Prevalence of markers of beta cell autoimmunity and thyroid disease in children with coeliac disease.

BACKGROUND: Over the last decades, the prevalence of coeliac disease (CD), an autoimmune disorder, rose to 1-2%. Whether patients with CD have higher risk of developing other autoimmune disorders such as type 1 diabetes, Hashimoto thyroiditis, or Graves` disease remains unclear. AIM: The aim of this study was to determine the prevalence of biomarkers of beta cell and thyroid autoimmunity in children with CD. METHODS: Retrospective cross-sectional cohort study comparing pediatric patients suffering from CD with age and sex-matched healthy controls (HC). Participant`s serum was tested by immunoassay for following autoantibodies (aAb): TSH-receptor antibodies (TRAb), anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), anti-glutamic acid decarboxylase (anti-GAD), anti-zinc transporter 8 (anti-ZnT8), anti-islet antigen 2 (anti-IA2) and anti-insulin. RESULTS: A total of 95 patients with CD (mean age 8.9 years; 63% female) and 199 matched healthy controls (mean age 9.2 years; 59.8% female) were included in the study. For patients with CD, a seroprevalence of 2.1% (vs. 1.5% in HC) was calculated for anti-GAD, 1.1% for anti-IA2 (vs. 1.5% in HC), 3.2% for anti-ZnT8 (vs. 4.2% in HC), and 1.1% (vs. 1% in HC) for anti-insulin. For thyroid disease, a seroprevalence of 2.2% for TRAb (vs. 1% in HC), 0% for anti-TPO (vs. 2.5% in HC) and 4.3% for anti-Tg (vs. 3.5% in HC) was found for patients with CD. CONCLUSION: This study suggests a higher prevalence of autoimmune antibodies againstthyroid in children with CD compared to HC, whilst it is similar for pancreatic antibodies. Prospective cohort studies are needed to first evaluate the occurrence of autoimmune antibodies against beta cells and thyroid over a longer follow-up time and second to explore their clinical relevance.

Variable and inaccurate serum IgG4 levels resulting from lack of standardization in IgG subclass assay calibration.

Background The quantification of serum IgG4 is commonly performed during the diagnostic workup of IgG4-related diseases (IgG4-RD). According to recent literature, IgG4 values above 1.35 g/L are characteristic of IgG4-RD and support its diagnosis at initial presentation. The purpose of this study was to evaluate comparability and accuracy of the two main commercially available IgG4 assays (Siemens Healthineers and The Binding Site). Methods Method comparison was performed for IgG and IgG subclasses using a collective of selected samples with elevated serum IgG4. In addition, we assessed the accuracy of both assays using purified polyclonal and monoclonal IgG4 preparations. Results Our data show significant discrepancies between the two IgG subclass assays for the measurement of IgG4 and, to a lesser extent, IgG3. Conclusions The lack of standardization between the two main providers of commercially available IgG4 assays leads to significant inter-assay result discrepancies, which might potentially cause unnecessary clinical workup. We conclude that serum IgG4 assay-specific decision limits, and not an assay-independent single cut-off level for IgG4 (e.g. 1.35 g/L), should be used when assessing patients for IgG4-RD. An internationally recognized, certified reference material for IgG subclasses is urgently needed, and assay manufactures are encouraged to undertake steps toward standardization of measurements of IgG4 and other IgG subclasses.

Comparison of Five TSH-Receptor Antibody Assays in Graves' disease: results from an observational pilot study.

BACKGROUND: Early diagnosis and relapse prediction in Graves' disease influences treatment. We assessed the abilities of four TSH-receptor antibody tests [TRAb] and one cyclic adenosine monophosphate bioassay to predict relapse of Graves' disease. METHODS: Observational study investigating patients presenting with Graves' disease at a Swiss hospital endocrine referral center or an endocrine outpatient clinic. Main outcomes were diagnosis and relapse of Graves' disease after stop of anti-thyroid drugs. We used Cox regression to study associations of TRAb levels with relapse risk and calculated c-statistics [AUC] to assess discrimination. Blood draws took place as close as possible to treatment initiation. RESULTS: AUCs ranged from 0.90 (TSAb Biossay by RSR) to 0.97 (IMMULITE TSI by Siemens). Highest sensitivity (94.0%) was observed for IMMULITE TSI and RSR TRAb Fast, while the greatest specificity (97.9%) was found with the EliA anti-TSH-R (by Thermo Fisher). In Cox regression analysis comparing the highest versus the lower quartiles, the highest hazard ratio [HR] for relapse was found for BRAHMS TRAK (by Thermo Fisher) (2.98, 95% CI 1.13-7.84), IMMULITE TSI (2.40, 95% CI 0.91-6.35), EliA anti-TSH-R (2.05, 95% CI 0.82-5.10), RSR Fast TRAb (1.80, 95% CI 0.73-4.43), followed by RSR STIMULATION (1.18, 95% CI 0.46-2.99). Discrimination analyses showed respective AUCs of 0.68, 0.65, 0.64, 0.64, and 0.59. CONCLUSION: The assays tested had good diagnostic power and relapse risk prediction with few differences among the new assays. Due to the small sample size and retrospective design with possible selection bias, our data need prospective validation.

