Funkcija štitaste žlezde i prisustvo antitireoidnih autoantitela kod bolesnika sa sistemskim bolestima vezivnog tkiva

Autoimmune thyroid disease (ATD) has been described in patients with connective tissue diseases (CTD). The aim of this study was to estimate and compare the prevalence of ATD in a group of 91 CTD patients, and in their subgroups: 53 systemic lupus erythematosus (SLE), 24 rheumatoid arthritis (RA), 7 primary Sjogren’s syndrome (SSy) and 7 progressive systemic sclerosis (SSc) patients. A control group of 34 healthy blood volunteers was used for comparison. Serum levels of free thyroxine (FT4), thyroid stimulating hormone (TSH), as well as thyroid autoantibodies (Abs) specific of thyroperoxidase (TPO) and thyroglobulin (TG) were examined. CTD patients, in general, as well as SLE and RA subgroups, had significantly higher number of thyroid dysfunction than the control group (p lt 0.05). The most prominent thyroid dysfunction was subclinical hypothyroidism, with a higher prevalence in all subgroups of patients when compared to the control. Anti-TPO Abs were detected in a significant number of CTD patients, especially in SLE subgroup when compared to the control group. It was also found that a higher number of CTD patients, SLE and RA subgroups, had positive anti-Tg Abs, when compared to the control subjects. In conclusion, the prevalence of ATD in CTD patients was more frequent than in the control group. The patients with anti-TPO Abs and anti-Tg Abs at the time when they were analyzed, had hyperthyroidism, hypothyroidism or were clinically and biochemically euthyroid. The prevalence of hypothyroidism was greater than the prevalence of hyperthyroidism in all subgroups of patients.Autoimunske bolesti štitaste žlezde (AITD) opisane su kod bolesnika sa sistemskim bolestima vezivnog tkiva (SBVT). Cilj ovog rada bio je da se ispita prevalencija AITD u grupi od 91 bolesnika sa SBVT, koja je uključila 53 bolesnika sa sistemskim eritemskim lupusom (SLE), 24 obolelih sa reumatoidnim artritisom (RA) i po 7 obolelih od primarnog Sjogrenovog sindroma (SSy) i progresivne sistemske skleroze (SSc). Kontrolnu grupu ispitanika činila su 34 dobrovoljna davaoca krvi. Kod svih učesnika u studiji merene su serumske koncentracije slobodnog tiroksina (FT4), tireostimulišućeg hormona (TSH), kao i autoantitela specifičnih za tireoperoksidazu (anti-TPO At) i tireoglobulin (anti-Tg At). U grupi bolesnika sa SBVT, kao i u podgrupama obolelih od SLE i RA, nađena je statistički značajno veća učestalost poremećaja funkcije štitaste žlezde u odnosu na kontrolnu grupu (p lt 0.05), a od svih poremećaja funkcije štitaste žlezde najčečće je detektovana subklinička hipotireoza. Anti-TPO At nađena su kod značajno većeg broja bolesnika sa SBVT i SLE, u odnosu na kontrolnu grupu. Isto tako, i anti-Tg At su detektovana kod većeg broja ispitanika u grupi SBVT, i podgrupama SLE i RA, nego kod zdravih osoba. U zaključku, prevalencija AITD kod obolelih od SBVT veća je nego u kontrolnoj grupi. Bolesnici sa anti- TPO At i anti-Tg At u vreme kada su analizirani, imali su subkliničku ili klinički manifestnu hipotireozu ili hipertireozu, ili su još bili u stadijumu bolesti u kome se ne može detektovati poremećaj funkcije štitaste žlezde. Prevalencija hipotireoze bila je veća od prevalencije hipertireoze u svim podgrupama bolesnika sa SBVT

Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides

Clinical and serological profiles of idiopathic and drug-induced autoimmune diseases can be very similar. We compared data from idiopathic and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA)-positive patients. From 1993 to 2003, 2474 patients were tested for ANCA in the Laboratory for Allergy and Clinical Immunology in Belgrade. Out of 2474 patients, 72 (2.9%) were anti-proteinase 3 (PR3)- or anti-myeloperoxidase (MPO)-positive and their clinical and serological data were analyzed. The first group consisted of ANCA-associated idiopathic systemic vasculitis (ISV) diagnosed in 56/72 patients: 29 Wegener's granulomatosis (WG), 23 microscopic polyangiitis (MPA) and four Churg-Strauss syndrome. The second group consisted of 16/72 patients who became ANCA-positive during ATD therapy (12 receiving propylthiouracil and four receiving methimazole). We determined ANCA and antinuclear (ANA) antibodies by indirect immunofluorescence; PR3-ANCA, MPO-ANCA, anticardiolipin (aCL) and antihistone antibodies (AHA) by ELISA; and cryoglobulins by precipitation. Complement components C3 and C4, alpha-1 antitrypsin (α1 AT) and C reactive protein (CR-P) were measured by nephelometry. Renal lesions were present in 3/16 (18.8%) ATD-treated patients and in 42/56 (75%) ISV patients (p <0.001). Skin lesions occurred in 10/16 (62.5%) ATD-treated patients and 14/56 (25%) ISV patients (p <0.01). ATD-treated patients more frequently had MPO-ANCA, ANA, AHA, aCL, cryoglobulins and low C4 (p <0.01). ISV patients more frequently had low α1 AT (p = 0.059) and high CR-P (p <0.001). Of 16 ATD-treated patients, four had drug-induced ANCA vasculitis (three MPA and one WG), while 12 had lupus-like disease (LLD). Of 56 ISV patients, 13 died and eight developed terminal renal failure (TRF). There was no lethality in the ATD-treated group, but 1/16 with methimazole-induced MPA developed pulmonary-renal syndrome with progression to TRF. ANCA-positive ISV had a more severe course in comparison with ATD-induced ANCA-positive diseases. Clinically and serologically ANCA-positive ATD-treated patients can be divided into two groups: the first consisting of patients with drug-induced WG or MPA which resemble ISV and the second consisting of patients with LLD. Different serological profiles could help in the differential diagnosis and adequate therapeutic approach to ANCA-positive ATD-treated patients with symptoms of systemic disease

Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis (vol 49, pg 598, 2022)

J Rheumatol 2022; doi: 10.3899/jrheum.210931 In the Methods section, under the subheading “Follow-up and study outcome,” the last sentence should be as follows: “All new DUs were recorded by contacting all 39 patients once every 1–3 months during follow-up.” The error does not affect the results or conclusions of the study. This correction only applies to the April 1 First Release. The correct text appears in the print and online issues

Influence of promoter polymorphisms of the TNF-α (-308G/A) and IL-6 (-174G/C) genes on therapeutic response to etanercept in rheumatoid arthritis

Uvod: Genetički faktori su značajni za predviđanje ishoda lečenja bolesnika sa reumatoidnim artritisom (RA). Cilj studije bio je da se ispita uticaj-308G/A TNF-α (rs 1800629) i -174G/C IL-6 (rs1800795) promotorskih polimorfizama na terapijski odgovor na etanercept. Metode: U studiju su bila uključena 73 pacijenta sa aktivnim RA. Terapijski odgovor je procenjivan posle 6 i 12 meseci terapije po kriterijumima Evropske lige protiv reumatizma. Genotipizacija pacijenata za polimorfizme -308G/A TNF-α i -174G/C IL-6 urađena je PCR-RFLP metodom i procenjivan je uticaj genotipova na odgovor na etanercept. Rezultati: Nije bilo razlike u procentu respondera (pacijenti kod kojih se DAS28 popravio gt 1,2) između pacijenata sa TNF-α -308GG, GA i AA genotipom ni posle 6 ni posle 12 meseci tretmana. Posle 12 meseci lečenja procenat respondera je bio značajno veći kod pacijenata sa IL-6 -174GG u odnosu na pacijente sa GC ili CC genotipom (p= 0,006, x2 test). Poređenje pacijenata prema kombinovanim IL-6/TNF-α genotipovima pokazalo je da je IL-6 -174GG / TNF-α -308GG genotip učestaliji kod respondera u odnosu na druge kombinovane genotipove (p= 0.022, x2 test). Tačnije, svi pacijenti sa kombinovanim IL-6 -174GG / TNF-α -308GG genotipom bili su responderi posle 12 meseci terapije etanerceptom. Zaključak: Studija pokazuje da bolesnici sa genotipovima koji se povezuju sa manjom produkcijom TNF-α i IL-6 najbolje odgovaraju na terapiju etanerceptom.Background: The study was undertaken to assess the influence of functional -308G /A TNF-α (rs 1800629) and -174G/C IL-6 (rs1800795) promoter polymorphisms on the therapeutic response to etanercept, a TNF-α blocker, in patients with rheumatoid arthritis (RA). Methods: Seventy-three patients suffering from active RA were studied, at baseline and 6 and 12 months after therapy. The therapeutic response was estimated according to the European League Against Rheumatism response criteria. Patients were genotyped for -308G /A TNF-α and -174G/C IL-6 polymorphisms by the PCR-RFLP method, and the influence of genotype on etanercept response was assessed. Results: No difference in the percentage of responders (patients who had DAS28 improvement gt 1.2) between patients with the TNF-α -308GG and GA and AA genotype was detected after 6 and 12 months of treatment. After 12 months of treatment the percentage of responders was significantly increased in patients with the IL-6 -174GG genotype compared with those with the GC or CC genotype (p=0.006 by Chi-square test). Evaluation of the patients according to their combined IL-6/TNF-α genotypes showed that patients with the IL-6 -174GG / TNF-α -308GG genotype were more frequent among the responders compared to those with other combined genotypes (p=0.022 by Chisquare test). More precisely, all patients with the combined IL-6 -174GG / TNF-α -308GG genotype were responders after 12 months of etanercept treatment. Conclusions: The study suggests that patients who are genetically low TNF-α and IL-6 producers are the best responders to etanercept therapy

