Adolescence-onset atypical hemolytic uremic syndrome: is it different from infant-onset?

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, mostly complement-mediated thrombotic microangiopathy. The majority of patients are infants. In contrast to infantile-onset aHUS, the clinical and genetic characteristics of adolescence-onset aHUS have not been sufficiently addressed to date. METHODS: A total of 28 patients (21 girls, 7 boys) who were diagnosed as aHUS between the ages of ≥10 years and <18 years were included in this study. All available data in the Turkish Pediatric aHUS registry were collected and analyzed. RESULTS: The mean age at diagnosis was 12.8±2.3 years. Extra-renal involvement was noted in 13 patients (46.4%); neurological involvement was the most common (32%). A total of 21 patients (75%) required kidney replacement therapy. Five patients (17.8%) received only plasma therapy and 23 (82%) of the patients received eculizumab. Hematologic remission and renal remission were achieved in 25 (89.3%) and 17 (60.7%) of the patients, respectively. Compared with the infantile-onset aHUS patients, adolescent patients had a lower complete remission rate during the first episode (p = 0.002). Genetic analyses were performed in all and a genetic variant was detected in 39.3% of the patients. The mean follow-up duration was 4.9±2.6 years. At the last visit, adolescent patients had lower eGFR levels (p = 0.03) and higher rates of chronic kidney disease stage 5 when compared to infantile-onset aHUS patients (p = 0.04). CONCLUSIONS: Adolescence-onset aHUS is a rare disease but tends to cause more permanent renal dysfunction than infantile-onset aHUS. These results may modify the management approaches in these patients.

Salivary levels of hBDs in children and adolescents with type 1 diabetes mellitus and gingivitis.

OBJECTIVES: Type 1 diabetes mellitus (T1DM), a chronic autoimmune disease characterized by insulin deficiency, is related to periodontal diseases in children and adolescents. Our aim was to profile salivary human beta-defensin (hBD)-2 and hBD-3 concentrations in relation to periodontal and T1DM status in children and adolescent populations. MATERIAL AND METHODS: Unstimulated saliva samples were collected from 66 participants including periodontally healthy T1DM patients (T1DM + C; n = 18), T1DM patients with gingivitis (T1DM + G; n = 20), systemically and periodontally healthy individuals (SH + C: n = 15), and systemically healthy gingivitis patients (SH + G; n = 13). Full mouth plaque index (PI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) were recorded. Salivary hBD-2 and hBD-3 concentrations were evaluated by sandwich ELISA method. A p value of < 0.05 was considered statistically significant. RESULTS: Salivary hBD-3 concentrations were lower in T1DM groups in comparison to systemically healthy counterparts (SH + G vs. T1DM + G; p < 0.001 and SH + C vs. T1DM + C; p < 0.001). Salivary hBD-2 levels did not differ between related groups. The difference in hBD-3 concentrations between T1DM and control groups was still significant (p = 0.008) after being adjusted for PI%, BOP%, and age. CONCLUSION: In the limits of study, T1DM patients were found to have decreased salivary hBD-3 concentrations, regardless of their gingival inflammatory status. CLINICAL RELEVANCE: Altered salivary hBD-3 concentration can partly explain why diabetic children are more prone to periodontal diseases.

Nephrolithiasis during the first 6 months of life in exclusively breastfed infants.

BACKGROUND: We investigated etiology and prognosis of infantile nephrolithiasis, including whether lithogenic and anti-lithogenic content of breast milk affects its formation. METHODS: Thirty infants with nephrolithiasis and 30 healthy infants exclusively breastfed for the first 6 months of life were included in this prospective cohort case-control study. At entry, age, sex, and timing of birth of patients and controls were recorded. All patients were diagnosed and followed up periodically using ultrasonography. All infants received oral vitamin D (400 units/day). Lithogenic (calcium, oxalate, uric acid, phosphate) and anti-lithogenic (citrate, magnesium) components of maternal milk, serum calcium, phosphate, magnesium, 25-hydroxy vitamin D and parathormone, as well as spot urine calcium, uric acid, cystine, oxalate, magnesium, citrate/creatinine ratio, and calcium/citrate ratio were compared. RESULTS: Mean follow-up period was 56.1 ± 6.8 months. There was no difference concerning lithogenic and anti-lithogenic content of breast milk. Serum calcium, phosphorus, alkaline phosphatase, and 25-hydroxy vitamin D levels (49.1 ± 19 vs. 26.7 ± 4 ng/ml, p < 0.001) were significantly higher and parathormone level significantly lower in patients. Random urine calcium/creatinine and calcium/citrate ratios were significantly higher in patient group (0.63 ± 0.40 vs. 0.42 ± 0.10 and 0.62 ± 0.12 vs. 0.41 ± 0.25 mg/mg, respectively, p < 0.01). Three patients were lost to follow-up after the first year. At last follow-up, calculi disappeared in 25/27 remaining patients without interventions or therapy. CONCLUSIONS: Breast milk does not have an etiologic effect in infantile nephrolithiasis. Higher serum vitamin D levels may have roles in development of lower levels of PTH and higher levels of serum and urine calcium, leading to stone formation. The prognosis for infantile stones is excellent. Graphical abstract.

