Clinical Relevance of Autoantibodies and Inflammatory Parameters in Non-infectious Scleritis.

PURPOSE: Scleritis is a potentially blinding disorder, with highly unpredictable course and outcome. We analyzed the prevalence and clinical relevance of autoantibodies and inflammatory parameters in non-infectious scleritis. METHODS: Retrospective analysis of laboratory findings in all consecutive patients at the department of Ophthalmology of the Erasmus MC with non-infectious scleritis. RESULTS: We included 81 patients with non-infectious scleritis. A systemic autoimmune disease was present in 46%. Positive anti-nuclear antibodies were found in 30%, anti-neutrophil cytoplasmic antibodies were positive in 19%, and the presence of rheumatoid factor was shown in 17%. The aforementioned autoantibodies, as well as inflammatory parameters, failed to show prognostic clinical value. In contrast, anti-citrullinated peptide antibodies (ACPA), found in 9% of scleritis patients, were significantly associated with the development of scleral necrosis (P = .01). CONCLUSIONS: The presence of ACPA in patients with non-infectious scleritis was associated with the development of scleral necrosis.

Peanut components measured by ISAC: comparison with ImmunoCap and clinical relevance in peanut allergic children.

BACKGROUND: Specific IgE (sIgE) against the peanut component Arachis hypogaea (Ara h) 2 has been shown to be the most important allergen to discriminate between peanut allergy and peanut tolerance. Several studies determined sIgE cut off values for Ara h 2, determined by singleplex measurements. However, cut off values for Ara h 2 from multiplex arrays are less well defined. The aim of this study was to evaluate the correlation between Ara h 2 sIgE determined by singleplex versus multiplex measurements and to assess the diagnostic value of the different peanut components included in Immuno Solid-phase Allergen Chip (ISAC) multiplex analysis in children with a suspected peanut allergy. METHODS: In this retrospective study we analyzed Ara h 2 sIgE values with singleplex Fluorescence Enzyme Immunoassay (FEIA, ImmunoCap) and multiplex microarray (ISAC) measurements in 117 children with a suspected peanut allergy. Also, other peanut components measured by ISAC were analyzed. Double blinded placebo controlled oral food challenges were used as golden standard. RESULTS: Among all studied peanut components FEIA Ara h 2 sIgE showed the highest area under the curve (AUC, 0.922), followed by ISAC Ara h 6 and Ara h 2 sIgE with AUCs of respectively 0.906 and 0.902. Best cut off values to diagnose peanut allergy were 4.40 kU/l for FEIA Ara h 2 sIgE and, 7.43 ISU and 8.13 ISU for respectively Ara h 2 and Ara h 6 sIgE in ISAC microarray. Ara h 2 sIgE determined in FEIA and ISAC showed a good correlation (r = 0.88; p < 0.01). CONCLUSION: Ara h 6 and Ara h 2 sIgE in multiplex ISAC are both good predictors of clinical peanut allergy in Dutch children, and their performance is comparable to the use of Ara h 2 in singleplex FEIA. The simultaneous measurement of different peanut components using ISAC is an advantage and clinically useful to detect peanut allergic children that are Ara h 2 negative but sensitized to other peanut proteins such as Ara h 6.

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.

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time.

A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term 'VGKC-complex antibodies' should be abolished.

Mono-sensitisation to peanut component Ara h 6: a case series of five children and literature review.

UNLABELLED: Here, we summarise the current clinical knowledge on Ara h 6 sensitisation and clinical relevance of this sensitisation pattern using five illustrative clinical cases. The literature search yielded a total of 166 papers, and an additional relevant article was found by 'snowballing'. A total of ten articles were considered relevant for this review. Most studies included patients with a sensitisation to Ara h 6 and cosensitisation to Ara h 2. Only three studies showed patients with a mono-sensitisation to Ara h 6. This illustrates that Ara h 6 mono-sensitisation has been neglected in literature. We present a case series of five children with sensitisation to peanut component Ara h 6. Only one of these five patients showed Ara h 8 cosensitivity. Three out of the five children had a positive double-blind placebo-controlled food challenge (DBPCFC), with moderate to strong reactions. CONCLUSION: A mono-sensitisation to peanut component Ara h 6 is uncommon but can cause severe allergic reactions. Therefore, the determination of sIgE to Ara h 6 is warranted in patients with a suspected peanut allergy, especially in the absence of sensitisation to Ara h 1, 2, 3 and 9. WHAT IS KNOWN: • Peanut allergy is common and can cause severe allergic reactions. • The diagnostics of peanut allergy has recently improved with the use of component resolved diagnosis What is new: • A mono-sensitisation to peanut component Ara h 6 is uncommon, but can cause severe allergic reactions • Determination of sIgE to Ara h 6 is warranted in patients with a suspected peanut allergy, especially in the absence of sensitisation to Ara h 1, 2, 3 and 9.

