Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies.

Characteristics and course of patients with AA amyloidosis: single centre experience with 174 patients from Turkey.

OBJECTIVES: This study aimed to evaluate the clinical, laboratory and genetic characteristics and outcomes of patients with AA amyloidosis. METHODS: Patients followed up in a tertiary referral centre in Turkey with the diagnosis of inflammatory rheumatic diseases and immunohistologically proven AA amyloidosis were included in the study and retrospectively analysed. RESULTS: Among 184 patients with the diagnosis of AA amyloidosis, 174 (83 female, 91 male) were included in the analysis. The most common cause of AA amyloidosis was FMF (78.7%), and 91% of FMF-AA amyloidosis patients were carrying the p.M694V variant (74.1% homozygous). AA amyloidosis was identified earlier in patients with homozygous or compound heterozygous MEFV exon 10 variants compared with the heterozygous patients (27, 30 and 41 years, respectively). Patients with an estimated glomerular filtration rate <60 ml/min at admission had a higher frequency of progression to end-stage renal disease (P < 0.001). The overall mortality rate was 15.3% and it increased gradually in association with the amyloid burden (10% in patients with renal, 15% in renal + gastrointestinal and 43% in those with additional cardiac involvement). Renal findings responded completely to treatment in 31% of the patients, a partial response was observed in 4%, a stable course in 23.6% and progression in 38.5%. Amyloid storm was identified in nine patients and was found to be associated with increased mortality within 1 year. CONCLUSION: FMF patients still constitute the majority of AA amyloidosis patients in Turkey. The MEFV genotype and associated inflammatory load may affect the age of onset of AA amyloidosis, and earlier diagnosis and stricter follow-up and treatment may delay progression of the disease.

Analysis of 5-year hospitalization data of patients with systemic lupus erythematosus: Damage is a risk factor for frequent and longer stays.

OBJECTIVE: The annual hospitalization rate of patients with systemic lupus erythematosus (SLE) is approximately 10%, and hospitalizations are responsible for most of the healthcare expenses. Herein, we analyzed 5-year hospitalization data of SLE patients and determined factors leading to hospitalization. METHODS: Clinical, laboratory, and hospitalization data of SLE patients admitted to our rheumatology clinic in 2015-2020 were retrieved from our SLE database and analyzed. SLICC SLE damage index (SDI) and disease activity at admission (SLEDAI-2K) were determined. RESULTS: Among 161 hospitalized patients, 86% were females. Total rheumatologic hospitalization number was 298, and 38% of the patients were hospitalized more than once (1.85 ± 1.56). The mean hospitalization duration covering all stays for each patient was 25 ± 26.5 days. Active disease, infection, and damage-related complications were first three causes of hospitalization. Compared to patients hospitalized for active disease or damage, patients hospitalized for infection had a significantly higher number of readmissions (p < .05) and their total hospital stay was longer (p < .01).The frequency of patients with damage and the mean SDI score was significantly lower in the active disease group (68%, 1.93 ± 2.05) than hospitalizations for infection (90%, 2.68 ± 1.63) and damage-related causes (96%, 3.04 ± 1.65) (p < .05). The mean SDI score and duration (r = 0.551, p < .001) and the number of hospitalizations (r = 0.393, p < .001) were positively correlated. The mean disease activity scores of patients hospitalized for active disease, infection, and damage-related reasons were 11.03 ± 6.08, 3.21 ± 2.80, and 2.96 ± 3.32, respectively (p < .001). Renal active disease was the most common (44%), followed by hematological (34.8%), articular (21.7%), and mucocutaneous (21%) activity.Ten percent of the patients all of whom had damage were admitted to intensive care unit (ICU). Total hospitalization duration, mean SDI, antiphospholipid syndrome, lupus anticoagulant, thrombocytopenia, serositis, pulmonary hypertension, history of alveolar hemorrhage, and cardiac valve involvement were associated with ICU admission (p < .05 for all). CONCLUSION: Disease activity, infections, and damage are the leading causes of hospitalization in SLE patients. Damage prolongs hospital stay and increases hospitalization rate and ICU need. Tight control of disease activity with rational use of immunosuppressive treatment is important to reduce damage and hospitalizations.

