Pregnancy outcomes in ANCA-associated vasculitis patients: A systematic review and meta-analysis.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), namely granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis constitute a group of rare systemic vasculitides, affecting small vessels. Genders are equally affected, with symptoms most commonly presenting during and/or after the fifth decade of life, but AAV may also present in younger individuals. As advanced maternal age is becoming common and safe over the last decades, it is now more feasible for middle-aged women suffering from AAV to get pregnant. Although adverse pregnancy outcomes have been thoroughly investigated in other systemic diseases, the exact prevalence of pregnancy complications and unfavorable outcomes in pregnant women with AAV has not been systematically evaluated. METHODS: We researched PubMed, Scopus, Cochrane Library and Cinahl databases until September, 2022. Three blinded investigators extracted data and assessed the risk of bias. A random effects model was used for the analysis. The outcomes studied were pre-term delivery, intrauterine growth restriction (IUGR) neonates and disease flare. RESULTS: We included six studies with 92 pregnancies in patients with AAV. The prevalence of pre-term delivery, IUGR neonates and disease flare were 18% (CI: 0.10-0.30, P=non-significant), 20% (CI: 0.11-0.33, P=non-significant) and 28% (CI: 0.09-0.59, P<0.01), respectively. CONCLUSION: The analysis demonstrated higher occurrence of adverse outcomes in pregnant women suffering from AAV accompanied by an increased risk of disease flare during pregnancy. These findings underline the importance of preconception counseling and the necessity of close monitoring in these patients similarly to other systemic inflammatory diseases.

Pregnancy outcomes in Takayasu arteritis patients: a systematic review and meta-analysis.

Takayasu arteritis (TA) is a systemic disease affecting women of reproductive age. Similarly to other systemic autoimmune diseases, pregnancies in patients suffering from TA are at high risk for adverse outcomes; however, the precise incidence of adverse events has not been assessed in a systematic approach. To evaluate the prevalence of adverse pregnancy outcomes in TA. Searches were conducted on PubMed, Cochrane Library, Scopus and Cinahl databases from inception to 25 May 2022. Three independent investigators extracted data and assessed the risk of bias using ROBINS-1 tool. We used a random effects model to calculate the prevalence of the adverse pregnancy outcomes in TA, namely miscarriage, hypertension and pre-eclampsia. We calculated the prevalence of the adverse outcomes in pregnancy for TA. We included 27 studies, with 825 pregnancies. The occurrence of miscarriage, hypertension and pre-eclampsia in patients with TA was 16% (CI 12-21%, p < 0.01), 37% (CI 30-45%, p < 0.01) and 14% (CI 8-23%, p < 0.01), respectively. The results of our meta-analysis indicate that pregnancies in patients with TA are at increased risk for adverse pregnancy outcomes compared to the general population, suggesting that pregnant women with TA should be closely monitored.Trial registration: There was no registration for this systematic review. The aim of this study was to evaluate etc in order to be correct by syntax.

Remission or low disease activity at pregnancy onset are linked to improved foetal outcomes in women with systemic lupus erythematosus: results from a prospective observational study.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients show variably increased risk for pregnancy complications. We analysed pregnancy outcomes (foetal and maternal), patterns of disease activity and use of medications in a contemporary Caucasian SLE population. METHODS: Prospective observational study, involving hospital units and private rheumatologists in Greece, of incident pregnancies (period 2015-2018) in women with SLE. Clinical and obstetrical monitoring was performed at regular intervals up to 9 months post-partum. Regression and mixed model analyses were used to determine predictors for adverse foetal outcomes and flares. RESULTS: We monitored 82 pregnancies in 64 SLE patients. Foetal loss, prematurity and small for gestational age neonate occurred at 15.8%, 34.1% and 8.5%, respectively; 53.7% of pregnancies were complicated with at least one adverse outcome. Patients with antiphospholipid antibodies (aPL) had increased risk (odds ratio [OR] 5.67, p=0.015), whereas those at low disease activity at pregnancy onset were protected (OR 0.20, p=0.024) against foetal complications. Persistent activity and glucocorticoid intake during pregnancy also predicted poor foetal outcomes. SLE patients experienced an average 1.08 mild/moderate and 0.27 severe flares. The latter occurred more frequently post-partum, in patients with alopecia (OR 8.92, p=0.003), hypocomplementaemia (OR 10.34, p=0.038) and nephritis (OR 7.32, p=0.052). Lupusactivity post-labour was paralleled by decreased use of hydroxychloroquine, glucocorticoids and azathioprine. CONCLUSIONS: In SLE women, foetal complications are common especially in the presence of aPL and increased activity, which corroborates the importance of pregnancy planning and tight disease control at pregnancy onset. Flares, mostly mild or moderate, can occur both during and after pregnancy.