Analysis of the genetic component of systemic sclerosis in Iranian and Turkish populations through a genome-wide association study.

Objectives: SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study. Methods: This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case-control sets was conducted by the inverse variance method. Results: The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11: 04 [P = 2.10 × 10-24, odds ratio (OR) = 3.14] and DPB1*13: 01 (P = 5.37 × 10-14, OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11: 04 (P = 4.90 × 10-11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 × 10-7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 × 10-7, OR = 1.47). Conclusion: We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis.

Remarkable damage along with poor quality of life in Takayasu arteritis: cross-sectional results of a long-term followed-up multicentre cohort.

OBJECTIVES: We aimed to assess the outcome of a large Takayasu arteritis (TAK) cohort using the vasculitis damage index (VDI) and quality of life (QoL) scale, tools which have been validated for vasculitis. METHODS: Disease activity, damage and QoL were cross-sectionally evaluated in 165 TAK patients from 6 centres. SF-36 were applied to 51 age-matched healthy controls (HC). Persistent activity for ≥6 months was considered as treatment resistance (r-TAK). The correlation between VDI, clinical characteristics and mental (MCS)/physical (PCS) component scores of SF-36 were analysed. SF-36 and VDI scores were compared between TAK subgroups and HC. RESULTS: The median age, follow-up time and disease duration were 40 (17-68), 60 (6-384), and 72 (6-396) months, respectively. 35% of them were r-TAK. VDI scores (VDIs) in TAK 4 (1-12) were mainly due to the disease itself [4 (1-10)]. VDIs in r-TAK were significantly higher than nr-TAK [5 (2-12) vs. 3 (2-10), p<0.001)]. In the TAK patients, MCS and PCS were found as 43±10 and 38±11, respectively. A high proportion of poor MCS (70%) and PCS (80%) were demonstrated in TAK. A significantly negative but weak correlation was observed between VDI and MCS (p=0.003, r=-0.23), PCS (p<0.001, r=-0.34). Higher VDIs were detected in patients with PCS <50 [5 (1-12) vs. 2 (1-6) p<0.001)]. SF-36 score was significantly lower in TAK than HC. CONCLUSIONS: Disease-related damage mainly caused by peripheral vascular involvement was more predominant than treatment-related damage without reaching the level of severe damage scores, but contributing to poor QoL, in the TAK cohort.

Investigation of the association between Rho/Rho-kinase gene polymorphisms and systemic sclerosis.

Systemic sclerosis (SSc) is a disease characterized by inflammation, vascular abnormalities and fibrosis. The role of Rho/Rho-kinase pathway was demonstrated in the pathogenesis of fibrosis, inflammation and vascular abnormalities. This study was aimed to investigate the relation between SSc and Rho/Rho-kinase gene polymorphisms. The study included 339 patients with SSc and 302 healthy subjects who were apparently healthy and at similar age and gender. Genotype distributions and allele frequencies were detected by using Chi-square test or Fisher's exact Chi-square test between groups, and the haplotype analysis was applied using online program (SHEsis). Significant association was found in a polymorphism in the ROCK1 gene (rs35996865), a polymorphism in ROCK2 gene (rs10178332), a polymorphism in RhoA gene (rs2177268) and two polymorphisms in RhoC gene (rs11102522 and rs11538960) with SSc disease (p < 0.0022). In this study, association between SSc disease and Rho/Rho-kinase gene polymorphisms was investigated for the first time; significant associations between ROCK1, ROCK2, RhoA and RhoC gene polymorphisms and SSc disease were demonstrated. The results strongly suggest that this SNP may be an important risk factor for development of SSc. However, further validation of these findings in an independent cohort is necessary.