DIAGNOSTIC ACCURACY OF BASAL CORTISOL LEVEL TO PREDICT ADRENAL INSUFFICIENCY IN COSYNTROPIN TESTING: RESULTS FROM AN OBSERVATIONAL COHORT STUDY WITH 804 PATIENTS.

OBJECTIVE: Adrenocorticotrophic hormone (ACTH) stimulation testing is the current standard for assessing primary and secondary adrenal insufficiency (AI). We aimed to investigate the value of basal cortisol level for prediction of AI. METHODS: We retrospectively analyzed 804 consecutive patients who had high-dose (250 µg, HDT) or low-dose (1 µg, LDT) ACTH testing as part of their diagnostic work-up. Site-specific cut-off levels for AI were <550 in and <500 nmol/L in HDT and LDT, respectively. RESULTS: Overall, 70/400 (17.5%) in the LDT group and 118/404 (29.2%) in the HDT group showed an insufficient increase of cortisol and were categorized as AI. The receiver operating characteristic curve analysis showed an overall area under the curve (AUC) for basal cortisol of 0.88, which was comparable in LDT (area under the curve [AUC] 0.88) and HDT (AUC 0.88). If basal cortisol levels were ≥450 nmol/L (n = 234/804, 29.1%), the negative predictive value to rule out AI was 98.7%. If cortisol was ≤100 nmol/L (n = 69/804, 8.6%) the positive predictive value was 93.2% to rule in AI. There was a minimal additional value of the 30-minute cortisol level in HDT as compared to the 60-minute result, as well as for delta values. CONCLUSION: Basal cortisol levels ≤100 and ≥450 nmol/L were found in almost half of patients tested for possible AI and had high diagnostic accuracy, abolishing the need for formal ACTH testing. The 30-minute cortisol value in HDT did not increase diagnostic accuracy. These data may help guide clinicians when testing can safely be omitted, thereby reducing expenses and simplifying test protocols. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency AUC = area under the curve CI = confidence interval HDT = high-dose test HPA axis = hypothalamus-pituitary-adrenal axis ITT = insulin tolerance test LDT = low-dose test NR = normal responders LR+/- = positive/negative likelihood ratio NPV = negative predictive value PPV = positive predictive value.

Complement C1s deficiency in a male Caucasian patient with systemic lupus erythematosus: a case report.

Deficiencies of the early complement components of the classical pathway (CP) are well-documented in association with systemic lupus erythematosus (SLE) or SLE-like syndromes and severe pyogenic infections. Among these, complete C1s deficiency has been reported in nine cases so far. Here, we describe a 34-year-old male patient who presented with severe, recurrent infections since childhood, including meningitides with pneumococci and meningococci, erysipelas, subcutaneous abscess, and recurrent infections of the upper airways. The patient also exhibited adult-onset SLE, meeting 7/11 of the ACR criteria and 34 of the 2019 EULAR/ACR classification criteria, along with class IV-G (A) proliferative lupus nephritis (LN). A screening of the complement cascade showed immeasurably low CH50, while the alternative pathway (AP) function was normal. Subsequent determination of complement components revealed undetectable C1s with low levels of C1r and C1q, normal C3, and slightly elevated C4 and C2 concentrations. The patient had no anti-C1q antibodies. Renal biopsy showed class IV-G (A) LN with complement C1q positivity along the glomerular basement membranes (GBMs) and weak deposition of IgG, IgM, and complement C3 and C4 in the mesangium and GBM. In an ELISA-based functional assay determining C4d deposition, the patient's absent complement activity was fully restored by adding C1s. The genome of the patient was analyzed by whole genome sequencing showing two truncating variants in the C1S gene. One mutation was located at nucleotide 514 in exon 5, caused by a nucleotide substitution from G to T, resulting in a nonsense mutation from Gly172 (p.Gly172*). The other mutation was located at nucleotide 750 in exon 7, where C was replaced by a G, resulting in a nonsense mutation from Tyr250 (p.Tyr250*). Both mutations create a premature stop codon and have not previously been reported in the literature. These genetic findings, combined with the absence of C1s in the circulation, strongly suggest a compound heterozygote C1s deficiency in our patient, without additional defect within the complement cascade. As in a previous C1s deficiency case, the patient responded well to rituximab. The present case highlights unanswered questions regarding the CP's role in SLE etiopathogenesis.