Capturing the enthesitis related arthritis contemporary profile of Caucasian patients in the era of biologics.

To describe the profile of Enthesitis Related Arthritis' (ERA) patients, in the era of biologic DMARDs (bDMARDs). This retrospective cohort study included patients with ERA monitored on a 3-month schedule for at least 1 year. Their metric assessment included the disease status and damage by applying the contemporary tools clinical-Juvenile Arthritis Disease Activity Score (c-JADAS), Juvenile Spondyloarthritis Disease Activity Index (JSpADA), clinical remission (CR) on/off medication and Juvenile Arthritis Damage Index (JADI). 43 patients (males 26) were enrolled, with a mean disease onset of 10.75 years. Median lag time from diagnosis to bDMARDs was 8.5 months. Patients with sacroiliitis received earlier bDMARDs (hazard ratio, HR 3.26). 36/43 patients achieved CR on medication (median time 11 months), which was correlated with compliance (HR: 3.62). The percentage of CR in patients with or without sacroiliitis was 35% and 63% respectively (p = 0.02). Twenty patients (47%) experienced a flare following CR (75%). The median flare-free survival following CR on/off medication was 42 and 34 months, respectively. At the last evaluation, both median baseline cJADAS and JSpADA dropped to 0, 13/43 patients had a persistent disease activity, while 17/43 and 13/43 patients were in CR on/off medication, respectively. The median patient percentage of CR was 54% and no patient had a JADI > 0. Increased lag time to bDMARDs was associated with increased CR (Odds ratio: 1.48). Early administration of bDMARDs and compliance improved long-term outcome of ERA. Sacroiliitis was a negative prognostic factor with an increased need for bDMARDs and diminished rates of CR.

Low disease activity-irrespective of serologic status at baseline-associated with reduction of corticosteroid dose and number of flares in patients with systemic lupus erythematosus treated with belimumab: A real-life observational study.

BACKGROUND: Low disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy. The aim of this study was to assess the ability of belimumab to achieve low disease activity states in real-life settings. METHODS: Multicentre prospective observational study of consecutive SLE patients receiving belimumab for at least 3 months, due to active disease refractory to at least one conventional immunosuppressant. Disease activity, including the recently defined lupus low disease activity state (LLDAS) and remission (clinical SLEDAI-2K = 0), accrual of organ damage, flares and side effects were documented. RESULTS: Ninety-one patients were included [94.5% women, mean (SD) age 45.9 (12.5) years]. Most frequent manifestations were arthritis (76.7%), rash (72.5%), serologic activity (low C3/C4 and/or high anti-dsDNA; 54.9%), hair loss (47.2%) and mucosal ulcers (27.5%). Median (range) duration of treatment was 10.5 (3.0-42.1) months. Belimumab significantly decreased average SLEDAI-2K, physician global assessment (PGA) and daily prednisone dose over time, as early as 3 months after initiation, with over 20% of patients discontinuing corticosteroids. Although reduction in clinical (i.e., excluding serology) SLEDAI-2K was more pronounced in patients who were serologically active (from 8 to 1.5 at 12 months) as compared to serologically inactive (from 6 to 4) at baseline, attainment of LLDAS did not differ between the two groups and was reached by more than 40% of completer patients after 9-12 months. In addition, the number of flares and severe flares was reduced by 62% and 50%, respectively, during the first 12 months of treatment. Twenty patients (22.0%) discontinued treatment due to inadequate response and two due to side effects potentially related to the drug. CONCLUSIONS: In real-life, belimumab is efficacious in achieving low disease activity in over 40% of unselected patients, in combination with reduction of corticosteroid dosage and number of flares. Both serologically active and inactive patients respond to the drug.