The IL-33 gene is related to increased susceptibility to systemic sclerosis.

Systemic sclerosis (SSc) is a chronic inflammatory disease characterized by widespread fibrosis of the skin and several visceral organs. The pro-fibrotic potential of interleukin (IL)-33 has been demonstrated by in both in vitro and in vivo settings; moreover, increased level of IL-33 has also been reported in patients with SSc. Therefore, the aim of the present study was to detect the potential association of IL-33 gene polymorphisms on the susceptibility of SSc. A total of 300 SSc patients and 280 healthy controls (HC) were enrolled in this multicentric preliminary candidate gene study. DNA samples were harvested using an appropriate commercial DNA isolation kit. Four single nucleotide polymorphisms (SNPs) of IL-33 gene (rs7044343, rs1157505, rs11792633 and rs1929992) were genotyped using the appropriate commercial primer/probe sets on real-time PCR. There was no significant difference in terms of the allelic distributions and minor allele frequencies of evaluated four IL-33 polymorphisms between the SSc and HC groups (P > 0.05 for all). Moreover, the genotypic distributions of rs1157505, rs11792633 and rs1929992 polymorphisms were not significantly different (P > 0.05 for all). However, CC genotype of rs7044343 SNP was significantly higher in the SSc group compared to the HC group (P = 0.013, OR 1.75, 95 % CI 1.12-2.72). This preliminary candidate gene study demonstrates that rs7044343 polymorphism of IL-33 gene is associated with the susceptibility to the SSc in Turkish population. It may be suggested that IL-33 gene may be a candidate gene to research in SSc.

Anxiety and depression predict quality of life in Turkish patients with systemic lupus erythematosus.

OBJECTIVES: The aim of our study was to evaluate quality of life (QoL) in patients with systemic lupus erythematosus (SLE) and assess the impact of disease activity and psychological distress on health-related quality of life (HRQoL) in Turkey. METHODS: The Medical Outcomes Study Short Form (SF) -36 was used in a cohort of 113 consecutive patients with SLE and 123 age- and gender-matched healthy subjects to measure HRQoL. Patients' disease activity was assessed with SLE disease activity index (SLEDAI) and psychological distress was evaluated by the Hospital Anxiety and Depression Scale (HADS) for all participants. Patients' demographic and clinical data were recorded at the time of HRQoL and HADS testing. Multiple logistic regression analysis was performed to explore the relationships between demographics, disease duration, disease activity as well as psychological (anxiety and depression) variables and the HRQoL. RESULTS: SLE patients have lower quality of life than healthy controls. No relationship between HRQoL and SLE activity or disease duration were observed. Patients with anxiety and/or depression reported worse SF-36 scores than those without psychological distress. The results of multivariate analysis suggested that HADS-A, HADS-D scores and working status were associated with the impairment of HRQoL. CONCLUSIONS: HRQoL is impaired in patients with SLE and is associated with mood disorders. Physicians should pay close attention to detect anxiety and depression and manage them in order to improve the quality of life in patients with SLE.

Unveiling cancer risk in ANCA-associated vasculitis: result from the Turkish Vasculitis Study Group (TRVaS).

To investigate cancer incidence in patients with ANCA-associated vasculitis (AAV), compare it with the age/sex-specific cancer risk of the Turkish population, and explore independent risk factors associated with cancer. This multicenter, incidence case-control study was conducted using the TRVaS registry. AAV patients without cancer history before AAV diagnosis were included. Demographic and AAV-related data of patients with and without an incident cancer were compared. Standardized cancer incidence rates were calculated using age-/sex-specific 2017 Turkish National Cancer Registry data for cancers (excluding non-melanoma skin cancers). Cox regression was performed to find factors related to incident cancers in AAV patients. Of 461 AAV patients (236 [51.2%] male), 19 had incident cancers after 2022.8 patient-years follow-up. Median (IQR) disease duration was 3.4 (5.5) years, and 58 (12.6%) patients died [7 with cancer and one without cancer (log-rank, p = 0.04)]. Cancer-diagnosed patients were older, mostly male, and more likely to have anti-PR3-ANCA positivity. The cumulative cyclophosphamide dose was similar in patients with and without cancer. Overall cancer risk in AAV was 2.1 (SIR) ((1.3-3.2), p = 0.004); lung and head-neck [primary target sites for AAV] cancers were the most common. In Cox regression, male sex and ≥ 60 years of age at AAV diagnosis were associated with increased cancer risk, while receiving rituximab was associated with decreased cancer risk. Cancer risk was 2.1 times higher in AAV patients than the age-/sex-specific cancer risk of the Turkish population population, despite a high rate of rituximab use and lower dose of cyclophosphamide doses. Vigilance in cancer screening for AAV patients covering lung, genitourinary, and head-neck regions, particularly in males and the elderly, is vital.

