Increasing incidence of type 1 diabetes mellitus in young children in Slovakia.

OBJECTIVES: We aimed to study the prevalence of the early onset Type 1 diabetes in Slovakia during the years 1996-2017. BACKGROUND: Prevalence of Type 1 diabetes in young children is increasing worldwide. However, recent data from Slovakia are missing. METHODS: All children with newly diagnosed Type 1 diabetes included in the study were diagnosed in the Children Diabetes Centre in Bratislava during the years 1996-2017. The incidence of T1D in children aged below 3 and below 5 years was calculated and compared to the T1D incidence in older children. Incidence trends were calculated with the Poissed regression. RESULTS: Gender-adjusted incidence of T1D annually increased by 5.4 % (CI: 3.9-6.8; p < 0.001) in children <3 years, and by 3.4 % (95 % CI 2.2-4.6; p<0.001) in children <5 years during the last two decades. Moreover, the proportion of young children <3 years of age among all newly diagnosed children and adolescents increased over time (4.2±2.8 % in years 1996-1998; 12.2±5.8 % in years 2004-2008, and 13.7±7.4 % during the years 2013-2017). CONCLUSION: We found a significant increase in the incidence and proportion of T1D in young children during the last two decades. Similar data were also found in other European countries. This could be explained by changing environmental conditions (Fig. 1, Ref. 32).

Increased levels of soluble ST2 in patients with active newly diagnosed ANCA-associated vasculitis.

OBJECTIVE: ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA-associated vasculitides (AAV). METHODS: 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. RESULTS: Newly diagnosed AAV patients had higher sST2 levels than controls (P < 0.01). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (P < 0.001). IL-33 levels were higher in AAV patients than in the control groups (P = 0.002). However, serum IL-33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (P = 0.012). CONCLUSIONS: Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients.

Rituximab use in patients with ANCA-associated vasculitis: clinical efficacy and impact on immunological parameters.

Rituximab (RTX) was reported effective in ANCA-associated vasculitis (AAV). We aimed to evaluate clinical efficacy of RTX in AAV along with its impact on immunological parameters. Eighteen RTX-treated AAV patients (M/F 11/7; median age 37.5; 15× PR3-ANCA, 3× MPO-ANCA; 16× relapsing/refractory, 2× first-line therapy) were enrolled. Clinical response, ANCA, total serum IgG levels and cellular immunity parameters were examined. The patients were followed up (FU) for a median of 26 months (range 3-82, 15 for ≥6 months). All patients achieved B cell depletion (lasting 3-24 months). No significant increase was noted in T cell or NK cell subpopulations. At 6 months, partial remission was achieved in 5/15 patients (33 %) and complete in 8 (53 %). The median prednisone dose (30..10 mg/d) and ANCA levels (17.2..2.7 IU/mL) decreased (p < 0.01). RTX retreatment was used in nine (8× pre-emptive, 1× relapse). Six patients relapsed (none of the pre-emptively treated). Three patients died of infection. IgG levels at 3 months decreased compared to baseline (9.0 vs 5.7 g/L, p < 0.01). Higher percentage of HLA-DR+CD3+ cells and lower percentage of CD4+CD45RA+ naive T cells persisted during FU. IFN-γ production increased at 6 months compared to baseline (27.3 vs 41.5 %). No significant change was noted in the intracellular IL-10 and IL-12 production. RTX helped to lower the glucocorticosteroids dose and withdraw cytotoxic drugs in most AAV patients. Hypogammaglobulinaemia was common but well tolerated. Peripheral circulating T cells remained activated despite B cell depletion.

Association of systemic lupus erythematosus with low serum bilirubin levels.