ABO blood groups and increased risk for the development of vascular involvement in Behçet's disease.

OBJECTIVES: Inflammatory endothelial activation is a prominent feature of vascular involvement in Behçet's disease (BD), which is usually accompanied by a thrombotic tendency. Recent studies suggest an association between ABO blood groups and thrombotic vascular disease in those carrying non-O (A, B, and AB) groups. This study aimed to analyse the contribution of ABO blood groups to the vascular involvement in BD. METHODS: In this retrospective study, BD patients with available ABO blood group data and meeting the ISG criteria were included in the study. The presence of vascular involvement, its clinical characteristics, and the data about other manifestations were recorded from the patient charts. RESULTS: This study was conducted in 411 patients; 143 (34.8%) were carrying O and 268 (65.2%) were carrying non-O groups. The vascular involvement was significantly more frequent and the risk for overall vascular and venous events was up to 2-fold higher in the patients with non-O groups. After adjustments for age, sex, and comorbidities, the risk for arterial disease was also found to be increased in association with non-O groups. ABO blood groups were shown to be independent risk factors for vascular BD by multiple regression models based on known predisposing factors. Compared with other non-O blood groups, the patients carrying blood group B had a higher risk for vascular events. CONCLUSIONS: The results of this preliminary study show the potential contribution of ABO blood groups to the vascular-BD phenotype and suggest an increased risk for vascular BD in association with non-O blood groups.

Utility of positron emission tomography as a new tool for muscle involvement in patients with idiopathic inflammatory myositis: a controlled study.

OBJECTIVES: Idiopathic inflammatory myositis (IIM) represents a rare group of disease that can affect multiple organs in addition to the muscles. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is an emerging scanning method that is widely used in diagnosing, staging and response to treatment in patients with cancer. In this study, we aimed to evaluate the muscle involvement in PET/CT which was performed for malignancy screening and its correlation with myositis-specific antibodies (MSA) and/or myositis-associated antibodies (MAA) in patients with IIM. METHODS: IIM patients who fulfilled 2017 EULAR/ACR classification criteria and had PET-CT scans during the active phase of myositis (within two weeks of starting steroids) were included into the study. Age and sex matched participants with history of malignancy (non-IIM patients) were defined as control group. RESULTS: Data of 160 IIM patients were evaluated and 34 patients (of 64.7% female) whose PET/CT results were available, included into the study. Fourteen patients with diagnosis of malignancy without IIM (non-IIM patients) defined as the control group. Sensitivity and specificity of a positive FDG muscle uptake were 37.1% and 100%, 65.7% and 92.9%, 91.4% and 7.1% compared to liver, mediastinum and LTM uptakes, respectively. In multivariate analysis, higher baseline CRP (p=0.017, confidence interval [CI] 95%: 1.03-1.36, OR:1.18) and LDH (p=0.029, CI 95%:1.001-1.017, OR:1.01) levels were associated with muscle PET/CT positivity. CONCLUSIONS: In patients with active IIM, median muscle FDG uptake with PET/CT was higher compared to non-IIM. PET/CT may be used for the evaluation of extent and activity in patients with IIM.

AA Amyloidosis: A Contemporary View.