Prevalence and target attainment of traditional cardiovascular risk factors in patients with systemic lupus erythematosus: a cross-sectional study including 3401 individuals from 24 countries.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterised by increased cardiovascular morbidity and mortality risk. We aimed to examine the prevalence of traditional cardiovascular risk factors and their control in an international survey of patients with systemic lupus erythematosus. METHODS: In this multicentre, cross-sectional study, cardiovascular risk factor data from medical files of adult patients (aged ≥18) with SLE followed between Jan 1, 2015, and Jan 1, 2020, were collected from 24 countries, across five continents. We assessed the prevalence and target attainment of cardiovascular risk factors and examined potential differences by country income level and antiphospholipid syndrome coexistence. We used the Systemic Coronary Risk Evaluation algorithm for cardiovascular risk estimation, and the European Society of Cardiology guidelines for assessing cardiovascular risk factor target attainment. People with lived experience were not involved in the research or writing process. FINDINGS: 3401 patients with SLE were included in the study. The median age was 43·0 years (IQR 33-54), 3047 (89·7%) of 3396 patients were women, 349 (10.3%) were men, and 1629 (48·1%) of 3390 were White. 556 (20·7%) of 2681 patients had concomitant antiphospholipid syndrome. We found a high cardiovascular risk factor prevalence (hypertension 1210 [35·6%] of 3398 patients, obesity 751 [23·7%] of 3169 patients, and hyperlipidaemia 650 [19·8%] of 3279 patients), and suboptimal control of modifiable cardiovascular risk factors (blood pressure [target of <130/80 mm Hg], BMI, and lipids) in the entire SLE group. Higher prevalence of cardiovascular risk factors but a better blood pressure (target of <130/80 mm Hg; 54·9% [1170 of 2132 patients] vs 46·8% [519 of 1109 patients]; p<0·0001), and lipid control (75·0% [895 of 1194 patients] vs 51·4% [386 of 751 patients], p<0·0001 for high-density lipoprotein [HDL]; 66·4% [769 of 1158 patients] vs 60·8% [453 of 745 patients], p=0·013 for non-HDL; 80·9% [1017 of 1257 patients] vs 61·4% [486 of 792 patients], p<0·0001 for triglycerides]) was observed in patients from high-income versus those from middle-income countries. Patients with SLE with antiphospholipid syndrome had a higher prevalence of modifiable cardiovascular risk factors, and significantly lower attainment of BMI and lipid targets (for low-density lipoprotein and non-HDL) than patients with SLE without antiphospholipid syndrome. INTERPRETATION: High prevalence and inadequate cardiovascular risk factor control were observed in a large multicentre and multiethnic SLE cohort, especially among patients from middle-income compared with high-income countries and among those with coexistent antiphospholipid syndrome. Increased awareness of cardiovascular disease risk in SLE, especially in the above subgroups, is urgently warranted. FUNDING: None.

Impaired quality of life, disability and mental health in Takayasu's arteritis.

OBJECTIVE: Patient-reported outcomes (PROs) are increasingly accepted to be among the major tools for outcome assessment in rheumatic disorders. In this study we aimed to assess quality of life (QoL), disability, anxiety and depression in patients with Takayasu's arteritis (TAK). METHODS: Patients followed with the diagnosis of TAK (n = 165) and healthy controls (HCs) (n = 109) were enrolled to the study. The 36-item Short Form Health Survey (SF-36) and hospital anxiety and depression scales (HADS) were used to assess QoL and mental status together with HAQ for disability. RESULTS: In SF-36 subscale assessment, all items were observed to be statistically lower in TAK patients; similarly HAQ scores were also higher (P < 0.001) in this group. In mental assessment, anxiety was found to be more common in TAK patients [90 (54.5%) vs 38 (34.9%), P = 0.001]. Depression also tended to be higher in TAK patients [70 (66.7%) vs 35 (33.3%)], without reaching significance (P = 0.086). Most of the SF-36 subgroup parameters were lower in TAK patients with active disease. Patients having anxiety and depression or with high HAQ scores reported worse SF-36 scores. In multivariate analysis, HADS-A, HADS-D and HAQ were associated with most SF-36 subscales. CONCLUSION: PROs demonstrate that not only general health but also physical and social functioning with physical role limitations and mental health parameters were impaired in TAK. Our results, especially in active disease, suggest that PROs such as SF-36 can be core domains of disease assessment in TAK, similar to ANCA-associated vasculitides.