OBJECTIVE: Systemic lupus erythematosus (SLE) is accompanied by severe oxidative stress. Bilirubin has been reported as a strong negative predictor of oxidative stress-mediated diseases, such as atherosclerosis. The objective of our study was to evaluate the association between serum bilirubin levels and SLE manifestation. METHODS: The study was performed with 259 SLE patients, diagnosed according to American Rheumatism Association (ARA) criteria. A subset of these patients, having normal hepatic function (n = 218, mean age 39.5 years), was studied in greater detail to eliminate the possible confounding effects of any underlying or drug-induced liver disease on the serum bilirubin levels. Age-matched healthy subjects (n = 180) served as the control group. A standard biochemical and immunological work-up was performed on all subjects. RESULTS: Compared to the controls, substantially lower levels of serum bilirubin were detected in SLE patients (p < 10⁻5); these were inversely correlated with disease activity and extent (p < 0.05). Furthermore, each 1 µmol/L decrease in serum bilirubin was associated with a 37% increase in the odds for a positive SLE status [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.28-1.47, p < 10⁻5]. Simultaneously, the odds of unconjugated hyperbilirubinaemia (a phenotypic sign of Gilbert's syndrome) were more than four times lower in SLE patients (OR 0.235, 95% CI 0.072-0.764, p = 0.016). CONCLUSION: Low serum bilirubin represented a strong predictor of the manifestation of SLE symptoms. The most likely explanation for this finding is the increased consumption of bilirubin due to the severe oxidative stress accompanying SLE. Subjects with higher serum bilirubin levels, such as those with Gilbert's syndrome, might be protected from the development of SLE.

Renal AA amyloidosis: survey of epidemiologic and laboratory data from one nephrology centre.

Renal amyloid involvement results, especially, from AL (primary) or AA (secondary) amyloidosis. The extent of amyloid tissue deposits in the kidneys and the clinical course of amyloidosis not only depend on the type of basic process but also reflect the time of diagnosis and the ability to affect the underlying disease. We analyzed laboratory and clinical data from patients with bioptically proven renal amyloidosis. Renal amyloidosis was found in 99 patients (4.65%) from an overall number of 2,128 renal biopsies (RB) performed in our department during a period of 11 years (from 1995 to 2006). AA amyloidosis was diagnosed in 46 patients. Nephrotic syndrome was diagnosed in 27 patients (59%) with AA amyloidosis; all these patients had different degrees of proteinuria. Impaired renal function was discovered in 24 patients (52%); in three of these patients (6.5%) we had to start renal replacement therapy. Patients were treated with corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biological therapy in various regimens. Nine patients (19.5%) died during the one-year follow-up period; complications such as sepsis and cardiac failure were the leading causes of death. Median survival in the AA group was 54 months. Although for approximately half of patients different treatment regimens can lead to a partial remission or disease stabilization, the prognosis of patients with amyloidosis could be regarded as unsatisfactory.

T cells in the pathogenesis of ANCA-associated vasculitis: current knowledge.

AAV are a group of systemic immune-mediated diseases with a strong and highly specific association with ANCA. In recent years, there has been increasing evidence that ANCA might play a direct pathogenic role in triggering AAV. Nevertheless, effectors of cell-mediated immunity prevail in the inflammation sites in patients with AAV. Numerous studies found increased markers of T-cell activation in AAV. Moreover, this activation persisted even in remission and despite treatment. Finally, successful therapeutic attempts using T cell-directed treatment were also reported. There has therefore been substantial evidence that T cells are involved in the pathogenesis of AAV, even though the exact mechanisms are yet to be elucidated. In this review, recent findings on the contribution of T cells to the pathogenic processes in AAV will be briefly summarized. Special emphasis will be placed on the Th1/Th2 concept, the role of T-regulatory cells, and the role of effector memory T cells in the pathogenesis of AAV.

Optimizing the therapeutic strategies in ANCA-associated vasculitis--single centre experience with international randomized trials.

ANCA-associated vasculitides, including Wegener's granulomatosis and microscopic polyangiitis, are systemic autoimmune diseases with poor prognosis in untreated patients, which can be dramatically improved by current therapeutic modalities. The aim of multi-centre randomized trials of the European Vasculitis Study Group is to optimise and standardise treatment of these diseases. From 1995-2001 our department contributed a total of 40 patients to the trials CYCAZAREM (cyclophosphamide versus azathioprine during remission for generalised vasculitis), MEPEX (plasma exchange versus methylprednisolone for severe renal vasculitis) and CYCLOPS (daily oral versus pulse cyclophosphamide during induction phase for generalised vasculitis). In this paper, we report on the preliminary results of long-term follow up of our patients included in international trials. The mean time of follow-up of the patients was 55.7 months with the patient survival rate of 72% and renal survival rate of 65%. Remission was achieved in 82% of patients, out of which 42% suffered a relapse. In generalised forms of vasculitides, treatment with cyclophosphamide is nowadays established as the standard therapy. The aim, however, is to further minimise its toxic effects by choosing the optimal therapeutic strategies. Complete results of all trials have not yet been published; nevertheless, the preliminary available data have already revealed new potential therapeutic approaches.