PURPOSE OF REVIEW: Amyloid A (AA) amyloidosis is an organ- or life-threatening complication of chronic inflammatory disorders. Here, we review the epidemiology, causes, pathogenesis, clinical features, and diagnostic and therapeutic strategies of AA amyloidosis. RECENT FINDINGS: The incidence of AA amyloidosis has declined due to better treatment of the underlying diseases. Histopathological examination is the gold standard of diagnosis, but magnetic resonance imaging can be used to detect cardiac involvement. There is yet no treatment option for the clearance of amyloid fibril deposits; therefore, the management strategy primarily aims to reduce serum amyloid A protein. Anti-inflammatory biologic agents have drastically expanded our therapeutic armamentarium. Kidney transplantation is preferred in patients with kidney failure, and the recurrence of amyloidosis in the allograft has become rare as transplant recipients have started to benefit from the new agents. The management of AA amyloidosis has been considerably changed over the recent years due to the novel therapeutic options aiming to control inflammatory activity. New agents capable of clearing amyloid deposits from the tissues are still needed.

Cytokine Signature Differences in Major Phenotypic Groups of Behçet Disease.

OBJECTIVES: Behçet disease (BD) has heterogeneous presentations, mainly mucocutaneous, vascular, and ocular manifestations. The mechanisms associated with different phenotypes have not been clarified. We aimed to investigate the expression of innate and adaptive immunity-related cytokines in these 3 main BD phenotypes in active and untreated states and remission after treatment to be able to develop a cytokine-based treatment algorithm. METHODS: Serum samples were isolated from 41 patients with newly diagnosed active BD (aBD), which consisted of 19 mucocutaneous aBD, 11 ocular aBD (o-aBD), and 11 vascular aBD patients, 35 patients in remission (rBD), and 9 healthy controls (HC). Serum levels of each cytokine were measured with sandwich enzyme-linked immunosorbent assay and analyzed as both raw measurements and corrected levels for each 1 million white blood cells. RESULTS: The study included 41 aBD patients (female/male [F/M]: 9/32; median age, 29 years), 35 rBD patients (F/M: 9/26; median age, 29 years), and 9 HC (F/M: 3/6; median age, 28 years). The serum interferon γ level was significantly higher in the aBD group than in the rBD (116 vs. 92 pg/mL, p = 0.022). The serum interleukin 35 (IL-35) level was significantly higher in the HC group compared with aBD and rBD (p = 0.05). IL-17-related cytokines were lower in o-aBD. With treatment, they increased in o-aBD but decreased in mucocutaneous aBD and vascular aBD patients. CONCLUSION: This study supports the involvement of both innate and TH1-predominated adaptive immune responses across all BD phenotypes. The IL-17 and TH17-related immune responses appear less prominent in ocular BD, which may explain the ineffectiveness of IL-17 blockade in treating ocular BD. These findings support the need for further studies using comprehensive gene expression analyses to develop targeted treatment strategies for BD phenotypes.

Mortality and Associated Factors in Patients with Systemic Sclerosis Associated Pulmonary Hypertension with and without Interstitial Lung Disease: A Long-Term Follow-up Study.

OBJECTIVES: We aimed to analyze the prevalence, mortality, and prognostic factors in systemic sclerosis (SSc) patients with pulmonary hypertension (PH) with or without interstitial lung disease (ILD). METHODS: The associations between mortality and demographics, transthoracic echocardiography, right heart catheterization (RHC), pulmonary functional parameters at baseline, and treatment modalities in two groups; patients with pulmonary arterial hypertension (PAH, PH without significant ILD) and PH + ILD were evaluated. RESULTS: The mean age of the patients was 56.6±13.5 (range: 34-82, 44 women/ 2 men), and 23 (52.3%) were deceased during a median follow-up of 45 months. The survival rates of PH-SSc patients were 91% for the first year, 75% for 2 years, 68% for 3 years, and 43.1% for 5 years. The majority of deceased patients were in the PH + ILD group (p=0.007). The PH + ILD group had more diffuse skin involvement, anti-Scl-70 positivity, high C-reactive protein, low FVC, and lower DLCO values. The deceased patients had higher ePASP, low CO, and FVC values compared to surviving patients. Median survival time was significantly better in patients on combined therapy (44 vs. 61 months, p=0.01). The mortality-related factors in the PH + ILD group were decreased initial FVC, high ePASP on echocardiography, low cardiac output on RHC, deteriorated functional class, and monotherapy. CONCLUSION: This is the first reported SSc-PH cohort from Turkey by a multidisciplinary team after the implementation of PAH-specific drugs. SSc-PH is a severe complication of SSc with high mortality especially in patients with accompanying severe ILD.

