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Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.

Hereditary angioedema (HAE), an inherited deficiency offunctional C1 esterase inhibitor (C1-INH), is characterized byrecurrent episodes of disabling and often painful swelling insubcutaneous and/or submucosal tissues.1HAE attacks aregenerally unpredictable, but triggers for an attack can includehaving a dental or medical procedure (eg, surgery), other trauma,or stress. A preemptive management plan for patients under-going these types of situations may reduce the risk of HAE at-tacks. Recommendations include administration of short-termprophylaxis in patients with HAE before invasive medical pro-cedures, especially those involving the upper airways or digestivetract, with C1-INH concentrate typically the medication ofchoice.

Adults with systemic anaphylactic reactions (SAR) to insect sting show often multiple-positivity of serum-specific IgE (sIgE) to Hymenoptera venoms. Unnecessary long-lasting venom-specific immunotherapies (VIT) in false-positive patients increase the risk of recurrent SAR. This report aims to analyze the diagnostic importance of recombinant allergen IgE testing in patients with SAR to Hymenoptera sting.In 82 patients we measured sIgE to honeybee venom (HBV), wasp venom (WV) and hornet venom (HV) extracts, recombinant phospholipase A2 from HBV (sIgE-rApi m1), recombinant antigen 5 from WV (sIgE-rVes v5), and cross-reactive carbohydrate determinants-CCD-bromelain by ImmunoCAP. We analyzed the correlation of ImmunoCAP and Immunoblot for HBV and WV extracts, rApi m1, and rVes v5 in 39/82 patients. According to the history of the culprit insect, we compared sensitivity and specificity between the two methods.The severity of the SAR does not depend on the sIgE level to venom extracts and recombinant allergens. Fifty-one percent of the patients had a multiple-positivity to HBV/WV or HBV/WV/HV extracts. Severe SAR and CCD-sIgE were more frequent in multiple-positive than single-positive patients. CCD-sIgE were more frequent in HBV allergic patients than WV and HV allergic patients. There was a significant correlation between levels of sIgE to venom extracts and recombinant allergens measured by ImmunoCAP and Immunoblot. ImmunoCAP has higher sensitivity and specificity than Immunoblot for diagnosis of SAR to Hymenoptera venoms.IgE testing to recombinant CCD-free allergens is necessary for the adequate selection of long-lasting VIT, especially in patients with multiple sensitivities to venom extracts.

Introduction. Triple-positivity (TP) or double-positivity (DP) for serum-specific immunoglobulin E (sIgE) antibodies against hornet venom (HV), wasp venom (WV) and/or honeybee venom (BV) causes significant problem in a selection of appropriate venom immunotherapy. However, DP/TP can be caused by cross-reactions resulting either from partial sequence identity of protein allergens in the venoms, or may be related to cross-reacting carbohydrate determinants (CCDs). Case report. A 60-year-old man was stung by a wasp and two days later by hornet. In both cases, within 15 minutes he developed hypotension and generalized urticaria and he was successfully treated with epinephrine, corticosteroids and fluids. After eight weeks, the examination revealed the negative skin prick test for all three venoms, but the sIgE-determination (ELISA, Biopharm) showed triple sensitization to native BV (0.55 IU/mL), WV (3.35 IU/mL) and HV (0.37 IU/mL). He was receiving the venom immunotherapy with venom mixtures for one year. In order to distinguish true multiple sensitization from cross-reactivity, the molecular-allergy testing by ImmunCAP with the CCD-free recombinant major allergens was performed. A high sensitization to Antigen 5-rVes v5 of WV (31.4 kU/L) was demonstrated while sIgE to phospholipase A2-rApi m1 of BV (0.15 kU/L) was negative; sIgE to CCDMUXF3- bromelain (0.75 kU/L) explained the sIgE-positivity for native BV. After these findings, a venom immunotherapy only with WV was initiated. Conclusion. In our patient, triple-IgE-positivity to native venoms detected by the ELISA was caused by cross-reactivity to CCDs. We recommend the molecular-allergy testing with the nonglycosylated recombinant allergens before starting the venom immunotherapy in patients with multiple-sIgE-positivity to native Hymenoptera venoms.