Associations between HLA class II alleles and type 1 diabetes mellitus in the Slovak population.

OBJECTIVES: Several associations between HLA complex and diabetes mellitus type IA were found in various groups of patients of Caucasoid population. This study was therefore prompted to be conducted in Slovak population, since any such has not yet been performed in Slovak population. METHODS: Patients suffering from DM-1A originated from all regions of Slovakia. Their age ranged from 1 to 42 years; but the criterion for including the subject to the study was the definition of diagnosis in older patients before their age of 15 (Table 1). The diagnosis was set up according to internationally accepted criteria. A total of 460 patients was typed for HLA-DQB1 alleles, among them 97 also for HLA-DQA1 and 146 for HLA-DRB1 alleles. HLA-typing was performed by a PCR-SSP method. Control group consisted of 196 (DQA), 143 (DQB1) and 130 (DRB1) unrelated blood donors aged 19-55 years old irrespective of their age or sex. The data obtained were expressed in a 2 x 2 contingency table and statistical significance was calculated by the Fisher exact test. RESULTS: Among 11 HLA-DQB1 alleles tested DOB1*0302 was the most frequent in DM-1A patients (30.33% vs. 5.59% in healthy subjects (HS), followed by DQB1*0201 (22.93% vs. 12.94%, respectively). In contrast, the frequency rate of DQB1*0301 (10.66% vs. 24.48%), DOB1*0602 (2.17% vs. 10.14%) and DQB1*0603 (2.5% vs. 8.39 %) were decreased in DM-1A patients. Out of 14 DQA1 alleles the highest occurrence rate showed DQA1*0301 (30.93% vs. 17.09) and DQA1*0501 (34.02% vs. 25.76%), while DQA1*0102 (8.76% vs. 16.58%) and DQA1*0201 (6.18 % vs. 13.51%7), respectively, were found to be the least frequent. Among 13 HLA-DRB1 alleles tested, the most common occurrence rates showed DRB1*03 (26.37% vs. 9.62%) and DRB1*04 (7.19% vs. 14.23%), while the least frequent alleles were DRB 1*15 (2.74% vs. 12.31%), DRB1*07 (7.19% vs. 14.23%), and DRB1*11 (2.74% vs. 20.38%). The alleles DQB1*0302 and DQA1*0301, respectively, were present in the same individual in all DRB1*04 positive patients, suggesting that they belong to the haplotype. Similar situation was observed with the alleles DQB1*0201, DQA1*0501, and DRB*0301, respectively, forming the second HLA haplotype so characteristic for DM1A.

Daily oral versus pulse intravenous cyclophosphamide in the therapy of ANCA-associated vasculitis--preliminary single center experience.

The aim of the multicentric randomized trial CYCLOPS is to optimize the treatment of induction of remission in patients with generalized, but not immediately life-threatening ANCA (antineutrophil cytoplasmic antibodies) -associated vasculitis. This will be achieved by reducing the dose of cyclophosphamide by administering it as intermittent pulses. The lower cumulative dose will be very probably accompanied with lower toxicity, whereas the effectivity should be comparable. We have enrolled 28 patients to the study. At present, 18 of them are suitable for evaluation. Our preliminary results show that pulse intermittent administration of cyclophosphamide is safer from the point of morbidity and mortality due to infectious complications. In our hands, this treatment modality does not seem to be less effective than the conventional daily oral cyclophosphamide. However, unambiguous results and treatment recommendations will not be available until the final evaluation of all patients enrolled in the trial.

ANCA-associated renal vasculitis--epidemiology, diagnostics and treatment.

The pauciimmune small-vessel vasculitides are multisystem diseases with frequent renal involvement. They are strongly associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). In this review we have focused on the ethiopathogenesis and the role of ANCA, clinical presentation and histopathologic findings of different ANCA - associated vasculitides (AAV). Current treatment strategies and the overall and renal outcome of patients with AAV are also discussed.