Evaluation of baseline F-18 FDG positron emission tomography in the diagnosis and assessment of giant cell arteritis.

Background/aim: The aim of this study is to evaluate the baseline F18-FDG PET/CT findings of individuals diagnosed with giant cell arteritis (GCA) and to explore its association with clinical findings and classification criteria. Materials and methods: We analysed data from patients who underwent F18-FDG PET/CT scans to investigate large vessel (LV) involvement between 2010 and 2019. Only patients with a clinical diagnosis of GCA and at least 6 months of follow-up were included. We compared initial clinical features and laboratory findings based on the presence of LV vasculitis on PET/CT and the maximum standard uptake value (SUVmax) of vascular territories. Results: Twenty-nine patients (median age at diagnosis: 70, F/M: 24/5) were included in the study. Among them, 21 patients (72.4%) presented with cranial symptoms, while 8 patients (27.5%) had isolated LV-GCA. Twenty-two patients (75.9%) met the ACR/EULAR 2022 GCA classification criteria. LV vasculitis was detected on PET/CT in 23 patients (79.3%). A positive correlation was observed between SUVmax in the thoracic aorta and both CRP and ESR levels (r = 0.50, p = 0.026 and r = 0.63, p = 0.002, respectively). PET/CT positive patients were found to be younger (p = 0.016) and more frequently female (p = 0.017). They also exhibited fewer headaches (56.5% vs. 100%, p = 0.04), experienced fewer flares during follow-up (p = 0.03), and had a lower cumulative glucocorticoid dose at the 6th month (p = 0.036). Comparison of PET/CT-positive patients (n = 23) based on the fulfilment of the ACR/EULAR 2022 classification criteria revealed that patients who met these criteria were older (p = 0.02) and had significantly lower CRP levels at diagnosis (p = 0.02). Conclusion: The performance of F18-FDG PET/CT in diagnosing LV involvement in GCA is favourable, and the severity of FDG uptake in the vessel wall correlates with the acute phase response. Patients with extracranial involvement on PET/CT exhibit distinct features, including a younger age and female predominance. Additionally, these patients appear to experience fewer relapses and require lower doses of glucocorticoids. However, the clinical significance of PET/CT in patients who met ACR/EULAR classification criteria, predominantly consisting of patients with ischemic cranial symptoms, could not be determined in our study.

Serum and urine interferon-inducible protein 10, galectin-9, and SIGLEC-1 as biomarkers of disease activity in systemic lupus erythematosus.

Background/aim: In this prospective study, we aimed to investigate the association of serum (s) and urine (u) IP-10, galectin-9, and SIGLEC-1 with disease activity in patients with systemic lupus erythematosus (SLE). Materials and methods: Sixty-three patients with active SLE (31 renal, 32 extrarenal) were included. Thirty patients with inactive SLE (15 renal, 15 extrarenal), 17 with renal active AAV, and 32 healthy volunteers were selected as control groups. Serum and urine IP-10, galectin-9, and SIGLEC-1 were tested using ELISA. Results: Levels of sIP-10 (p = 0.046), uIP-10 (p < 0.001), sGalectin-9 (p = 0.03), and uSIGLEC-1 (p = 0.006) were significantly higher in active SLE group compared to the inactive SLE; however, no differences were detected in the comparison of uGalectin-9 (p = 0.18) and sSIGLEC-1 (p = 0.69) between two groups. None of the biomarkers discriminated patients with active renal SLE from active extrarenal SLE. ROC analyses revealed an AUC of 0.63 (0.52-0.73) for sIP-10, 0.78 (0.68-0.86) for uIP-10, 0.64 (0.53-0.74) for sGalectin-9, and 0.68 (0.57-0.77) for uSIGLEC-1 in discriminating disease activity in SLE, which did not outperform C3 (0.75, 0.64-0.84) and C4 (0.72, 0.61-0.82). sIP-10 (p = 0.001), uIP-10 (p = 0.042), and uGalectin-9 (p = 0.009) were significantly increased in patients with active renal SLE compared to active renal AAV. sGalectin-9 (p < 0.001) and sIP-10 levels (p = 0.06) were decreased after 8 (5-22.5) months of treatment. Conclusion: sIP-10, uIP-10, sGalectin-9, and uSIGLEC-1 reflect global disease activity in SLE but do not outperform C3 and C4. sIP-10 and uIP-10 may be specific for active SLE compared to active AAV. sIP-10 and sGalectin-9 might be valuable in monitoring response after treatment.