The etiology of recurrent aphthous stomatitis (RAS) remains unknown. RAS can be presented as primary, idiopathic condition and as a secondary RAS, which is associated with a systemic disease. The aim of our study was to evaluate the presence and concentrations of antibodies specific for celiac disease (CeD) and antibodies related to inflammatory bowel diseases (IBD) in patients with RAS without gastrointestinal symptoms. Antibodies against tissue transglutaminase (anti-tTG), deaminated gliadin peptides (DGP), deaminated gliadin-analogous fragments (anti-GAF-3X) and Saccharomyces cerevisiae (ASCA) were determined by ELISA and antineutrophil cytoplasmic antibodies (ANCA) by indirect immunoflurescence (IIF) in 57 patients with RAS and 60 control subjects. The prevalence of CeD specific antibodies did not differ between RAS patients and controls. However, the concentrations of IgA anti-tTG, IgA anti-GAF-3X antibodies in patients with RAS were significantly higher compared to controls (p = 0.002 and p = 0.04 respectively). Histological changes consistent with CeD were confirmed by duodenal biopsy in one RAS patient with highly positive IgA anti-tTG, anti-GAF-3X and anti-DGP antibodies. Higher prevalence along with higher concentrations of IgG ASCA were found in RAS patients compared to controls (p < 0.01). Patients with positive IgG ASCA in the absence of clinical symptoms decided not to pursue any further testing. Dysfunction of oral mucosa and the exposure to various antigens might be a reason for the loss of tolerance resulting in increased production of autoantibodies. It seems likely that antibodies are markers of aberrant immune response, rather than key effectors involved in the pathogenesis of the disease..

Summary Background Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. Methods We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Findings Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p Interpretation Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. Funding Pharming Technologies.

Background/Aim. Common variable immunodeficiency (CVID) is an immunologically and clinically heterogeneous disorder. Disturbed cytokine production is implicated in dysfunctional immune response. The aim of this study was to investigated B-cell activating factor (BAFF) and interleukin (IL)- 10 levels in CVID patients. Methods. The study included 28 CVID patients diagnosed and followed during a 20-year period (mean follow-up 14.5 years). Control groups consisted of 4 patients with X-linked agammaglobulinemia (XLA) and 21 healthy subjects. According to clinical characteristics, the CVID patients were divided into four groups which partly overlap: chronic pulmonary diseases (n = 21), splenomegaly (n = 13), autoimmune diseases (n = 9) and patients with recurrent infections despite regular intravenous immunoglobulin (IVIg) substitution (n = 4). The serum levels of BAFF and IL-10 were measured by commercial ELISA. Results. The BAFF levels were found to be higher in all CVID patients compared to the healthy controls (p < 0.01). The most significant differences were observed in the patients with pulmonary diseases and splenomegaly (p < 0.0001). Also, concentrations of IL-10 were higher in all CVID patients in comparison with the XLA patients (p < 0.05) and healthy subjects (p < 0.01). A statistically significant positive correlation (r = 0.86; p < 0.01) was found between the levels of BAFF and IL-10 in the CVID patients with autoimmune diseases. We demonstrated that the CVID patients with chronic pulmonary diseases had higher levels of IL-10, while the CVID patients with recurrent infections had higher BAFF concentrations in comparison to the patients without these features (p < 0.05). Conclusion. In spite of the limited number of patients, this is the first report from Serbia, examining the serum levels of BAFF and IL-10 in the CVID patients. Our study showed significantly increased concentrations of serum BAFF and IL-10 in the patients with CVID compared to the healthy subjects. Further studies are needed to confirm our findings that the BAFF levels are more pronounced in patients with recurrent infections while IL-10 levels are higher in patients with chronic pulmonary diseases. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175065]

