Candidate autoantibodies for primary Sjögren's syndrome: where are they now?

Although ANA, SSA and SSB antibody testing are universally accepted biomarkers for Sjögren's syndrome (SS) diagnosis, they do not occur in all patients. Up to 18% of SS patients are seronegative, with potential for delayed or missed diagnosis. There are no clinically available autoantibodies with predictive value for SS end-organ complications. Over the last three decades, novel autoantibodies for SS diagnosis and monitoring have been identified but few have transitioned from research studies to clinical use. We performed a literature review of candidate serum autoantibodies to examine their persistence in the literature and potential clinical utility. Of the nineteen autoantibodies we identified, AQP5, SP-1, CA6, and PSP Abs have the most promise. Larger cohort studies are needed to determine their potential contribution in SS management.

Immunoglobulin E Sensitization to Mammalian Oligosaccharide Galactose-α-1,3 (α-Gal) Is Associated With Noncalcified Plaque, Obstructive Coronary Artery Disease, and ST-Segment-Elevated Myocardial Infarction.

BACKGROUND: Treating known risk factors for coronary artery disease (CAD) has substantially reduced CAD morbidity and mortality. However, a significant burden of CAD remains unexplained. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal) was recently associated with CAD in a small observational study. We sought to confirm that α-Gal sensitization is associated with CAD burden, in particular noncalcified plaque. Additionally, we sort to assess whether that α-Gal sensitization is associated with ST-segment-elevated myocardial infarction (STEMI) Methods: We performed a cross-sectional analysis of participants enrolled in the BioHEART cohort study. We measured α-Gal specific-immunoglobulin E antibodies in serum of 1056 patients referred for CT coronary angiography for suspected CAD and 100 selected patients presenting with STEMI, enriched for patients without standard modifiable risk factors. CT coronary angiograms were assessed using coronary artery calcium scores and segmental plaque scores. RESULTS: α-Gal sensitization was associated with presence of noncalcified plaque (odds ratio, 1.62 [95% CI, 1.04-2.53], P=0.03) and obstructive CAD (odds ratio, 2.05 [95% CI, 1.29-3.25], P=0.002), independent of age, sex, and traditional risk factors. The α-Gal sensitization rate was 12.8-fold higher in patients with STEMI compared with matched healthy controls and 2.2-fold higher in the patients with STEMI compared with matched stable CAD patients (17% versus 1.3%, P=0.01 and 20% versus 9%, P=0.03, respectively). CONCLUSIONS: α-Gal sensitization is independently associated with noncalcified plaque burden and obstructive CAD and occurs at higher frequency in patients with STEMI than those with stable or no CAD. These findings may have implications for individuals exposed to ticks, as well as public health policy. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12618001322224.

Added Diagnostic Value of Peanut Component Testing: A Cross-Sectional Study in Australian Children.

BACKGROUND: Peanut components are widely used in clinical practice; however, their utility to predict challenge outcome in the Australian children, outside of infants, is not well studied. OBJECTIVE: Can peanut component testing predict outcome of challenge in peanut-allergic children. METHODS: All children attending peanut challenges, regardless of previous allergic reactions to peanut or sensitization (skin prick test or peanut IgE) alone, were recruited. Serum collected before the challenge was analyzed for peanut IgE and Ara h 1, 2, 3, 6, 8, and 9 (ImmunoCap). RESULTS: Of the 222 children recruited, 89 (40%) were allergic on oral food challenge. Ara h 2 and 6 performed similarly to peanut IgE and skin prick test in predicting challenge outcome (area under the curve, 0.84-0.87). No baseline clinical characteristics, including past history, predicted challenge outcome. By logistic regression, degree of polysensitization to Ara h 1, 2, or 3 increased the odds of allergic reaction at oral food challenge at 0.35 and 1.0 kUA/L cutoff levels (P < .001 for both). All 11 children sensitized (>0.35 kUA/L) to Ara h 1, 2, and 3 reacted to peanut challenge. Degree of polysensitization at more than 1.0 kUA/L was associated with a lower cumulative eliciting dose (P = .016) and with severity of allergic reaction on challenge (P = .007). CONCLUSIONS: In our cohort, sensitization to the combination of Ara h 1, 2, and 3 was highly predictive of peanut allergy. Overall, only Ara h 2 as individual component most correlated with severity of reaction at challenge and adrenaline use. Ara h 8 and 9 were not useful in predicting challenge outcome.

Fungal Pneumonia in The Immunocompetent Host: A Possible Statistical Connection Between Allergic Fungal Sinusitis with Polyposis and Recurrent Pulmonary Infection Detected by Gastroesophageal Reflux Disease Scintigraphy.