Clinically silent Crohn's disease in a patient with Takayasu's arteritis unresponsive to conventional therapies.

Takayasu arteritis (TA) and Crohn's disease (CD) are chronic inflammatory diseases with granulomatous nature. Here, we report a case of TA with a silent course of CD who was refractory to corticosteroid and immunosuppressive treatments and improved with adalimumab therapy.

Immunoglobulin subtypes predict therapy response to the biologics in patients with rheumatoid arthritis.

To analyze the effectiveness of rituximab (RTX) versus alternative TNF antagonists (aTNFs) on rheumatoid arthritis (RA) disease activity in different subgroups of patients and relation with extraarticular manifestations of RA and to assess that RF-subsets have potential as predictors of clinical response to RTX. Patients with RA (n = 40, M/F: 3/37) who received aTNFs at least 6 months with good response (group I; n = 20) or discontinued at least one aTNFs because of the ineffectiveness and subsequently received RTX at least one course (group II; n = 20) were retrospectively evaluated. IgM-, IgA-, IgG-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) levels were measured by ELISA technique. Extraarticular manifestations and radiological scores were also recorded. The mean (SD) age was 51.7 ± 6.5 years in group I and 52.1 ± 6.1 years in group II patients (p > 0.05). The median disease durations were higher in group II than group I [8.0 (2-30) vs. 13 (3-35) years, respectively, p = 0.04]. Presence of RF [13(61.9 %) vs. 20(100 %) p = 0.001] and extraarticular involvement [5(25 %) vs. 13(65 %) p = 0.01] were higher in group II patients. When Ig-RF subgroups analyzed, all subgroup (IgA, IgM, IgG) levels were higher in group II (p = 0.001, p = 0.05, p = 0.001). IgA-RF levels were significantly high in patients with extraarticular involvement (p = 0.04). Association between high RF levels and having extraarticular manifestations in RA patients may largely be attributed to the IgA isotype.

Role of tyrosine kinase inhibition with imatinib in an encapsulating peritoneal sclerosis rat model.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is characterized by neovascularization, increased inflammation, and interstitial fibrosis of the peritoneum. We investigated the effects of imatinib on the peritoneal membrane in an experimental EPS model. METHODS: We separated 24 non-uremic Wistar rats into four groups: the control group which was injected with 2 mL isotonic saline intraperitoneally (IP) daily for 3 weeks, the CG group which was injected with chlorhexidine gluconate (CG) IP daily for 3 weeks, the resting group which was injected with CG IP between weeks 0-3 followed by a peritoneal rest period between weeks 3-6, and the CG + Imatinib mesylate group (CG + IMA) which received CG through weeks 0-3 followed by 50 mg/kg imatinib mesylate through weeks 3-6. At the end of the study, we performed a 1-h-peritoneal equilibration test and examined the peritoneal function and transforming growth factor-ß1 (TGF-ß1) in dialysate. Morphologic changes were evaluated by microscopy and immunohistochemistry. RESULTS: An increased ultrafiltration, dialysate/plasma-creatinine-ratio, end-to-initial-dialysate-glucose-ratio, decreased active mesothelial cell ratio and inflammation, and a slightly decreased TGF-ß1 of dialysate were found in the CG + IMA group compared to CG alone. Furthermore, the CG + IMA group had a lower concentration of active mesothelial cells than did the resting group. Ultrafiltration was improved in CG + IMA group compared to resting group, however, significant decrease in peritoneal thickness and inflammation were not found compared to those in resting group. Furthermore, there was no significant difference in fibrosis or TGF-ß1-positivity on immunohistochemistry between the groups. CONCLUSIONS: Tyrosine kinase inhibition with imatinib may lead to a decrease in mesothelial cell activity and an increase in ultrafiltration. However, peritoneal fibrosis was unchanged by imatinib in EPS model.