Introduction Patients with hereditary angioedema (HAE) are at risk for an acute attack after medical procedures. Short-term prophylaxis may minimize this risk. This study evaluated recombinant C1 esterase inhibitor (rhC1-INH) as short-term prophylaxis. Methods Patients with angioedema were treated with rhC1-INH prior to medical procedures/stressful life events; HAE attacks were recorded through 2 days and >2-7 days postprocedure. Results Fifty-one patients (median age, 44 years [range, 17-73 years]; 62.7% female; 92.2% HAE type 1) were included. A median rhC1-INH dose of 3075 IU (range, 2100-4200 IU) was administered as prophylaxis, median of 60 minutes prior, for 70 procedures (52.9% [n=37] dental [median, 60 minutes preprocedure]); 30.0% [n=21] surgical [median, 45 minutes preprocedure]; 15.7% [n=11] endoscopy [median, 30 minutes preprocedure, and 1.4% [n=1] stressful life event). Majority (n=48; 68.6%) of 70 cases had rhC1-INH administered 10-65 minutes preprocedure: 25 of 48 (52.1%) dental, 16 (33.3%) surgical, and 7 (14.6%) endoscopy. Nineteen (27.1%) cases involved long-term prophylaxis (danazol/tranexamic acid). Overall, 97.1% (68/70) of cases did not have an HAE attack within 2 days postprocedure; 91.4% (64/70) during >2-7 days postprocedure. For 2 attacks occurring within 2 days, rhC1-INH was administered 230 minutes and ≥24 hours preprocedure, respectively. No adverse events were reported. As a self-control group, 76.9% of 26 cases with no long-term/short-term prophylaxis preprocedure had an attack within 2 days postprocedure. Conclusions Short-term prophylaxis with rhC1-INH, administered within several hours preprocedure, was efficacious and safe in adolescents/adults and reduced the risk of an HAE attack postprocedure.

We assessed the relationship between the serum levels of antibodies against double-stranded DNA (dsDNA), C1q, nucleosomes, histones, C3 and C4 complement components with one another, with organ involvement and overall disease activity in patients with systemic lupus erythematosus (SLE). One hundred seventy-five sera from 99 patients with SLE, 31 sera of patients with other connective tissue diseases, and 20 sera from healthy blood donors were tested. SLE disease activity was assessed by modified SLEDAI-2K (M-SLEDAI-2K), not including complement and anti-dsDNA descriptors. Anti-dsDNA antibodies were measured by indirect immunofluorescence on Crithidia luciliae (CLIFT), standard enzyme-linked immunosorbent assay (ELISA) and ELISA for high-avidity antibodies. The most significant risk factor for renal involvement were anti-C1q antibodies (OR = 3.88, p 0.05), high-avidity anti-dsDNA antibodies for polyserositis (OR = 7.99, p 0.01), anti-histone antibodies for joint involvement (OR = 2.75, p 0.05), and low C3 for cytopenia (OR = 11.96, p 0.001) and mucocutaneous lesions (OR = 3.32, p 0.01). Multiple linear regression analysis showed that disease activity in SLE could be predicted by the levels of antibodies against dsDNA determined by standard (p 0.05) and high-avidity (p 0.001) ELISA, and inversely associated with concentration of C3 (p 0.001). Using stepwise method, high-avidity anti-dsDNA antibodies were found to be in the closest association to M-SLEDAI-2K. Moreover, positive test for high-avidity anti-dsDNA antibodies appeared as an independent risk factor for moderately to severely active disease (M-SLEDAI-2K5) (OR = 5.5, p 0.01). The presence of high-avidity anti-dsDNA antibodies represented a risk for renal, joint, and most importantly for serosal involvement. Our results suggest that simple and reliable ELISA for high-avidity anti-dsDNA antibodies is the test of good clinical utility for the assessment of global SLE activity.

Mixed cryoglobulinemia is the most prevalent extrahepatic manifestation of chronic HCV infection. It is usually a benign lymphoproliferative disorder which presents as vasculitis affecting different organs. Although life-threatening cryoglobulinemic vasculitis (CryoVas) is rare, it is sometimes the first and possibly lethal complication. Its treatment depends on the severity of vasculitis and can be challenging. High dose of corticosteroids, immunosuppressive agents and plasma exchange represent the first-line treatment, which should be followed by antiviral therapy. Rituximab is an effective and safe treatment option. However, the data about its use in life-threatening conditions are scarce. We report the case of a patient with severe, relapsing and life-threatening HCV-related CryoVas resistant to standard therapy who had had an initial beneficial response to rituximab added to plasma exchange that was later compromised by the development of sepsis. We also review the literature and discuss manifestations and therapy of life-threatening Cryovas with focus on rituximab use.