Behçet disease, familial Mediterranean fever and MEFV variations: More than just an association.

Behçet disease (BD) and familial Mediterranean fever (FMF) are two inflammatory disorders that share many features including historical background, ethnical distribution and inflammatory characteristics. Several studies suggested that BD and FMF might occur in the same individual more commonly than expected. Additionally, the pathogenic MEFV gene variants, especially p.Met694Val, activating the inflammasome complex have been shown to increase the risk for BD in regions where both FMF and BD are prevalent. Whether these variants are associated with certain disease subtypes and whether they may help in the planning of treatment need to be explored. This review provides a recent overview of the plausible association between FMF and BD and the role of MEFV variants in the pathogenesis of BD.

Treat to target in Behcet's disease: Should we follow the paradigm of other systemic rheumatic diseases?

During the last decades the efficacy of biologic agents, mainly of anti-TNFs, in controlling the activity of serious manifestations of Behcet's Disease (BD) has been established. On the other hand, the clinical heterogeneity of BD has precluded the validation of a widely-accepted composite index for disease assessment and for target disease-state definitions, such as low disease activity and remission, and the testing of their implementation in clinical practice. Therefore, in contrast to other systemic rheumatic diseases, a treat-to-target strategy has not yet been developed in BD. There are several challenges towards this approach, including standardization of outcome measures for assessing the disease activity in each-affected organ and construction of a composite disease activity index. The challenges for the development of a treat-to-target strategy and possible solutions are discussed in this position paper, which stemmed from a round table discussion that took place in the 19th International Conference on BD.

Expression and characterization of recombinant IL-1Ra in Aspergillus oryzae as a system.

BACKGROUND: The interleukin-1 receptor antagonist (IL-1Ra) is a crucial molecule that counteracts the effects of interleukin-1 (IL-1) by binding to its receptor. A high concentration of IL-1Ra is required for complete inhibition of IL-1 activity. However, the currently available Escherichia coli-expressed IL-1Ra (E. coli IL-1Ra, Anakinra) has a limited half-life. This study aims to produce a cost-effective, functional IL-1Ra on an industrial scale by expressing it in the pyrG auxotroph Aspergillus oryzae. RESULTS: We purified A. oryzae-expressed IL-1Ra (Asp. IL-1Ra) using ion exchange and size exclusion chromatography (53 mg/L). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed that Asp. IL-1Ra is N-glycosylated and approximately 17 kDa in size. We conducted a comparative study of the bioactivity, binding kinetics, and half-life between Asp. IL-1Ra and E. coli IL-1Ra. Asp. IL-1Ra showed good bioactivity even at a low concentration of 0.5 nM. The in vitro half-life of Asp. IL-1Ra was determined for different time points (0, 24, 48, 72, and 96 h) and showed higher stability than E. coli IL-1Ra, despite exhibiting a 100-fold lower binding affinity (2 nM). CONCLUSION: This study reports the production of a functional Asp. IL-1Ra with advantageous stability, without extensive downstream processing. To our knowledge, this is the first report of a recombinant functional and stable IL-1Ra expressed in A. oryzae. Our results suggest that Asp. IL-1Ra has potential for industrial-scale production as a cost-effective alternative to E. coli IL-1Ra.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Improved sensitivity of the skin pathergy test with polysaccharide pneumococcal vaccine antigens in the diagnosis of Behçet disease.