Birth Registry of Women With Systematic Lupus Erythematosus: The Greek Experience.

Pregnancy in women with SLE (Systematic Lupus Erythematosus) is considered of "high risk" since it has been related with adverse events both in the mother and the foetus. Many studies have reported relapse of the disease during the pregnancy and the first trimester post-labour, while others have found no difference in terms of frequency and type of relapses. Moreover, adverse obstetrical events like recurrent pregnancy loss, preeclampsia, prematurity, intrauterine growth restriction and neonatal lupus syndrome tend to occur more often in patents with SLE. However, most of these data regarding the burden and pregnancy outcomes in SLE come from retrospective studies of previous decades, and in non-Caucasian patients. To this end, more recent studies have suggested overall improved outcomes of pregnancy, still their results are often conflicting. The purpose of this study is to record, through a prospective observational (non-interventional) study, the contemporary prognosis of pregnancy in women with SLE who are followed-up by private and hospital physicians in Greece. In particular, we aim to establish a registry to study the course of the disease during pregnancy, the outcome of pregnancy and the possible negative or positive prognostic factors, the effect of drugs on pregnancy and the foetus.

Predictors and long-term outcome in Greek adults with juvenile idiopathic arthritis: a 17-year continuous follow-up study.

Objectives: To describe the disease characteristics, continuous course and long-term outcome and to evaluate predictors of outcome in JIA in Greece. Methods: We performed a retrospective cohort analysis of 17 years' prospective data on JIA. Outcome assessment included radiographic (modified Sharp-van der Heidje score), articular and extra-articular damage (Juvenile Arthritis Damage Index), functional ability (HAQ Disability Index), and the cumulative percentage time spent in a state of active disease and also in clinical remission off medication (CR) (according to Wallace's criteria). Results: One hundred and two (72 females) patients under regular follow-up were enrolled. The disease age of onset [mean (SD)] was 7.7 (4) years, the interval from onset to last visit was 17.2 (6.7) years and the patients' current age was 25 (5.9) years. At the last follow-up visit, 53 patients (52%) had disease activity, while 23.5% were in CR. The cumulative percentage time spent in a state of active disease and CR over the disease course was 52.6 and 17.8%, respectively. Polyarticular subtype of onset and longer disease activity during the first 5 years were independent predictors of worse outcome. Additional telephone-based interviews of 205 former JIA patients who had been lost to follow-up as adults were performed to extend the interpretation of our findings to a broader JIA population. Almost half (47.6%) of the total cohort of 307 patients were found to be in CR at the final evaluation and 69.7% had no disability. Conclusion: The available data indicate that JIA as a whole is a heterogeneous disease with significant variability in course and long-term outcome.

Τhe genetics of juvenile idiopathic arthritis: Searching for new susceptibility loci.