Nonspecific interstitial pneumonia (NSIP) is often associated with connective tissue diseases (CTD). The diagnosis of NSIP was confirmed in a 63-year-old man by high-resolution computed tomography and an open lung biopsy. Anti-Golgi complex autoantibodies (AGA) and anti-Ro52 antibodies were simultaneously detected at high concentrations. Autoantibodies to aminoacyl-tRNA synthetases (ARS) were negative. The patient was treated with corticosteroids for six months. During the seven-year follow-up, NSIP had a slow progression and patient had not developed the clinical features of CTD. The present study potentially demonstrates that the autoimmune process elicited by AGA and/or Ro/SSA may play a role in promoting idiopathic NSIP independently of the typical ARS routes, which has not been reported thus far.

The production of autoantibodies against a vast array of self antigens, most notably double stranded (ds) DNA, characterized systemic lupus erythematosus (SLE). The purpose of this work is to study specific Ig fractions isolated from normal human serum (NHS) and their effect on the binding of anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies (Abs) to dsDNA. A fraction named immunoglobulin G (IgG)-reactive IgG was purified from total NHS IgG by absorption onto (CNBr)-activated Sepharose 4B linked to intact IgG molecules (IgG-Sepharose column). IgG-reactive IgG was co-incubated with systemic lupus erythematosus (SLE) patients serum and binding of the anti-dsDNA Abs to dsDNA was measured by enzyme-linked immunosorbent assay (ELISA). Co-incubation of SLE patients serum with IgG-reactive IgG resulted in a dose-dependent reduction in binding of anti-dsDNA Abs to dsDNA. A reduction greater than 70% was observed at a concentration of 300 mu g of IgG-reactive IgG per mL of a 400-fold diluted SLE patients serum whereas total NHS IgG, at the same concentration, resulted in a 10% reduction in binding. The purification process used to isolate IgG-reactive IgG was based on interactions between intact Ig rather than on interactions between F(ab)(2) portions. IgG(2) is the predominant immunoglobulin (Ig) subclass in IgG-reactive IgG. Thus, IgG(2) might have an important role in the connectivity characteristics of NHS IgG. The capacity of IgG-reactive IgG to inhibit anti-DNA Ab binding to dsDNA may have potential application in the treatment of SLE. This targeted biological approach may provide an alternative strategy to immunosuppressants. (C) 2011 Elsevier GmbH. All rights reserved.

Summary: The aim of this study was to investigate the influence of: autoantibodies (anticardiolipin, antioxLDL, anti-b2gpI, lupus anticoagulant), apolipoproteins (apo) AI and apoB, and homocysteine on the clinical features of patients with primary antiphospholipid syndrome, and to compare analyzed parameters with those from control subjects. Patients who were positive for anti-oxLDL antibodies had venous thrombosis associated with lower levels of apolipoprotein AI (p < 0.05). Patients with a history of thrombosis of peripheral arterial blood vessels had higher concentrations of apo B (p < 0.05) and this finding was also present in patients with a history of cerebrovascular insults (p < 0.05). Patients with myocardial infarction had significantly higher concentrations of homocysteine (p < 0.05). In patients with PAPS, testing the above-mentioned parameters is justified.

Background. Hashimoto's encephalopathy (HE) is a rare autoimmune syndrome characterized by various neuropsychiatric manifestations, responsive to steroid treatment and associated with Hashimoto's thyroiditis. There are only a few reports suggesting that intravenous immunoglobulins (IVIG) might represent an efficacious treatment modality for the severe steroid-resistant HE cases. We presented a patient with HE who developed a complete recovery after the IVIG therapy followed by a long-lasting remission. Case report. We described herien a female patient with the one-year history of autoimmune thyroiditis before the development of neuropsychiatric manifestations. In May 1999, a 38-year-old woman presented at the Institute of Neurology, Clinical Center of Serbia, Belgrade, with the brain-stem syndrome which responded well to steroid treatment. After detailed examinations, the diagnosis of Hashimoto's encephalopathy was established. Two years later, in June 2001, new manifestations (unsteadiness in gait, personality changes, seizures, and persistent headache) gradually developed during a 6-month period. Response to steroids was unsatisfactory and partial, since headaches and personality changes had continuously worsened. In January 2002, the patient received IVIG (0.4 g/kg body weight daily for 5 days). Gradual improvement was noticed and a complete recovery developed over the following weeks. Up to March 2009, during a 7-year follow-up period, remission persisted. Conclusion. To our best knowledge, this is the first report of a long-lasting remission of Hashimoto’s encephalopathy after IVIG therapy. Therefore, this case further supports administration of IVIG, as a potentially beneficial treatment modality, in severe cases of Hashimoto's encephalopathy which are completely or partially resistant to steroids.

