Mixed cryoglobulinemia

Mixed cryoglobulinemia (MC), type II and type III, refers to the presence of circulating cryoprecipitable immune complexes in the serum and manifests clinically by a classical triad of purpura, weakness and arthralgias. It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of 'essential' MC is reported as approximately 1:100,000 (with a female-to-male ratio 3:1), but this term is now used to refer to a minority of MC patients only. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as a late complication. MC may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called 'essential' MC. The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection is suggested to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjögren's syndrome. Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low C4 levels and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium- and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions. Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren's syndrome, polyarthritis, and B-cell lymphomas. The first-line treatment of MC should focus on eradication of HCV by combined interferon-ribavirin treatment. Pathogenetic treatments (immunosuppressors, corticosteroids, and/or plasmapheresis) should be tailored to each patient according to the progression and severity of the clinical manifestations. Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies

Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in Sjögren's syndrome

Objectives: The purpose of this study was to evaluate the prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies (anti-CCP-Abs), IgM and IgA rheumatoid factors (RFs) in primary Sjogren's Syndrome (pSS). Materials and Methods:We compared clinical and serological. characteristics of 31 pSS and 31 Rheumatoid Arthritis (RA) patients. Both, anti-CCP-Abs and RFs (IgM, IgA) directed against Fc determinants of IgG from humans and rabbit were detected by enzyme-linked immunosorbent assay (ELISA). We included 31 blood donors as control group for the evaluation of RFs and anti-CCP-Abs. Nine (29%) pSS patients presented arthritis, and 10 (32,3%) RA patients also had secondary Sjogren's syndrome (sSS) Results: IgM and IgA RFs prevalence was similar in pSS and RA, whichever the antigene (Human or Rabbit IgG) used. However, RA patients with sSS showed a tendency to present more often RF positivity, longer disease duration and higher ESR and CRP when compared with pSS patients with arthritis. Anti-CCP-Abs were detected in 64,5% of RA patients and in only 6,9% of pSS patients (p<0,0005). Anti-CCP-Abs were more often positive in RA patients with sSS (RA/sSS) (8 patients, 80%) than in RA patients without sSS (18 patients, 58,1%), and were absent in pSS patients with arthritis. RF-positive pSS patients presented more often pulmonary involvement and higher inflammatory parameters, and less often neuropathy compared to RF-negative patients. In controls, anti-CCP-Abs were absent and REs were negligible. Conclusions: Anti-CCP-Abs were detected in only a few pSS patients, none of whom presented arthritis, which contrasts with the high frequency of these antibodies in RA/sSS. These results suggest that anti-CCP-Abs could be useful in the distinction between pSS and RA with sSS. Although not useful for the differential diagnosis between RA and pSS, RFs may have a prognostic role in pSS.publishersversionpublishe