Exploring the Link between Hydrodynamic Size and Immunoglobulins of Circulating Immune Complexes in Rheumatoid Arthritis Patients

The function of immune complexes in rheumatoid arthritis (RA) is related to their composition and size. Using dynamic light scattering (DLS), we investigated the link between the RA circulating immune complex (CIC) particles’ size and the CIC immunoglobulin level. In this study, 30 RA patients and 30 healthy individuals were included. IgA, IgG, and IgM were found in all analyzed CICs, but more IgA and IgG were found in RA than in control CICs. In both control and RA CICs, DLS detected 50 particles that differed in size and clustered around two size groups: with a 7.5–164 nm radius and with a 342–1718 nm radius. An increased level of IgA in RA CICs, compared to control ones, was associated with more than 50% of CIC particles. In RA, compared to the control, a higher number of CICs with 28.2 nm, 531 nm, 712 nm, and 1718 nm particles and a lower number of CICs with 78.8 nm particles were detected. This particle distribution pattern did not reflect the changes in the CIC immunoglobulin level. Thus, RA elevated CIC IgA was linked with all these particles (except the 1718 nm particle), the IgM increase was linked with 43.8 nm and 712 nm particles, and the IgG increase was linked with the 712 nm particle only. This study provides the very first data on the association between CIC particles’ size, CIC immunoglobulin level, and RA. It opens the possibility that the size of CICs determined by DLS can be used as a criterion in RA diagnosis or monitoring after a large-scale study confirmation

Influence of Promoter Polymorphisms of the Tnf-α (-308g/A) and IL-6 (-174g/C) Genes on Therapeutic Response to Etanercept in Rheumatoid Arthritis

Background: The study was undertaken to assess the influence of functional -308G/A TNF-alpha (rs 1800629) and -174G/C IL-6 (rs1800795) promoter polymorphisms on the therapeutic response to etanercept, a TNF-alpha. blocker, in patients with rheumatoid arthritis (RA). Methods: Seventy-three patients suffering from active RA were studied, at baseline and 6 and 12 months after therapy. The therapeutic response was estimated according to the European League Against Rheumatism response criteria. Patients were genotyped for -308G/A TNF-alpha and -174G/C IL-6 polymorphisms by the PCR-RFLP method, and the influence of genotype on etanercept response was assessed. Results: No difference in the percentage of responders (patients who had DAS28 improvement > 1.2) between patients with the TNF-alpha -308GG and GA and AA genotype was detected after 6 and 12 months of treatment. After 12 months of treatment the percentage of responders was significantly increased in patients with the IL-6 -174GG genotype compared with those with the GC or CC genotype (p=0.006 by Chi-square test). Evaluation of the patients according to their combined IL-6/INF-alpha genotypes showed that patients with the IL-6 -174GG / TNF-alpha -308GG genotype were more frequent among the responders compared to those with other combined genotypes (p=0.022 by Chi-square test). More precisely, all patients with the combined IL-6 -174GG / TNF-alpha -308GG genotype were responders after 12 months of etanercept treatment. Conclusions: The study suggests that patients who are genetically low TNF-alpha and IL-6 producers are the best responders to etanercept therapy

J.Serb.Chem.Soc. 67 (8–9)567–572(2002) UDC 577.153.004.12:582.998.2 JSCS–2977 Original scientific paper

Isolation and partial characterization of an acid phosphatas

Physicochemical and immunologic characterization of low molecular-weight allergoids of Dactylis glomerata pollen proteins

Background: Orchard grass (Dactylis glomerata) pollen proteins were chemically modified by means of acid anhydrides (maleic and succinic anhydride) to obtain low-molecular-weight allergoids. Chemical modification in both cases led to the replacement of one positive charge (epsilon amino group of Lys) by one negative charge, yielding proteins with changed physicochemical properties in comparison to the native orchard grass-pollen proteins. Methods: Physicochemical characterization of derivatives was done by gel chromatography, SDS-PAGE, and isoelectric focusing. To examine the IgE-binding properties of these derivatives, we carried out immunoblotting. To examine the ability of derivatives to induce IgG production, we immunized rabbits. Skin prick testing with the allergoids was performed on 15 individuals allergic to orchard grass pollens and on two healthy subjects. Results: II was shown that the modified proteins retain their original molecular weights, but change pi to more acidic values. In the case of allergoids, a strong reduction in IgE binding was found. Immunization of rabbits with allergoids showed that the derivatives retain the ability to induce IgG production, and that the antisera obtained in such a way react to native (unmodified) extract. The ability of derivatives to induce allergic reaction was significantly reduced. The patients (86.6%) included in our study exhibited less than 50% of native extract response. Among them, 53.3% had no response to one or both allergoids. Conclusions: These modification procedures yield allergoids with a reduced allergenic activity and preserved immunogenic potential suitable for use in immunotherapy

Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis

Objective. To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease. Methods. We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naive) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored. Results. Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P lt 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0-1.1 and OR 1.2, 95% CI 1.1-1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs. Conclusion. Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc