported. Rescue therapy with infliximab and rituximab has been tried in eight centres (n = ∼19) and nine centres (n = ∼16), respectively. CONCLUSIONS: Prednisolone remains the preferred first-line induction agent in JAILD. MRC at presentation is performed by the large majority of participants. Participants reported a wide variation in performing liver biopsy for therapy evaluation during follow-up. Within the paediatric members of the IAIHG there is considerable experience with second-line therapeutic agents.

Match of psychosocial risk and psychosocial care in families of a child with cancer.

OBJECTIVE: The Psychosocial Assessment Tool (PAT) was developed to screen for psychosocial risk, aimed to be supportive in directing psychosocial care to families of a child with cancer. This study aimed to determine (i) the match between PAT risk score and provided psychosocial care with healthcare professionals blind to outcome of PAT assessment, and (ii) the match between PAT risk score and team risk estimation. METHODS: Eighty-three families of children with cancer from four pediatric oncology centers in the Netherlands participated (59% response rate). The PAT and team risk estimation was assessed at diagnosis (M = 40.2 days, SD = 14.1 days), and the content of provided psychosocial care in the 5-month period thereafter resulting in basic or specialized care. RESULTS: According to the PAT, 65% of families were defined as having low (universal), 30% medium (targeted), and 5% high (clinical) risk for developing psychosocial problems. Thirty percent of patients from universal group got basic psychosocial care, 63% got specialized care, and 7% did not get any care. Fourteen percent of the families at risk got basic care, 86% got specialized care. Team risk estimations and PAT risk scores matched with 58% of the families. CONCLUSIONS: This study showed that families at risk, based on standardized risk assessment with the PAT, received more specialized care than families without risk. However, still 14% of the families with high risks only received basic care, and 63% of the families with standard risk got specialized care. Standardized risk assessment can be used as part of comprehensive care delivery, complementing the team.

Expert clinical management of autoimmune hepatitis in the real world.

BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis.

BACKGROUND: Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low-dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease. AIM: To describe the effect of adding allopurinol to low-dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism. METHODS: We describe the clinical efficacy and tolerability of allopurinol-thiopurine combination therapy with allopurinol 100 mg and low-dose thiopurine (25-33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose-limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment. RESULTS: All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol-thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 10(8) red blood cells (RBC) at 3 months (P = 0.04). Median 6-MMP levels decreased in all patients from 6090 to 175 pmol/8 × 10(8) RBC (P = 0.01). CONCLUSION: Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.

A case of autoimmune hepatitis and bisphosphonate-related osteonecrosis of the jaw.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown aetiology usually requiring long-term immunosuppressive therapy. We present the case of an AIH patient who received long-term corticosteroids and azathioprine. As treatment for concomitant osteoporosis she was also treated with potent intravenous bisphosphonate (BP). This treatment was complicated by the development of BP-related osteonecrosis of the jaw (BRONJ). BRONJ is an uncommon complication of BP treatment regimes that occurs at increased frequency in the presence of other risk factors, including chronic inflammatory conditions. Our patient suffered from a severe and complicated clinical course of BRONJ which, despite adequate therapy, resulted in death of the patient. Here we discuss the risk factors for the development and clinical course of BRONJ in AIH and the implications for management of these patients.

Comparative responsiveness of four elbow scoring instruments in patients with rheumatoid arthritis.

OBJECTIVE: This prospective study investigated the comparative responsiveness to change of 4 different elbow scoring instruments: 2 Hospital for Special Surgery elbow assessment scales, the Mayo Clinic Elbow Performance Index, and the Elbow Functional Assessment (EFA) Scale. METHODS: A group of patients with rheumatoid arthritis (RA) (median age 60 yrs) undergoing either elbow arthroplasty (22 elbows) or synovectomy with radial head excision (3 elbows) were evaluated both before and after surgery (median 7 mo postoperatively). Changes in the scores obtained using the scales under study were calculated and analyzed. The patient's opinion of global perceived effect of the intervention was used as an external criterion to classify them as "improved" or "non-changed." Responsiveness was evaluated with 3 different statistical approaches: using paired t statistics (pre and postsurgery scores), effect size statistics (standardized response mean, effect size, and responsiveness ratios), and receiver operator characteristic curves. Minimal clinically important difference was estimated using patient satisfaction as the external criterion. RESULTS: Each of the elbow rating measures under study proved to be responsive to change when evaluating patients with RA undergoing elbow arthroplasty or synovectomy. The EFA scale had the highest power to detect a clinically meaningful difference and had the best discriminative ability to distinguish improved from no-change patients, as shown by all responsiveness statistics applied. CONCLUSION: Using the EFA scale requires smaller sample sizes to achieve a fixed level of statistical power than the other scales we studied.

Determining the optimal flexion-extension axis of the elbow in vivo - a study of interobserver and intraobserver reliability.