Risk factors and comorbidity in primary Sjögren’s syndrome

Primary Sjögren’s syndrome is an autoimmune disease, in which the immune system targets the exocrine glands. The disease is characterized by inflammation and dysfunction of the salivary and lacrimal glands, leading to dry eyes and mouth. The etiopathogenesis of autoimmune diseases is not entirely known. Genetic factors, primarily relating to the immune system, are central in the development of disease. In Sjögren’s syndrome, such genetic variations are associated with the production of autoantibodies to the Ro/SSA and La/SSB autoantigens and a more aggressive course of the disease. However, environmental factors are also involved in the development of autoimmunity. Viruses, smoking, alcohol and radiation include some of the more frequently proposed risk factors, although a causal relationship remains to be been proven. To expand the current understanding of environmental risk factors, the relationship between exposure to infections and smoking and the development of Sjögren’s syndrome were investigated in Study I and Study II, respectively. A clear association between infections and subsequent development of Sjögren’s syndrome was observed, as a history of infections was significantly more prevalent in individuals with Sjögren’s syndrome compared to controls from the general population. Notably, this association was even more prominent in patients who developed Ro/SSA and La/SSB autoantibodies. Exposure to smoking could however not be linked to an increased risk of the disease, despite the wellknown association with development of other rheumatic diseases. Rather, we observed that individuals who developed Sjögren's syndrome were more prone to stop smoking during the decades preceding diagnosis. This finding may indicate that the appearance of very early symptoms of the disease leads to the discontinuation of smoking. Sjögren’s syndrome is a systemic disease, and may cause adverse events in various organ systems. The risk of cardiovascular and hematological disease in patients with Sjögren’s syndrome was analyzed using the Swedish national health-care registers in Study III and Study IV, respectively. Compared to the general population, individuals with Sjögren’s syndrome had a significantly increased risk of myocardial infarction, cerebral infarction, and venous thromboembolism. Moreover, the results indicate that Ro/SSA and La/SSB autoantibodies demark the subgroup of patients with the highest risk of cardiovascular comorbidity. Similarly, an increased risk of multiple myeloma was observed in patients with Sjögren’s syndrome, which was confined to individuals with Ro/SSA and La/SSB autoantibodies. Long-term outcomes for individuals with congenital heart block, which may develop in fetuses whose mothers carry Ro/SSA autoantibodies, were analyzed in Study V. The results indicate that these individuals have an increased risk of cardiovascular complications, and also illnesses related to infections and chronic inflammation, suggesting that a systematic follow-up would benefit these patients. In conclusion, the findings indicate that infections contribute to the development of Sjögren’s syndrome. Furthermore, the presence or absence of Ro/SSA and La/SSB autoantibodies discriminate between two distinct patient subgroups, and is a useful parameter for predicting the risk of comorbidity. Lastly, the findings reveal the risk of longterm complications in patients with congenital heart bloc

Prevalence and clinical implications of Scleroderma specific autoantibodies in Sjögren&apos;s syndrome.