OBJECTIVE: The skin pathergy test (SPT) is an important tool in the diagnosis of Behçet disease (BD), but its decreasing sensitivity over years has resulted in less frequent use in the clinical practice. This study aimed to improve the sensitivity of the SPT without compromising its specificity. METHODS: BD patients, patients with other inflammatory diseases, recurrent aphthous stomatitis, and healthy controls comprised the study group. The SPT was conducted using 20G needle and 21G lancet pricks, or with additional application of 23-valent polysaccharide pneumococcal vaccine (PS-23), Alum, or ATP to the prick site. Development of erythema and induration at 24 h/48 h were evaluated by the same observer. Induration (≥2 mm) with erythema at 48 h was accepted as a positive reaction. Proinflammatory cytokine production following stimulation with lipopolysaccharide or PS-23 was investigated by whole-blood assay (WBA) in a subgroup. RESULTS: Stimulation of the forearm skin by PS-23 and a 20G needle prick showed the highest sensitivity and specificity in BD (64.3% and 100%, respectively), especially in patients with active disease (80.3% and 100%, respectively), compared with a sensitivity of 4.8% in all and 6.1% in active patients using a single 20G prick. A positive result was associated with active disease and no use of immunosuppressives. In WBA, increased IL-1ß and IL-1Ra production in response to PS-23 was observed in the group with active BD, while the cytokine response to lipopolysaccharide was similar in all groups. CONCLUSIONS: The SPT conducted using a 20G needle prick and PS-23 antigens was shown to be a promising tool for the diagnosis of BD owing to its improved sensitivity compared with the standard approach.

Validation of the PEDiatric Behçet's Disease classification criteria: an evidence-based approach.

OBJECTIVES: to validate the PEDiatric Behçet's Disease classification criteria (PEDBD) with an evidence-based approach. METHODS: 210 pediatric patients (70 Behçet's disease (BD), 40 Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis, 35 familial Mediterranean fever, 26 hyper-IgD syndrome, 22 TNF-Receptor associated Periodic fever Syndrome, 17 undefined recurrent fevers) were randomly selected from the Eurofever Registry. A set of 11 experienced clinicians/researchers blinded to the original diagnosis evaluated the patients. Using the table consensus as gold standard (agreement ≥ 80%), the PEDBD, ISG and ICBD criteria were applied to BD patients and to confounding diseases with other autoinflammatory conditions in order to define their sensitivity, specificity and accuracy. RESULTS: At the end of the third round, a consensus was reached in 139/210 patients (66.2%). The patients with a consensus ≥80% were classified as confirmed-BD (n = 24), and those with an agreement of 60-79% as probable-BD (n = 10). When comparing these patients with the confounding diseases group, an older age at disease onset, the presence of oral and genital ulcers, skin papulo-pustular lesions, a positive pathergy test and posterior uveitis were BD distinctive elements. The ISG, ICBD and PEDBD criteria were applied to confirmed-BD and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively. CONCLUSIONS: the PEDBD criteria were very specific, while the ICBD resulted to be more sensitive. The complexity of childhood BD suggests larger prospective international cohorts to further evaluate the performance of the criteria.

The correlation between pregnancy, disease activity and adverse pregnancy outcomes in patients with systemic lupus erythematosus.