OBJECTIVES: Fungal pneumonia in the immune competent host is a rarity with few reported cases in the literature. We present a series of 7 cases of recurrent fungal pneumonia in association with allergic fungal rhinosinusitis and gastroesophageal reflux disease (GERD). We hypothesised that recurrent infection may have been transported from the infected paranasal sinuses into the lung by GERD as the process was terminated by surgical fundoplication in 2 of these patients. METHODS: Patients were recruited into the study if they were immune competent and had recurrent fungal pneumonia and GERD. Allergic fungal rhinosinusitis was proven by biopsy. GERD was investigated by a scintigraphic test that assessed local oesophageal disease, lung aspiration and head and neck involvement with a hybrid gamma camera and X-ray computed tomography. RESULTS: All patients were shown to have GERD with 5/7 showing paranasal sinus contamination and 7/7 showing laryngopharyngeal involvement and 6/7 lung aspiration. One patient had characteristics strongly predictive of aspiration. Fundoplication led to cessation of fungal lung infection in two patients. CONCLUSION: Recurrent fungal pneumonia in the immune competent host should raise the possibility of re-infection from the paranasal sinuses, especially in patients with GERD.

Esophageal Clearance in Laryngopharyngeal Reflux Disease: Correlation of Reflux Scintigraphy and 24-hour Impedance/pH in a Cohort of Refractory Symptomatic Patients

Objectives: The role of gastroesophageal reflux disease (GERD) in the aetiology of laryngopharyngeal reflux (LPR) is poorly understood and remains a controversial issue. The 24-hour impedance monitoring has shown promise in the evaluation of LPR but is problematic in pharyngeal recording. We have shown the utility of scintigraphic studies in the detection of LPR and lung aspiration of refluxate. Correlative studies were obtained in patients with a strong history of LPR and severe GERD. Methods: A highly selected sequential cohort of patients with a high pre-test probability of LPR/severe GERD who had failed maximal medical therapy were evaluated with 24-hour impedance/pH, manometry and scintigraphic reflux studies. Results: The study group comprised 34 patients (15 M, 19 F) with a mean age of 56 years (range: 28-80 years). The majority had LPR symptoms (mainly cough) in 31 and severe GERD in 3. Impedance bolus clearance and pH studies were abnormal in all patients in the upright and supine position. A high rate of non-acid GERD was detected by impedance monitoring. LOS tone and ineffective oesophageal clearance were found in the majority of patients. Scintigraphic studies showed strong correlations with impedance, pH and manometric abnormalities, with 10 patients showing pulmonary aspiration. Conclusion: Scintigraphic studies appear to be a good screening test for LPR and pulmonary aspiration as there is direct visualisation of tracer at these sites. Impedance studies highlight the importance of non-acidic reflux and bolus clearance in the causation of cough and may allow the development of a risk profile for pulmonary aspiration of refluxate.

A case study of apple seed and grape allergy with sensitisation to nonspecific lipid transfer protein.

Lipid transfer proteins can be an important cause of allergy given their stability and high degree of protein sequence homology. We describe the case of a child who developed two separate episodes of anaphylaxis after consuming apple seed and grape, with evidence that nonspecific lipid transfer proteins may have been responsible for these reactions. Lipid transfer protein allergy should be considered when anaphylaxis is inconsistent, such as in patients who can tolerate fruit pulp but react to fresh whole fruit juices.

Dense fine speckled indirect immunofluorescence pattern in an Australian population.

The dense fine speckled (DFS) pattern is an antinuclear antibody (ANA) pattern that has recently become of interest. This particular pattern has not been associated with systemic autoimmune rheumatic disorders (SARD) but has been associated with other inflammatory conditions such as interstitial nephritis, autoimmune thyroid disease and atopic eczema as well as being found in healthy individuals. We have been reporting this pattern in our laboratory for the past 3 years. The objective of this study was to determine the frequency of the DFS pattern as detected on indirect immunofluorescence (IIF) in an Australian population and to assess association of this pattern with other laboratory autoimmune markers. ANA tests performed by IIF from July 2012 until June 2014 were reviewed and the frequency of DFS pattern was determined. All DFS positive samples that had undergone concurrent testing for antibodies to extractable nuclear antigens (ENA), anti-dsDNA antibodies, rheumatoid factor (RF), anti-citrullinated protein antibodies (CCP) and anti- phospholipid antibodies were compared. Over the 2 year period, 181,819 patients had ANA tests performed and 51,905 were ANA positive. The DFS pattern was found in 5.7% of ANA positive patients. Within this group of patients, only 1.8% were positive for antibodies to ENA and only 0.7% had anti-dsDNA antibodies level greater than 9 IU/mL. RF and anti-CCP antibodies were positive in 6.3% and 4.1% of DFS positive samples, respectively. There were only two samples positive for anti-phospholipid antibodies when the DFS pattern was present. The presence of the DFS pattern as detected by IIF is infrequently associated with autoimmune markers of SARD which is consistent with international studies.

HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in Vietnamese.