Introduction. Watermelon stomach (WS) or gastric antral vascular ectasia (GAVE) is a rare cause of upper gastrointestinal bleeding described in a variety of autoimmune disorders. Association of watermelon stomach with Sj?gren's syndrome is extremely rare. Case report. We presented a 67-year old female with primary Sj?gren's syndrome (SS) who had developed a persistent severe iron-deficiency anemia. An upper gastric endoscopy revealed the presence of gastric antral vascular ectasia (GAVE) as a cause of occult gastrointestinal bleeding. The treatment with argon-plasma coagulation was postponed as the conservative therapy with iron substitution and proton pump inhibitor led to improvement of anemia and hemoglobin levels normalization. Conclusion. This is the first report of WS in a patient with primary SS without the presence of coexisting autoimmune disorder. Recognition of this rare, but clinically important, cause of gastrointestinal bleeding may decrease comorbidity in patients with autoimmune disorders including primary Sj?gren's syndrome.

We present a 43-year-old woman with relapsing–remitting multiple sclerosis (MS) who developed lupus syndrome after 32 months of IFN-β-1a therapy. She presented with malaise, myalgia, arthralgia and fever. Laboratory tests showed high erythrocyte sedimentation rate, anaemia and lymphopenia. Antibodies to double stranded DNA (dsDNA) of IgG, IgM and IgA classes were detected on Critidia luciliae. Additionally, high levels of anti-nucleosomal antibodies, low levels of anti-histone and anti-Ro/SSA antibodies were also found. Diagnosis of drug-induced SLE was established. Treatment with IFN-β was discontinued and oral prednisone was started. Twelve weeks after cessation of IFN-β therapy, the patient’s symptoms completely resolved and autoantibodies disappeared. To the best of our knowledge, this is the first report of a patient with MS in whom treatment with IFN-β induced lupus syndrome and antibodies to dsDNA and nucleosome.

Sera from Wistar rats subjected to different stress procedures were tested by ELISA for the presence of autoantibodies with specificity for neuron-specific enolase (NSE) and S100 protein that are preferentially localized in neurons and glia, respectively. Autoantibodies were present in sera of animals before exposure to stress, and raised with age. Anti-NSE and anti-S100 autoantibody levels were increased one day after termination of restraint (2 hours daily, 10 days) and electric tail shock (80 shocks daily, 19 days), and in fifth and tenth week of overcrowding stress. Differences between stressed and control animals were not present one month following restraint and electric tail shock and in twentieth week of overcrowding.

Background : Decreased activity of serum desoxyribonuclease I (DNase I) in systemic lupus erythematosus (SLE) has been reported, but its role as a biomarker in SLE is still unelucidated. Methods : Seventy-seven SLE patients (aged 39.6 ± 13.1 years) were studied for serum DNase I activity, levels of antinuclear (ANA), anti-dsDNA [high-avidity ELISA, conventional ELISA and indirect immunofluorescence (IIF)], anti-nucleosome, anti-histone antibodies, complement components C3 and C4. SLE disease activity was evaluated by disease activity index (SLEDAI-2K). Thirty-five patients were serologically and clinically followed for 3 – 12 months (mean 5.6 ± 2.8). Thirty-seven healthy blood donors were the control group. Results : DNase I activity in SLE patients was lower than in healthy controls (p < 0.01). DNase I activity was in positive correlation with SLEDAI-2K (p < 0.01), levels of ANA, anti-dsDNA, anti-nucleosome and anti-histone antibodies (p < 0.01) and in negative correlation with C3 concentration (p < 0.05). The highest correlation was found between DNase I activity and anti-dsDNA concentrations determined by high-avidity ELISA (r = 0.624), followed by IIF (r = 0.541) and conventional ELISA (r = 0.405). In the follow-up study, DNase I activity also correlated with SLEDAI-2K (p < 0.01). SLE patients with low DNase I activity more frequently had SLE-specific cutaneous lesions (p < 0.05). Conclusions : Monitoring of DNase I activity simultaneously with SLEDAI-2K might be a useful tool in the followup of SLE. An increase of DNase I activity characterized relapse in most SLE patients, although it did not reach the levels of healthy individuals. A decrease of DNase I activity in SLE flare-ups might be a functional biomarker of a subset of patients with specific dysfunction of apoptotic chromatin degradation.

We report a 69-year-old Caucasian female with non-Hodgkin's lymphoma who subsequently developed leg ulcers as a manifestation of the antiphospholipid syndrome. Investigations revealed a mixed cryoglobulinaemia with monoclonal IgM-kappa and antiphospholipid activity with anticardiolipin antibodies, antimitochondrial type M5 antibodies and lupus anticoagulant. Significantly increased concentration of anticardiolipin antibodies was detected in the cryoprecipitate. Our case illustrates a connection between cryoglobulinaemia and lymphoproliferative and autoimmune disorders. Both cryoglobulins and anticardiolipin antibodies could participate in the vascular damage. Cutaneous manifestations in the presence of these disorders associated with non-Hodgkin's lymphoma have not been described previously.

Granulomatosis with polyangiitis (GPA), also known as Wegener's granulomatosis, is a rare disease in childhood. Of 39 GPA patients that we diagnosed during a 20-year period, only 3 (7.7%) were younger than 18 years. We report the course of GPA in three girls whose disease started at the ages of 16, 11, and 6 years. All had cutaneous manifestations: the first had necrotizing vasculitis, the second had palpable purpura, and the third had right upper-eyelid edema and infiltration and proptosis caused by extraocular pseudotumor, initially histologically misdiagnosed as orbital immunoglobulin G4 (IgG4)-related disease. Unlike with skin vasculitis and glomerulonephritis, upper-airway and orbital inflammation were resistant to immunosuppressive therapy. Our report emphasizes that children presenting with cutaneous vasculitis, chronic eyelid swelling, sinusitis, or hoarseness should be tested for antineutrophil cytoplasmic antibodies. We emphasize that the upper-eyelid edema and infiltration, with histologic characteristics of orbital IgG4-related disease, may be the initial presentation of localized GPA in children, a feature that, until now, has been described only in adults.

BACKGROUND Dysregulation of antimicrobial response may trigger inflammatory bowel diseases (IBD). This study analyzed specificity of anti-neutrophil cytoplasmic antibodies (ANCA) in IBD patients and its clinical significance. METHODS Data from 52 ulcerative colitis (UC) patients with 32 Crohn's disease (CD) patients were compared. Primary sclerosing cholangitis (PSC) was present in 12/84 patients. ANCA, ANA and anti-smooth muscle antibodies (ASMA) were detected by IIF. ANCA were tested by ELISA for proteinase 3 (PR3), myeloperoxidase, bactericidal/permeability increasing protein, elastase, cathepsin G, lysozyme and lactoferrin. RESULTS pANCA were more frequently present in UC than in CD patients (p

Chronic infections may mimic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). We investigated which markers may help in the diagnosis and the prognosis of infections associated with proteinase 3 (PR3) and myeloperoxidase (MPO)-ANCA. In this study (1993–2008)—with an average follow-up of 5.1 years—we compared 66 AAV patients with 17 PR3 and/or MPO-ANCA-positive patients with protracted bacterial (11/17) or viral (6/17) infections. Seven of 17 patients had subacute bacterial endocarditis (SBE), while six of 17 patients had various autoimmune manifestations of chronic hepatitis C virus (HCV) infection. We determined ANCA, antinuclear antibodies, anti-PR3, anti-MPO, anticardiolipin (aCL), antibeta 2 glycoprotein I (β2-GP I), cryoglobulins, C3, and C4. Patients with infections were younger than AAV patients (p < 0.01). There was no difference in frequency of renal and skin lesions. AAV patients more frequently had pulmonary and nervous system manifestations (p < 0.01). Patients with infections more frequently had dual ANCA (high PR3, low MPO), aCL, anti-β2-GP I, cryoglobulins, and hypocomplementemia (p < 0.001). Immunosuppressive therapy (IST) was used in five 17 patients who had persistently high ANCA, cryoglobulinemia, and hypocomplementemia. There was no difference in frequency of lethality and renal failure in the two study groups. In patients who are PR3- and/or MPO-ANCA positive, SBE and HCV infection should be excluded. Although similar in renal and skin manifestations in comparison to AAV, only patients with infections developed multiple serological abnormalities. In patients with infections, concomitant presence of ANCA, cryoglobulins, and hypocomplementemia was associated with severe glomerulonephritis. The serological profile should be repeated after specific antimicrobial or surgical therapy, since some cases might require IST.