Current treatment strategies in ANCA-positive renal vasculitis-lessons from European randomized trials.

Antineutrophil cytoplasmic antibody (ANCA)-positive renal vasculitis is the most common cause of rapidly progressive (crescentic) glomerulonephritis. Its life-threatening natural course may be modified substantially by current treatment modalities. The European Vasculitis Study Group (EUVAS) developed a subclassification of ANCA-positive vasculitides based on the disease severity at presentation, and have organized (so far) two waves of clinical trials. The first wave of randomized clinical trials had the aim of optimizing the existing therapeutic regimens; the second wave concentrated on testing some newer therapeutic approaches. Here, the design and available results of the first wave and the design of some second wave trials are reviewed briefly. The potential of the new targeted approaches (e.g. anti-tumour necrosis factor therapy) is also briefly mentioned.

Clinical features and natural history of IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. It is characterized by recurrent gross hematuria, microhematuria and/or proteinuria and diffuse mesangial IgA deposits in glomeruli. It is predominantly a disease of young males. Apart from primary IgAN (Berger's disease), IgA deposits in the glomeruli are also seen in Henoch-Schönlein purpura and in association with various of other diseases, particularly liver cirrhosis. Originally it was thought that IgAN was a benign disease, but it is now known that approximately 20-40% of patients develop progressive renal disease 5 to 25 years after diagnosis and progress to end-stage renal disease. Clinical predictors of progressive disease are elevated serum creatinine concentration at presentation, increased systemic blood pressure, persistent protein excretion > 1.0 g/day and histological predictors are glomerulosclerosis, tubular atrophy/interstitial fibrosis, extension of immune deposits to the perivascular space and crescent formation. Progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions. These features of IgAN reported in literature were mostly, but not completely, confirmed by analysis of all consecutive patients with biopsy proven IgAN and follow-up > 12 months in the renal units of Heidelberg and Prague using univariate analysis, multiple range test and multiple regression analysis.

[Early intensification of treatment in diabetes using a combination of insulin and nicotinamide--effect on C-peptide levels and the course of the disease]. / Vcasná intenzifikovaná liecba diabetu inzulínom v kombinácii s nikotínamidom--vplyv na hladiny C-peptidu a priebeh ochorenia.

Significantly higher C-peptide levels were found in a group of 49 juvenile diabetics treated with insulin in combination with nicotinamide compared to 33 diabetics treated with insulin only. There had been no significant differences in the initial values of C-peptide between the two groups. After six weeks the mean basal values of C-peptide in the blood of nicotinamide treated diabetics reached 1.21 +/- 0.79 ng/ml compared to 0.87 +/- 0.55 ng/ml determined in the group treated with insulin only (p less than 0.05). After one year of therapy the differences remained significant (p less than 0.01). The insulin requirement was significantly lower in the nicotinamide treated group after six weeks (p less than 0.001) and the difference remained significant also after two years of nicotinamide treatment (p less than 0.02). A longer period of partial remission was recorded in the group of diabetics who were administered nicotinamide. (Tab. 4, Fig. 2, Ref. 13.)

[The role of coxsackie virus infection in the development of type 1 diabetes mellitus and its effect on the postinitial course of the disease in childhood]. / Spoluúcast' infekcie vírusmi Coxsackie na vývoji diabetes mellitus typ 1 a vplyv na d'al'sí postiniciálny priebeh ochorenia v detskom veku.

The authors present the results of a three-year investigation of Coxsackie viruses in children diabetics. In paired serum samples of 66 newly diagnosed patients of virus neutralizing antibodies against eight types of Coxsackie viruses were estimated. Concurrently specific antibodies of class IgM were assessed and compared with a control group of 218 healthy children. Infection with Coxsackie viruses, in particular types B2, B4 and B5, were found in 38 diabetics (in 57.6%) as compared with 6% in healthy children. The findings indicate an evidence that diabetics with Coxsackie infection at the betics. The prospective three-year investigation provided evidence that diabetics with Coxsackie infection at the time of manifestation of the disease had a worse postinitial course. Their C-peptide levels were significantly lower (p less than 0.05). The frequency and intensity of partial remission were significantly worse in the group of diabetics who had just overcome a Coxsackie virus infection (p less than 0.02).