BACKGROUND: In Vietnam, we observed a high incidence of carbamazepine (CBZ)-induced severe cutaneous adverse drug reactions (SCARs)-Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity rash with eosinophilia and systemic symptoms (DRESS). In other Asian countries, HLA-B(*)1502 is an established risk factor for SCARs. OBJECTIVE: The aim of our study was to determine the frequency of HLA-B(*)1502 in SCARs patients at a large University Medical Center in Hanoi, Vietnam. METHODS: Thirty-eight cases of SCARs caused by CBZ and 25 patients with epilepsy tolerating CBZ were enrolled in a case-controlled study. Clinical manifestations and laboratory findings were recorded for each subject. Genomic DNA was isolated using the QIAamp DNA purification system. The combination of polymerase chain reaction and sequence specific oligonucleotide probes with the Luminex 100×MAP flow cytometry dual laser system was then used to quantitate fluorescently labelled oligonucleotides attached to colour-coded microbeads. RESULTS: Cases comprised 20 SJS (52.6%), 7 TEN (18.4%), 8 overlap syndrome (21.1%), and 3 DRESS patients (7.9%). A strong association between HLA B(*)1502 and bullous skin reactions such as SJS/TEN and overlap was confirmed with an odds ratio (OR) of 33.78 (95% confidence interval [CI], 7.55-151.03), p < 0.0001, Sensitivity 91.4%, Specificity 76.0%, positive predictive value 84.2%, and negative predictive value 86.4%. We did not, however, observe any correlation between the presence of this allele and CBZ-induced nonbullous skin reactions (DRESS) (OR, 6.33; 95% CI, 0.48-82.74; p = 0.1592). CONCLUSION: Our results indicate the presence of HLA-B(*)1502 in Vietnamese is a pharmacogenetic risk factor for developing CBZ-induced SJS/TEN.

Vaccines and risk of lymphoedema--a case report of a breast cancer patient.

BACKGROUND: Vaccinations have been linked to lymphoedema but there is no quality scientific evidence to support or refute a causative relationship. OBJECTIVE: We report on a case of a breast cancer patient who developed lymphoedema following vaccination in her 'at risk' arm. She had previously undergone mastectomy and axillary clearance but did not have lymphoedema before the vaccinations. DISCUSSION: The risk of lymphoedema is still present for many years following breast surgery. Patients who are at risk of lymphoedema should be warned to report persistent swelling after vaccination so that they can be referred early for physiotherapy intervention if required.

Molecular confirmation of pathological specimen integrity in Australasia.

AIM: Investigations into 14 suspected pathology sample identification errors and mix-ups were performed, as a service for several public hospital and private laboratories, from 2005 to 2007. METHODS: Analyses were performed with the forensic ABI Identifiler kit of 16 microsatellites (15 autosomal and amelogenin) on DNA from paraffin-embedded tissues or blood specimens and compared to independently verified (single or multiple) patient samples. RESULTS: Of 23 unique patient specimens referred for sample integrity confirmation because of pathologist, clinician or patient concern, six (26.1%) were demonstrated to be discordant, indicating that specimen identification errors or mix-ups had occurred. CONCLUSIONS: Due to their great sensitivity and high discrimination power, forensic identity multiplex systems using either microsatellites or single nucleotide polymorphisms (SNPs) can resolve concerns about pathology specimen identity and integrity.

A multi-centre evaluation of the intra-assay and inter-assay variation of commercial and in-house anti-cardiolipin antibody assays.

AIMS: To assess the intra-assay (intra-run) and inter-assay (inter-run) variation of commercial and in-house IgG and IgM anti-cardiolipin antibody (aCL) assays/kits, and to determine an appropriate maximum value for inclusion in consensus guidelines. METHODS: Frozen aliquots of two patient specimens and one commercial control were sent to nine laboratories for the evaluation of eight commercial kits and one in-house assay. Intra-assay and inter-assay evaluations were performed with all three samples for IgG aCL, and one patient specimen for IgM aCL. RESULTS: The IgG and IgM aCL values varied considerably between the nine assays/kits. The majority of assays/kits demonstrated less than 20% intra-assay and inter-assay variation, with lower intra-assay and inter-assay variation observed with the commercial control. Single calibrator assays were not consistently associated with higher inter-assay variation than multi-point calibrator assays. CONCLUSIONS: An inter-assay coefficient of variation of 20% was determined to be an appropriate maximum value for inclusion in the Australasian aCL Working Party consensus guidelines. Improved standardisation between different assay/kits is still required.

Consensus guidelines on anti-cardiolipin antibody testing and reporting.

UNLABELLED: Consensus guidelines on anti-cardiolipin antibody (aCL) testing have been developed to help minimise laboratory variation in the performance and reporting of aCL assays. These guidelines include minimum, optimum and optional recommendations for the following aspects of aCL testing and reporting: (1) isotype of aCL tested; (2) specimen type; (3) controls and assay precision; (4) calibrators; (5) patient samples; (6) rheumatoid factors and IgM aCL testing; (7) reporting of results; (8) cut-off values; and (9) interpretative comments. ABBREVIATIONS: aCL, anti-cardiolipin antibodies; APS, anti-phospholipid antibody syndrome; ASCIA, Australasian Society of Clinical Immunology and Allergy; ASTH, Australasian Society of Thrombosis and Haemostasis; beta2-GPI=beta2-glycoprotein I; ELISA, enzyme-linked immunosorbent assay; NCCLS, National Committee for Clinical Laboratory Standards; HSANZ, Haematology Society of Australia and New Zealand; QAP, Quality Assurance Program; RCPA, Royal College of Pathologists of Australasia; %CV, inter-assay inter-run coefficient of variation.