Το σύνδρομο Sjögren’s (σS) είναι μια χρόνια αυτοάνοση ασθένεια με βραδεία εξέλιξη που χαρακτηρίζεται από συμπτώματα ξηροφθαλμίας και ξηροστομίας ως αποτέλεσμα λεμφοκυτταρικής διήθησης των σιελογόνων και δακρυικών αδένων. Παρότι κατά βάσιν θεωρείται ένα καλόηθες σύνδρομο, το οποίο προσβάλλει κυρίως γυναίκες μέσης ηλικίας, πολλοί ασθενείς υποφέρουν από κόπωση, πόνο, και εξωαδενικά συμπτώματα, τα οποία συχνά οδηγούν σε επιδείνωση της ποιότητας ζωής τους. Αν και η ακριβής παθογέννεση του συνδρόμου είναι ακόμη αδιευκρίνιστη, κατά τις τελευταίες δεκαετίες έχει επανειλημμένα δειχθεί ότι η ενεργοποίηση του μονοπατιού της ιντερφερόνης τύπου Ι αποτελεί καίριο γεγονός καθώς τα επαγόμενα από ιντερφερόνη τύπου Ι γονίδια υπερεκφράζονται τόσο σε περιφερικό αίμα όσο και ιστούς σιελογόνων αδένων των ασθενών αυτών, οδηγώντας σε ενεργοποίηση Β λεμφοκυττάρων και παραγωγή αυτοαντισωμάτων έναντι Ro/SSA και La/SSB αντιγόνων. Παρότι τα anti-Ro/SSA και/ή anti-La/SSB αντισώματα αποτελούν σημαντικό στοιχείο των παλαιότερων κριτηρίων ταξινόμησης για σS, αυτά είναι απόντα σε ένα σημαντικό μέρος των ασθενών με σS. Επιπλέον, οι ασθενείς με συστηματικό σκληρόδερμα (ΣΣκ) -κλασσικά χαρακτηριζόμενο από φαινόμενο Raynaud και σκλήρυνση του δέρματος- έχει δειχθεί ότι εμφανίζουν συμπτώματα ξηρότητας, ενώ ένα μέρος των ασθενών με σS έχουν στον ορό τους αντισώματα έναντι κεντρομεριδίου. Κατά τα τελευταία χρόνια μια σειρά από νέα ειδικά αντισώματα ΣΣκ έχουν αναγνωριστεί σε σχέση με διακριτούς κλινικούς και προγνωστικούς φαινότυπους μεταξύ των ασθενών με ΣΣκ. Ενόψει αυτών των δεδομένων, αποφασίσαμε να μελετήσουμε τον επιπολασμό και πιθανές κλινικές επιπτώσεις αυτών των ειδικών αυτοαντισωμάτων ΣΣκ σε διαδοχικούς ασθενείς που παραπονούνται για συμπτώματα ξηρότητας. Για το σκοπό αυτό, μελετήθηκαν διαδοχικοί ασθενείς με συμπτώματα ξηρότητας που είχαν παραπεμφθεί στη Μονάδα Μοριακής και Εφαρμοσμένης Φυσιολογίας, στο Εργαστήριο Φυσιολογίας, της Ιατρικής Σχολής, του Εθνικού και Καποδιστριακού Πανεπιστημίου Αθηνών. Φάνηκε ότι τα ειδικά αυτοαντισώματα ΣΣκ ήταν συχνά παρόντα σε άτομα με συμπτώματα ξηρότητας [41.7% (90/216) ατόμων που εκτιμήθηκαν (19% ισχυρώς θετικά, 22.7% μετρίως θετικά)]. Να σημειωθεί ότι ειδικά αυτοαντισώματα ΣΣκ σε ισχυρούς τίτλους ανιχνεύονταν στατιστικά σημαντικά πιο συχνά σε ασθενείς με βιοψίες ελασσόνων σιελογόνων αδένων (ΕΣΑ) που πληρούσαν τα ισχύοντα παθολογοανατομικά κριτήρια για σS (30% έναντι 12.5%, p=0.009), μια συσχέτιση που παρέμενε στατιστικά σημαντική ακόμα και μετά τροποποίηση για αντισώματα έναντι Ro/SSA και La/SSB αυτοαντιγόνα [OR 95% (CI): 4.1 (1.5-10.6)]. Θεωρητικά, αν τα ειδικά αυτοαντισώματα ΣΣκ σε ισχυρούς τίτλους είχαν την ίδια βαρύτητα στην κατάταξη ασθενών με σS, περίπου ένα τρίτο των οροαρνητικών (anti-Ro/SSA αρνητικών) ατόμων με αρνητική ή μη διαθέσιμη βιοψία ΕΣΑ θα κατατάσσονταν ως σS. Επιπλέον, παρατηρήσαμε ότι βιοψίες ΕΣΑ ασθενών με συμπτώματα ξηρότητας που είχαν ισχυρά θετικά αυτοαντισώματα ΣΣκ παρουσίαζαν στοιχεία περιπορικής ίνωσης εκτός από λεμφοκυτταρική διήθηση όπου αυτή υπήρχε. Το εξαιρετικό αυτό εύρημα δίνει βάση σε εναλλακτική υπόθεση του μηχανισμού δυσλειτουργίας των ΕΣΑ στο σS, άγνωστο προς το παρόν αν αφορά μια καινούργια νοσολογική οντότητα ή μια υποκατηγορία των ασθενών με σS. Διενεργώντας μια προοπτική, σταθμισμένη και τυφλή μελέτη θα μπορούσε να διερευνηθεί περαιτέρω αυτή η υπόθεση. Τα βασικά ευρήματά μας συνοψίζονται στις ακόλουθες περιλήψεις ήδη δημοσιευμένων άρθρων: Περίληψη του άρθρου “ Η υπογραφή ιντερφερόνης τύπου Ι στο σύνδρομο Sjögren’s: παθοφυσιολογικές και κλινικές επιπλοκές” https://pubmed-ncbi-nlm-nih-gov.e.bibl.liu.se/31376268/ Συγγραφείς: Νικόλαος Μαρκέτος, Ηλίας Cinoku, Άννα Ράπτη, Κλειώ Π. Μαυραγάνη Οι ιντερφερόνες τύπου Ι έχουν από καιρού αναγνωριστεί ως μεσολαβητές των αμυντικών μηχανισμών φυσικής ανοσίας έναντι απειλών από ιούς. Ακράδαντα στοιχεία κατά τα τελευταία 15 έτη αποκαλύπτουν το σηματικό τους ρόλο στην παθογένεση συστηματικών αυτοανόσων νοσημάτων, συμπεριλαμβανομένων του συστηματικού ερυθηματώδους λύκου (ΣΕΛ) και του συνδρόμου Sjögren’s (σS). Παρόλη την πρόοδο, μέθοδοι για την ανίχνευση, αρχικοί εκκινητές, βιολογική λειτουργία, και κλινικές συσχετίσεις τους στα πλαίσια της αυτοανοσίας δεν έχουν εξακριβωθεί πλήρως. Καθώς οι θεραπευτικές επιλογές για το σS παραμένουν περιορισμένες, η αδρανοποίηση συγκεκριμένων στόχων της ιντερφερόνης τύπου Ι φαίνονται ως μια υποσχόμενη επιλογή. Σε αυτή την ανασκόπηση συνοψίζουμε τα μέχρι στιγμής δεδομένα σχετικά