OBJECTIVE: In this study, our pregnant systemic lupus erythematosus (SLE) cohort, which was under medical surveillance of both our Rheumatology and Obstetrics departments, was analyzed. We intended to determine the effects of pregnancy on disease activity and the correlation between disease flares and adverse pregnancy outcomes. METHODS: One hundred sixty eight pregnancy data involving 136 patients with SLE were examined. Cumulative clinical, laboratory, and serological parameters were described. Disease activity and flares were calculated using the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) in the pre/postpartum periods and the SLEPDAI in the three trimesters of pregnancy. Patients with a SLEDAI-2K or SLEPDAI ≥ 4 were classified as "active." Patients with lupus low disease activity state (LLDAS) during each of these periods were identified.Fetal/neonatal death, premature birth due to pre-eclampsia, eclampsia or hemolysis, elevated Liver enzymes (HELLP) syndrome, and neonates small for gestational age were determined as adverse pregnancy outcomes (APO). RESULTS: Out of 168 pregnancies, there were 60 (35.7%) pregnancies with flares covering the pregnancy and 6 months of postpartum period. The mean SLEDAI in the 6 months postpartum period was significantly higher compared to mean disease activity during pregnancy (p < .05). Of all pregnancies, 132 (78.6%) were in LLDAS during pregnancy. Comparison of the frequency of severe postpartum flares in patients who were in LLDAS during pregnancy revealed a lower percentage of flares compared to those who were not in the LLDAS group (11 vs 29%, p < .05). APO was observed in 33.9% of 168 pregnancies. The mean SLEPDAI score was significantly higher in APO+ pregnancies than in APO- pregnancies (4.9 ± 6.1 vs 2.8 ± 4.9, p = .002). Comparison of SLICC damage score between APO - and + pregnancies revealed a significantly higher score in APO+ pregnancies (1.8 ± 2.1 vs 0.8 ± 1.3, p = .001). CONCLUSION: Postpartum six-month period appears to have the highest risk for disease flares during SLE pregnancies. Disease activity during pregnancy increases the risk of APO. In order to achieve a positive pregnancy outcome and lower maternal morbidity, regular follow-up of patients is necessary.

Efficacy and safety of interleukin-1 blockers in kidney transplant recipients with familial Mediterranean fever: a propensity score-matched cohort study.

BACKGROUND: Data on use of interleukin (IL)-1 blockers in kidney transplant recipients (KTRs) with familial Mediterranean fever (FMF) are very limited. We aimed to evaluate the efficacy and safety of anakinra and canakinumab in the transplantation setting. METHODS: In this retrospective cohort study, we included KTRs who suffered from AA amyloidosis caused by FMF and treated with anakinra or canakinumab (study group, n = 36). Using propensity score matching, we selected 36 patients without FMF or amyloidosis from our database of 696 KTRs as the control group. Primary outcomes were patient and graft survival. Biopsy-confirmed graft rejection, changes in estimated glomerular filtration rate (eGFR), high-sensitivity CRP (hsCRP), erythrocyte sedimentation rate (ESR), proteinuria and number of monthly attacks were secondary outcomes. RESULTS: All KTRs with FMF began IL-1 blocker therapy with anakinra and nine (25%) were switched to canakinumab. Overall death was more frequent in the study group (19.4% vs 0%) (P = .005); however, overall graft loss was comparable between study (27.8%) and control groups (36.1%) (P = .448). Five- and 10-year graft survival rates were significantly higher in the study group (94.4% and 83.3%, respectively) than in the control group (77.8% and 63.9%, respectively) (P = .014 and P < .001, respectively). Rejections were numerically lower in study group (8.3% vs 25%), but it did not reach to statistical significance (P = .058). When compared with the pre-treatment period, with IL-1 blockers, the number of attacks per month (P < .001), and eGFR (P = .004), hsCRP (P < .001) and ESR (P = .026) levels were lower throughout the follow-up, whereas proteinuria levels were not. CONCLUSIONS: Anakinra and canakinumab are effective in KTRs suffering from FMF; however, the mortality rate may be of concern.