We present a patient who developed carbamazepine (CBZ)-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with high serum procalcitonin (PCT). The presentation (high fever, hepatosplenomegaly, leukocytosis), high PCT and CRP initially suggested sepsis, and he was treated with antibiotics, while CBZ was continued. The rash and hepatitis worsened. After withdrawal of CBZ, corticosteroid therapy was administered and the patient recovered with normalization of PCT. This case demonstrates that PCT may be increased in patients with DRESS. This is the first report of CBZ-induced DRESS associated with high PCT, and the second case of increased PCT in DRESS.

We compared serological and clinical presentation of 38 adults (5 males, 33 females) and 37 children (15 boys, 22 girls) with anti-endomysial antibodies (AEA). AEA, antinuclear (ANA), anti-parietal (APA), anti-thyroid microsomal (ATMA), anti-thyreoglobulin (ATGA), anti-smooth muscle (SMA) and anti-mitochondrial (AMA) antibodies were detected by IIF. Anti-tissue transglutaminase (tTG), anti-extractable nuclear antigens (ENA) and anti-actin (AAA) antibodies were studied by ELISA. There were no differences in frequency of ANA, APA, ATGA, SMA, AMA and AAA in children and adults. ATMA (p

The most important mitotic apparatus (MA) antigens are centrosome (CE), nuclear mitotic apparatus (NuMA-1, NuMA-2), midbody, and centromere F (CENP-F). We studied associations of anti-MA antibodies with other autoantibodies and their clinical significance. A total of 6270 patients were studied for the presence of anti-MA antibodies on HEp-2 cells. Sera positive for anti-MA were tested for anti-extractable nuclear antigens (ENA) antibodies. Anti-MA antibodies were detected in 56 (45 females and 11 males) of 6270 sera (0.9%). Of these 56, NuMA-1 was found in 23, NuMA-2 in 7, CE in 20, CENP-F in 5, and CENP-F/centrosome in 1 case. Anti-NuMA-1 were associated with anti-ENA antibodies (p < 0.001). Diagnoses were established in 43/56 patients: 22 connective tissue diseases, 7 infections, 6 autoimmune hepatitis, 3 vasculitis, 3 primary antiphospholipid syndrome, 1 malignancy, and 1 fever of unknown origin. The differential diagnosis of anti-NuMA-1-positive patients must include Sjogren's syndrome, while patients with anti-CE antibodies must be observed for HCV infection.

We report on a 28-year old patient with polycystic ovary syndrome (PCOS) who presented with fever and laboratory markers of inflammation. Her medical history was relevant for multiple ovulation inductions (OI) and ovarian hyperstimulation syndrome (OHSS). She had two miscarriages and one preterm delivery. Intracardiac thrombosis was diagnosed in the presence of antiphospholipid antibodies. We suggest that primary antiphospholipid syndrome (APS) was possibly triggered by OI.

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

The antiphospholipid antibody syndrome is a disorder characterised by the production of autoantibodies directed against negatively charged cell membrane phosholipids. Antiphospholipid antibodies have been described in various neurological disorders. It has been generally accepted that viral, bacterial, and parasitic infections can serve as a trigger factor for autoimmune reactions. Despite the growing knowledge that has accumulated, the relation between parasites and autoimmunity has not been clarified. Enterobius vermicularis (pinworm) is a nematode rarely found outside the gastrointestinal tract, but allergic reaction due to enterobiasis has been reported.1 We describe the case of transverse myelopathy preceded by intestinal pinworm infestation in the primary antiphospholipid antibody syndrome. To our knowledge, such an association has not been reported previously. Pinworm therapy was complicated by the Jarisch-Herxheimer reaction manifested by temporary exacerbation of pre-existing neurological symptoms. In March 1998, a 40 year old woman who complained of perianal itching noticed the presence of worms migrating from the anus. Three days later itching and numbness involved both legs, and the patient had weakness in the legs. These symptoms progressed over the next 3 days to severe paraparesis and urinary urgence. Her medical history was relevant for three unexplained miscarriages …