με τον ρόλο της ιντερφερόνης τύπου Ι στο σS. Περίληψη του άρθρου: “Αυτοαντισώματα ειδικά του σκληροδέρματος: θα έπρεπε να συμπεριλαμβάνονται στο διαγνωστικό αλγόριθμο του συνδρόμου Sjögren’s?” https://doi.org/10.1016/j.semarthrit.2022.152026 Συγγραφείς: Νικόλαος Μαρκέτος, Βασιλική Κουλούρη, Ευαγγελία Π. Πιπέρη, Μαρία Ε. Γεωργάκη, Νικόλαος Γ. Νικητάκης, Κλειώ Π. Μαυραγάνη Σκοπός: Τα συμπτώματα ξηρότητας αποτελούν συχνό αίτιο παραπομπής σε ρευματολόγο. Ο έλεγχος για τα ειδικά αντισώματα έναντι Ro/SSA και La/SSB αντιγόνων καθώς και βιοψία ελασσόνων σιελογόνων αδένων (ΕΣΑ) αποτελούν κύρια εργαλεία που χρησιμοποιούνται στη διαγνωστική προσέγγιση. Αντικεντρομεριδιακά αντισώματα και εκδηλώσεις ξηρότητας ανιχνεύονται συχνά σε σύνδρομο Sjögren’s (σS) και συστηματικό σκληρόδερμα (ΣΣκ), αντίστοιχα. Επί του παρόντος, στοχεύσαμε στη διευκρίνιση της συχνότητας και των κλινικών συσχετίσεων ενός ευρεός φάσματος ειδικών αυτοαντισωμάτων ΣΣκ σε διαδοχικούς ασθενείς που παραπέμφθηκαν προς διερεύνηση πιθανού σS. Μέθοδοι: Καταγράφηκαν δημογραφικά, κλινικοπαθολογικά, και εργαστηριακά δεδομένα 216 διαδοχικών ασθενών με συμπτώματα ξηρότητας. Όλοι οι συμμετέχοντες ελέγχθηκαν για ειδικά αυτοαντισώματα ΣΣκ (έναντι CENP, PM/Scl, Scl-70, Ku, NOR90, RP11, RP155, fibrillarin, PDGFR, and Th/To) χρησιμοποιώντας ένα εμπορικά διαθέσιμο κιτ ανοσοαποτύπωσης. Σύμφωνα με την ένταση του σήματος, τα αναγνωρισμένα αυτοαντισώματα κατετάγησαν περαιτέρω σε εκείνα με ισχυρώς θετικούς και μετρίως θετικούς τίτλους. Αποτελέσματα: Ειδικά αυτοαντισώματα ΣΣκ ανιχνεύθηκαν σε 41.7% (90/216) ασθενείς που αξιολογήθηκαν (19% σε ισχυρά θετικούς, 22.7% σε μετρίως ισχυρά θετικούς τίτλους) χωρίς σημαντικές διαφορές μεταξύ anti-Ro/SSA θετικών και αρνητικών ομάδων. Ισχυρά θετικοί τίτλοι ήταν σημαντικά συχνότεροι σε ασθενείς με βιοψίες ΕΣΑ που πληρούσαν τα ιστοπαθολογικά κριτήρια για σS (30% έναντι 12.5%, p=0.009). Αυτή η συσχέτιση παρέμεινε σημαντική μετά από τροποποίηση για αντισώματα έναντι Ro/SSA και La/SSB αυτοαντιγόνα [OR 95% (CI): 4.1 (1.5-10.6)]. Συμπεράσματα: Τα ειδικά αυτοαντισώματα ΣΣκ ανιχνεύονται συχνά σε ασθενείς που προσέρχονται με συμπτώματα ξηρότητας, και σε ισχυρά θετικούς αλλά όχι μετρίως ισχυρά θετικούς τίτλους εμφανίζουν συσχέτιση με τη θετικότητα βιοψίας ΕΣΑ. Συνολικά, τα δεδομένα αυτά υπονοούν ένα χρήσιμο ρόλο του ελέγχου για αντισώματα ΣΣκ στη διαγνωστική προσέγγιση και πιθανότατα στα διαγνωστικά κριτήρια για σS.Sjögren’s syndrome (SS) is a chronic, autoimmune disease with an indolent course characterized by ocular and oral dryness, as a result of lymphocytic infiltration of salivary and lachrymal glands. Although it is generally considered a benign syndrome affecting mainly middle-aged women, many patients suffer from fatigue, pain, and extra glandular symptoms, often worsening quality of life. Τhough exact pathogenesis is still unclear, over the last decades, it was consistently shown that type I interferon (IFN) pathway activation is a crucial event with type I IFN inducible genes being upregulated in both peripheral blood and salivary gland tissues derived from these patients contributing to B cell activation and autoantibody production against Ro/SSA and La/SSB antigens. While anti-Ro/SSA and/or anti-La antibodies have been a major component in previously adopted classification criteria for SS, in a significant subset of SS patients these are absent. Moreover, patients with systemic sclerosis (SSc) classicaly characterized by Raynaud’s phenomenon and hardening of the skin have been also shown to display sicca symptomatology, with a subset of SS pateints having in their serum antibodies against centromere antigens. Over the last years, an array of novel specific SSc antibodies was identified in association with distinct clinical and prognostic phenotypes among patients with SSc. In view of this data, we aimed to elucidate the prevalence and possible clinical implications of these SSc-specific autoantibodies in consecutive patients presenting with sicca complaints. Towards this end, we evaluated the presence of serum specific autoantibodies in consecutive patients with sicca complaints referred to the Molecular and Applied Physiology Unit, Department of Physiology, Medical School of Athens, National and Kapodistrian University of Athens, Greece. We found that SSc-specific autoantibodies were often present in sicca individuals [41.7% (90/216) patients evaluated (19% at strong, 22.7% at medium titers)]. Of note, SSc-specific