Increased progression of carotid intima media thickness in thyroid peroxidase antibodies-positive rheumatoid arthritis patients.

OBJECTIVE: Autoimmune diseases such as rheumatoid arthritis (RA) and hypothyroidism tend to cluster, and this coexistence amplifies the elevated cardiovascular risk in RA. Whether thyroid peroxidase antibodies (TPOabs) are associated with increased cardiovascular disease (CVD) risk has not been studied extensively. Therefore, this study determined firstly the prevalence of TPOabs in RA and secondly whether TPOabs were associated with CVD. Moreover, this study explored whether TPOabs were related to RA characteristics. DESIGN AND METHODS: Data from the CARRÉ Study, an ongoing study investigating CVDs and its risk factors in RA (n=322), was used to ascertain the prevalence of TPOabs in RA patients. In addition, cardiovascular and RA disease characteristics were compared between TPOabs-positive and -negative patients at baseline and at a second visit after 3 years. RESULTS: TPOabs were present in 47/322 (15%) RA patients and TSH levels were higher in TPOabs-positive patients (1.40 mU/l) compared with TPOabs-negative patients (1.26 mU/l, P=0.048). At baseline and after 3 years no association was observed between TPOabs and (risk factors for) CVD. Regression analyses revealed a significantly larger progression of carotid intima media thickness (cIMT; ß=0.13 mm) in TPOabs-positive compared with TPOabs-negative patients independent of risk factors for cIMT progression. RA disease activity scores (DAS28) were higher in TPOabs-positive compared with TPOabs-negative patients (4.4 vs 3.8 P=0.018). CONCLUSIONS: TPOabs were associated with increased cIMT progression. Moreover, an association between TPOabs and DAS28 was observed. Hence, TPOabs seems to have a role in the amplified cardiovascular risk in RA patients.

Serum I-FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies.

BACKGROUND: Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I-FABP) is a sensitive marker to study enterocyte damage. AIMS: To evaluate the severity of enterocyte damage in adult-onset CD and its course upon a gluten-free diet (GFD). Furthermore, the correlation among enterocyte damage, CD autoantibodies and histological abnormalities during the course of disease is studied. METHODS: Serum I-FABP levels were determined in 96 biopsy-proven adult CD patients and in 69 patients repeatedly upon a GFD. A total of 141 individuals with normal antitissue transglutaminase antibody (IgA-tTG) levels served as controls. I-FABP levels were related to the degree of villous atrophy (Marsh grade) and IgA-tTG. RESULTS: I-FABP levels were elevated in untreated CD (median 691 pg/mL) compared with controls (median 178 pg/mL, P < 0.001) and correlated with Marsh grade (r = 0.265, P < 0.05) and IgA-tTG (r = 0.403, P < 0.01). Upon a GFD serum levels decreased significantly, however, not within the range observed in controls, despite the common observed normalisation of IgA-tTG levels and Marsh grade. CD patients with elevated I-FABP levels nonresponding to GFD showed persistent histological abnormalities. CONCLUSIONS: Enterocyte damage assessed by serum I-FABP correlates with the severity of villous atrophy in coeliac disease at the time of diagnosis. Although enterocyte damage improves upon treatment, substantial enterocyte damage persists despite absence of villous atrophy and low IgA-tTG levels in the majority of cases. Elevated I-FABP levels nonresponding to gluten-free diet are indicative of histological abnormalities and warrant further evaluation.

Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy.

Autologous hematopoietic SCT (auto-SCT) has been effective therapy for refractory disease, in both malignancies and severe autoimmune diseases. It seems feasible and safe for refractory celiac disease (RCD) type II, although long-term results have not been evaluated yet. With current therapies, progression into enteropathy-associated T-cell lymphoma (EATL) occurs in 60-80% patients, with a high mortality rate. Therefore, it is important to evaluate new treatment strategies. Between March 2004 and February 2010, 18 RCD II patients were evaluated for auto-SCT preceded by conditioning with fludarabine and melphalan, as a consequence of unresponsiveness to cladribine therapy. Adverse events, survival rate, EATL development and change in clinical, histological and immunological course were monitored. Thirteen patients were transplanted successfully and followed up for >2 years, 4-year survival rate was 66%. Only one patient died because of transplant-related complications. The majority of patients showed an impressive clinical improvement and five a complete histological remission. In five patients, auto-SCT could not be performed; they all died with a median survival of 5.5 months. EATL was observed in one transplanted patient, only after 4 years of follow-up. Auto-SCT after conditioning with high-dose chemotherapy in RCD II patients unresponsive to cladribine therapy is feasible and seems promising.