Juvenile idiopathic arthritis (JIA) is an autoimmune disease that is characterized by persistent chronic arthritis and affected by genetic and environmental factors. Different genetic variations have been reported as risk factors for JIA. However, given that many results could not be replicated in individuals of different ancestral origin, it was assumed that heterogeneous genetic factors are involved in this disease. In the present study, we analyzed three single nucleotide polymorphisms (SNPs), namely PTPRC (rs10919563), TYK2 (rs34536443) and PRKCQ (rs4750316), which were found to be associated with JIA in previous studies. We also investigated whether the intron­4 located 27­bp VNTR of endothelial nitric oxide synthase (eNOS), is associated with risk for JIA in Greece. In total, 125 JIA patients and 221 healthy controls from northern Greece were included in the study as a sample set. Samples were then analyzed, and genotyped for the three SNPs with TaqMan primer­probe sets, using a Real­Time PCR platform (ViiA™ 7 Real­Time PCR system), while eNOS VNTR polymorphism was genotyped by PCR. Statistical analysis was performed using a GraphPad Prism statistical program. The χ2 test was used to examine differences of genotype and allele frequencies between patients and controls. Statistical significance was defined by using the two­tailed P<0.05 test. Bioinformatics analysis was conducted by using BlastP, Pymol, Maestro and Desmond. In the case­control association study performed, eNOS only was found to be associated with JIA. Genotype a/a and allele 'a' were found in a higher frequency in JIA patients than in controls [p<0.0001, odds ratio (OR)=0.15, 95% confidence intervals (CI): 0.065­0.37; and p<0.0001, OR=0.34, 95% CI: 0.23­0.49, respectively]. No associations with JIA were detected for TYK2, PTPRC or PRKCQ. Aiming to investigate the structural consequences and the structure/function relationships accompanying the Pro1104 to Ala (rs34536443) mutation on TYK2 protein, bioinformatics analysis was performed. Combining three­dimensional (3D)­modeling and molecular dynamics simulations we identified changes in structural flexibility, affecting the functionality of the kinase domain of TYK2. To the best of our knowledge, this is the first time that eNOS VNTR polymorphism is associated with susceptibility to JIA, suggesting a differential role of allele 'a' in various complex diseases. The current data emphasize the importance of comparative studies in populations of a different ancestral background towards the clarification of the role of specific alleles in the development of JIA.

Autoimmune Thrombotic Thrombocytopenic Purpura: Two Rare Cases Associated with Juvenile Idiopathic Arthritis and Multiple Sclerosis.

Secondary thrombotic microangiopathies are associated with several underlying conditions, with most of them being resolved after the treatment of background disease. Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathy presenting with anemia, thrombocytopenia, and neurological deficits, occurring most often in various autoimmune diseases due to inhibition of ADAMTS13 by autoantibodies, as well as in pregnant women with or without an autoimmune substrate. In this article, we report two newly diagnosed TTP cases, who have not been published so far. The first is a 27-year-old woman with a history of polyarticular rheumatoid factor negative juvenile idiopathic arthritis, who presented with thrombocytopenia, anemia, schistocytes on blood smear, headache, and active arthritis. Originally she was treated successfully with plasma exchange, intravenous prednisone, and vincristine, and a few months after the TTP episode, she was commenced on rituximab, resulting in remission of primary disease and no relapse of TTP. The second case refers to a 29-year-old pregnant woman complaining of dizziness and fatigue with microangiopathic hemolytic anemia. She was treated with plasma exchanges, intravenous prednisolone, and INN human normal immunoglobulin with full remission of the TTP episode. Six and half years later, she was diagnosed with multiple sclerosis and was commenced on interferon beta-1 alpha, with no recurrent episode of TTP. These cases broaden the spectrum of autoimmune disorders manifested or complicated clinically by TTP. Furthermore, biological agents such as rituximab appear to be an effective treatment option for refractory cases of TTP related to systemic rheumatic disease, indicating an alternative therapeutic solution in persistent cases of this disorder.

Infliximab as a treatment option for patients with rheumatoid arthritis and primary biliary cirrhosis.

Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease which commonly requires treatment with biologic agents targeting various inflammatory pathways. Tumor necrosis factor alpha is a proinflammatory cytokine which plays a pivotal role not only in the pathogenesis of RA but also in other autoimmune diseases such as primary biliary cirrhosis. The co-existence of more than one autoimmune disorder in the same individual is very challenging in the daily practice as therapy strategies applicable to one disease setting may cause clinical and/or biochemical relapse of the other clinical entity. As a result, treatment options able to control different diseases are highly desirable among rheumatologists and other specialties. In that respect, we present a case of a 61-year-old female patient with RA and concomitant primary biliary cirrhosis with poor clinical response to conventional disease-modifying drugs for RA. The introduction of tumor necrosis factor alpha antagonist infliximab led to significant clinical improvement of RA and to stabilization of liver function. In this case review study, we discuss aspects of pathophysiology of primary biliary cirrhosis associated with tumor necrosis alpha and we review the available data of similar published cases.