autoantibodies at strong titers were significantly more often detected in patients with minor salivary gland (MSG) biopsies compliant with current SS histopathological criteria (30% vs. 12.5%, p=0.009), an association that remained significant after adjustment for antibodies against Ro/SSA and La/SSB autoantigens [OR 95% (CI): 4.1 (1.5-10.6)]. Theoretically, if SSc-specific autoantibodies at strong titers held the same burden in SS classification as anti-Ro/SSA antibodies, approximately one-third of seronegative (anti-Ro/SSA negative) sicca patients with negative or unknown MSG biopsy would be characterized as suffering from SS. Furthermore, MSG biopsies from sicca patients with strong positive SSc-specific autoantibodies weew characterized by remarkable periductal fibrosis independently of the presence of lymphocytic infiltration. This finding fuels an alternative hypothesis of the mechanism of MSG dysfunction in SS, remaining unknown at present if we are upon a distinct clinical entity or a subgroup of SS. A prospective matched and blinded study quantitating the amount of fibrosis in MSG biopsies from sicca patients with distinct serological reactivities would help elucidate this hypothesis. Our main findings are summarized in the following previously presented abstracts in the published articles: Abstract of the article “Type I interferon signature in Sjögren’s Syndrome: Pathophysiological and clinical implications.” https://pubmed-ncbi-nlm-nih-gov.e.bibl.liu.se/31376268/ Reference: Nikolaos Marketos, Ilir Cinoku, Anna Rapti, Clio P. Mavragani Type I interferons (IFN) have long been recognized as mediators of innate immune defense mechanisms against viral threats. Robust evidence over the last 15 years revealed their significant role in the pathogenesis of systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Despite the progress, methods of detection, initial triggers, biological functions, and clinical associations in the setting of autoimmunity remain to be fully clarified. As therapeutic options for SS are currently limited, neutralizing specific targets of the type I IFN pathway seems a promising alternative. In this review, we summarize the current evidence regarding the role of type I IFN in SS. Abstract of the article: “Scleroderma-specific autoantibodies: Should they be included in the diagnostic work-up for Sjögren’s syndrome?” https://doi.org/10.1016/j.semarthrit.2022.152026 Reference: Nikolaos Marketos , Vasiliki Koulouri , Evangelia P. Piperi , Maria E. Georgaki , Nikolaos G. Nikitakis , Clio P. Mavragani Objectives: Sicca complaints are a frequent reason for rheumatologic consultation. Testing for specific antibodies against Ro/SSA and La/SSB antigens and minor salivary gland (MSG) biopsy are among the main tools implemented in the diagnostic work-up. Anticentromere antibodies and sicca manifestations are frequently detected in Sjögren’s syndrome (SS) and systemic sclerosis (SSc), respectively. Herein, we aimed to determine the frequency and clinical associations of a wide spectrum of scleroderma (SSc)-specific autoantibodies in consecutive patients referred for evaluation of possible SS. Methods: Demographic, clinicopathological, and laboratory data were recorded in 216 consecutive patients with sicca complaints. All study participants were tested for SSc-specific autoantibodies (against CENP, PM/Scl, Scl-70, Ku, NOR90, RP11, RP155, fibrillarin, PDGFR, and Th/To) using a commercially available immunoblot kit. According to band intensity, the identified autoantibodies were further classified in those with strong and medium titers. Results: SSc-specific autoantibodies were detected in 41.7% (90/216) patients evaluated (19% at strong, 22.7% at medium titers) without significant differences between anti-Ro/SSA positive and negative groups. At strong titers was significantly higher in patients with MSG biopsies fulfilling SS histopathological criteria (30% vs. 12.5%, p=0.009). This association remained significant after adjustment for antibodies against Ro/SSA and La/SSB autoantigens [OR 95% (CI): 4.1 (1.5-10.6)]. Conclusion: SSc-specific autoantibodies are frequently detected among patients presenting with sicca complaints and at strong but not medium titers are independently associated with MSG biopsy positivity. Taken together, these data imply a useful role of SSc antibody testing in the diagnostic work-up and possibly in the classification criteria for SS