Childhood coeliac disease: towards an improved serological mass screening strategy.

BACKGROUND: In 1997-1998, 6127 asymptomatic children aged 2-4 years were screened for coeliac disease (CD) by anti-endomysium (EmA) testing in the Netherlands. After 6 (+/-2) months, biopsies were performed in 57 seropositive children; 31(54%) had villous atrophy, but 26 (46%), all HLA-DQ2/DQ8 positive, had normal histology. AIMS: To reduce the number of unnecessary biopsies after serological mass screening for CD in asymptomatic young children by optimizing screening procedures. METHODS: Comparing different tests and optimizing their cut-off point: screening samples were tested for EmA, tissue-transglutaminase (tTGA), antigliadin and deamidated-gliadin-peptides (anti-DGP) antibodies. Determining serological persistence over time: persistence of EmA and tTGA was determined by testing serological samples obtained at biopsy. RESULTS: Tissue-transglutaminase and anti-DGP correlated with EmA. Optimization of standard cut-off points not only reduced unnecessary biopsies by 50-96% but also reduced sensitivity. EmA persisted in all CD children, but in only 50% of the non-CD children. tTGA persisted in 83% of CD, but in only 15% of non-CD children. CONCLUSIONS: Coeliac disease antibodies may be present transiently in genetically predisposed children. To avoid unnecessary biopsies, serological mass screening procedures may be improved by repeating EmA and/or tTGA in initially seropositive young children after 6 months, before proceeding to biopsy. This may reduce the number of unnecessary biopsies that are performed.

Aberrant T-lymphocytes in refractory coeliac disease are not strictly confined to a small intestinal intraepithelial localization.

BACKGROUND: Refractory coeliac disease (RCD) is characterized by persisting mucosal pathology in spite of a strict gluten free diet (GFD). In RCD type II, phenotypically aberrant (CD7+CD3-CD4/8-cytoplasmicCD3+) T-lymphocytes are present within the intraepitelial lymphocyte (IEL) population in the small intestine, and 50-60% of these patients develops an enteropathy associated T-cell lymphoma (EATL). AIM: To investigate whether aberrant T-lymphocytes in RCD II can be detected in other parts of the small intestinal mucosa besides the intraepithelial compartment. Additionally, the presence of aberrant T-lymphocytes was analyzed in two RCD II patients that developed atypical skin lesions. METHODS: Multiparameter flow cytometric immunophenotyping was performed on both IEL and lamina propria lymphocyte (LPL) cell suspensions, isolated from small bowel biopsy specimens of RCD II patients (n = 14), and on cutaneous lymphocytes isolated from skin-lesion biopsy specimens of RCD II patients (n = 2). In addition, immunofluorescence analysis of frozen RCD II derived small intestinal biopsies was performed. RESULTS: Our results clearly show that aberrant T-lymphocytes may be present in both the IEL and the LPL compartments of RCD II derived small intestinal biopsies. Although the highest percentages are always present in the IEL compartment, aberrant LPL can exceed 20% of total LPL in half the RCD II patients. Interestingly, cutaneous lymphocytes isolated from atypical skin lesions that developed in some RCD II patients showed a similar aberrant immunophenotype as found in the intestinal mucosa. CONCLUSIONS: In RCD II, the aberrant T-lymphocytes may also reside in the subepithelial layer of the small intestinal mucosa, in the lamina propria, and even in extraintestinal localizations including the skin. Whether this phenomenon represents a passive overflow from the intestinal epithelium or active trafficking towards other anatomical localizations remains to be elucidated. RCD II appears to be a disseminated disease, which may impose the risk of EATL development outside the intestine.

Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development.

We describe the effect on the neonate of administration of rituximab to a woman with idiopathic thrombocytopenic purpura (ITP). Rituximab, an anti-CD20 antibody, was given weekly for 4 weeks to a woman with ITP in her third trimester of pregnancy. One month after the last rituximab administration a healthy girl was born. She had normal growth and development during the first six months. At birth, B-lymphocytes were not detectable. Rituximab levels in mother and neonate were 24000 and 6700 ng/mL, respectively. Only 7 cases of rituximab administration during pregnancy were described. No adverse events are described for fetus and neonate. We demonstrate that rituximab passes the placenta and inhibits neonatal B-lymphocyte development. However, after 6 months B-lymphocyte levels normalized and vaccination titres after 10 months were adequate. No infection-related complications occurred. Rituximab administration during pregnancy appears to be safe for the child but further studies are warranted.