In the current study the interobserver and intraobserver reliability of a recently developed method to obtain the position and orientation vectors of the flexion-extension axis of the elbow in vivo is determined. The method uses the Flock of Birds six degrees-of-freedom electromagnetic tracking device. Ten subjects performed three trials comprising five flexion and extension cycles. The movements of the forearm with respect to the upper arm were recorded. Observer A measured two trials and observer B measured one trial. Optimal instantaneous helical axes were calculated in a humeral coordinate system for each trial. Intraclass correlation coefficients and 99% confidence intervals were computed to compare the three measurements. Zero was in the range of all the narrow confidence intervals, which is strong indication for resemblance. Interobserver intraclass correlation coefficients values for orientation vectors were good to excellent and intraobserver values were fair to good. The intraclass correlation coefficients values for position vectors were lower, probably due to the lack of variance between subjects. It is concluded that the method is reliable and can be used in certain clinical settings.

Clinical reliability and validity of elbow functional assessment in rheumatoid arthritis.

OBJECTIVES: (1) To investigate the measurement characteristics of the Hospital for Special Surgery (HSS) and Mayo Clinic elbow assessment instruments, utilizing methodological criteria including feasibility, reliability, validity, and discriminative ability; and (2) to develop an efficient and disease-specific rating system for elbow function assessment (EFA) in adult patients with RA, using a combination of self-reported subjective items and objective measures, and comparing its characteristics with the HSS and Mayo Clinic scales. METHODS: (1) Selection of elbow-specific items. (2) Investigation of reliability and validity of all separate items, as well as the total HSS and Mayo Clinic scores, in 42 patients with RA (mean age 60 yrs). Direct observation of functional elbow performance was defined as the gold standard against which criterion validity was compared. (3) Reaching agreement within a team of professionals on the different scale dimensions and the assigned weight. (4) Item reduction by eliminating unreliable, inaccurate, unfeasible, and ambiguous items. Finally, the EFA scale was constructed by selecting the most reliable and accurate items. RESULTS: The EFA scale showed a superior or equal degree of reliability as reflected in intraclass correlation coefficients of more than 0.88, and also superior validity, compared with the HSS and Mayo Clinic measures. CONCLUSION: Although the elbow scoring systems currently available provide a reliable measure, they seem restricted in evaluating elbow-specific functional ability. The EFA scale was found to be most suitable to measure elbow functional ability in RA, and was also shown to be highly reliable and practical in clinical practice.

Determination of the optimal elbow axis for evaluation of placement of prostheses.

OBJECTIVE: To present a method to determine the position and orientation of the mean optimal flexion axis of the elbow in vivo to be used in clinical research. DESIGN: Registering the movements of the forearm with respect to the upper arm during five cycles of flexion and extension of the elbow using a 6 degrees-of-freedom electromagnetic tracking device. BACKGROUND: Loosening of elbow endoprostheses could be caused by not placing the prostheses in a biomechanically optimal way. To evaluate the placement of endoprostheses with regard to loosening, a method to determine the elbow axis is needed. METHODS: The movements of the right forearm with respect to the upper arm during flexion and extension were registered with a 6 degrees-of-freedom electromagnetic tracking device. A mean optimal instantaneous helical axis of 10 elbows was calculated in a coordinate system related to the humerus. RESULTS: The average position of the flexion/extension axis was 0.81 cm (SD 0.66 cm) cranially and 1.86 cm (SD 0.72 cm) ventrally of the epicondylus lateralis. The average angle with the frontal plane was 15.3 degrees (SD 2 degrees). CONCLUSIONS: A useful estimation of the position and orientation of a mean optimal flexion axis can be obtained in vivo.

Physiological evaluation of a newly designed lever mechanism for wheelchairs.

Lever-propelled wheelchairs have been described as more efficient and less physically demanding than hand-rim-propelled wheelchairs. To evaluate a newly designed lever mechanism (MARC) in both one- and two-arm use, a series of wheelchair exercise tests were performed on a motor-driven treadmill. Eight able-bodied male subjects performed a standard exercise test in the prototype MARC, both in an asynchronic and a synchronic bimanual propelling mode and in an unilateral (left-sided) mode. Subsequently the subjects performed additional exercise tests in a conventional crank-to-rod lever mechanism with unilateral and bimanual propulsion and in a conventional hand rim wheelchair. Analysis of variance was used to study the effect of the different work modes upon power output and cardiorespiratory parameters statistically (p < 0.05). The MARC stood out well in comparison with the conventional lever design. The additional design features which are to be implemented (variable gearing, reverse gear) will make the MARC a useful wheelchair. One-arm wheelchair propulsion is a very strenuous form of locomotion, requiring careful consideration in terms of provision. Mechanical and ergonomic improvements are quite feasible in lever propulsion and may to a certain extent reduce this problem. To improve overall mobility of wheelchair-dependent subjects further, ergonomic and mechanical design improvements are very necessary in lever as well as hand-rim wheelchairs. A combined biomechanical and physiological research approach will help in the definition of design criteria and fitting guidelines.