Clinical Features of Autoimmune Autonomic Ganglionopathy and the Detection of Subunit-Specific Autoantibodies to the Ganglionic Acetylcholine Receptor in Japanese Patients

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the α3 and β4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-α3 and -β4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG

Serum SmD autoantibody proteomes are clonally restricted and share variable-region peptides

This article is under embargo for 12 months from the date of publication [Publication date: 7 Jan 2015] in accordance with publisher copyright policy.Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)- region peptide signatures to be derived from human autoantibodies present in complex serum mixtures. Here, we analysed the clonality and V-region composition of immunoglobulin (Ig) proteomes specific for the immunodominant SmD protein subunit of the lupus-specific Sm autoantigen. Precipitating SmD-specific IgGs were eluted from native SmD-coated ELISA plates preincubated with sera from six patients with systemic lupus erythematosus (SLE) positive for anti-Sm/RNP. Heavy (H)- and light (L)-chain clonality and V-region sequences were analysed by 2-dimensional gel electrophoresis and combined de novo database mass spectrometric sequencing. SmD autoantibody proteomes from all six patients with SLE expressed IgG1 kappa restricted clonotypes specified by IGHV3-7 and IGHV1-69 H-chains and IGKV3-20 and IGKV2-28 L-chains, with shared and individual V-region amino acid replacement mutations. Clonotypic sharing and restricted V-region diversity of systemic autoimmunity can now be extended from the Ro/La cluster to Sm autoantigen and implies a common pathway of anti-Sm autoantibody production in unrelated patients with SLE