Diagnostic relevance of free light chains in cerebrospinal fluid - The hyperbolic reference range for reliable data interpretation in quotient diagrams.

BACKGROUND: Free light chains, type kappa (FLC-K), in cerebrospinal fluid (CSF) were compared to oligoclonal IgG in many studies for sensitive detection of immune reactions in brain. The missing consensus about CSF data interpretation prevents reliable conclusions. This can be overcome by a theory-based hyperbolic reference range in CSF/serum quotient diagrams. METHODS: Mean Quotients for FLC-K, QKappa, and albumin, QAlb, of grouped, biochemically defined controls (N = 433) are fitted with the hyperbolic function QKappa(mean) = a/b (QAlb2 + b2)0.5 - c by a generally applicable procedure excluding outliers. RESULTS: With QKappa(mean), the coefficient of variation CV (22.5%) and the reference range (QKappa(mean) ±â€¯3 CV) we got the discrimination line QKappa(lim) = (3.27(QAlb2 + 33)0.5-8.2) ×10-3 in a FLC-K Reibergram. Intrathecal FLC-K was found in 8% of another control group without OCB (N = 388) but was missed in 7% of patients with definite Multiple sclerosis (N = 95). In MS the mean intrathecal fraction was threefold larger for FLC-K (95%) compared to total IgG (36%). Similar mean quantities of intrathecal FLC-K contradict an immunological conversion between a Clinically isolated syndrome and MS. DISCUSSION: The hyperbolic reference range is superior to linear FLC-K Index (10 to 15% false negatives) and exponential curves (30% false positive interpretations for controls) in the analytical range of MS data, with excellent data fit for up to ten-fold larger QAlb values. Dynamics of the small molecule FLC-K contribute to the understanding of molecular size dependent barrier functions.

External validation of the GREAT score to predict relapse risk in Graves' disease: results from a multicenter, retrospective study with 741 patients.

CONTEXT: First-line treatment in Graves' disease is often done with antithyroid agents (ATD), but relapse rates remain high making definite treatment necessary. Predictors for relapse risk help guiding initial treatment decisions. OBJECTIVE: We aimed to externally validate the prognostic accuracy of the recently proposed Graves' Recurrent Events After Therapy (GREAT) score to predict relapse risk in Graves' disease. DESIGN, SETTING AND PARTICIPANTS: We retrospectively analyzed data (2004-2014) of patients with a first episode of Graves' hyperthyroidism from four Swiss endocrine outpatient clinics. MAIN OUTCOME MEASURES: Relapse of hyperthyroidism analyzed by multivariate Cox regression. RESULTS: Of the 741 included patients, 371 experienced a relapse (50.1%) after a mean follow-up of 25.6 months after ATD start. In univariate regression analysis, higher serum free T4, higher thyrotropin-binding inhibitor immunoglobulin (TBII), younger age and larger goiter were associated with higher relapse risk. We found a strong increase in relapse risk with more points in the GREAT score from 33.8% in patients with GREAT class I (0-1 points), 59.4% in class II (2-3 points) with a hazard ratio of 1.79 (95% CI: 1.42-2.27, P < 0.001) and 73.6% in class III (4-6 points) with a hazard ratio of 2.24 (95% CI: 1.64-3.06, P < 0.001). CONCLUSIONS: Based on this retrospective analysis within a large patient population from a multicenter study, the GREAT score shows good external validity and can be used for assessing the risk for relapse in Graves' disease, which influence the initial treatment decisions.