Rheumatoid Arthritis from Easy to Complex Disease: From the "2022 GISEA International Symposium"

: Rheumatoid Arthritis (RA) is a systemic disease with many different clinical phenotypes. RA could be classified according to disease duration, seropositivity for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA), joint subtype, clinical behaviourbehavior and many other subgroups. In this review, we summarize and discuss the multifaceted aspects of RA, focusing on the relationship between autoimmunity status and clinical outcome, achievement of remission and influence on treatment response, from the 2022 International GISEA/OEG Symposium

Tapering and discontinuation of glucocorticoids in patients with rheumatoid arthritis treated with tofacitinib

Abstract Although the rapid onset of effect of glucocorticoids (GCs) allows rapid control of rheumatoid arthritis (RA) symptoms, their chronic use may be associated with several adverse events. The 2022 update of EUALR recommendations for the management of patients with RA suggests to reduce and discontinue oral GCs as quickly as possible. Considering GCs as a "bridging therapy" to promptly reduce symptoms and control inflammation, fast-acting drugs such as tofacitinib could allow faster and safer tapering of GCs. The purpose of this pilot study was to evaluate the steroid-sparing effect of adding tofacitinib in patients with RA inadequately responsive to methotrexate taking concomitant GCs. In this open-label pilot study, we enrolled patients with moderate to severe RA on a stable dose of prednisone (5–12.5 mg/day) who started treatment with tofacitinib. After 1 month, in patients who achieved at least a moderate EULAR response (decrease of > 1.2 in DAS28_CRP), GCs was tapered according to a predetermined schedule until complete discontinuation at week 12. Disease activity was assessed after 4, 12, 24 and 48 weeks of treatment. The primary endpoint was the percentage of patients discontinuing GCs after 12 weeks of tofacitinib treatment. We enrolled 30 patients (26 F: 4 M, mean age 60 ± 13 years, mean disease duration 13.2 ± 7.8 years). The primary endpoint was achieved: 9 patients (30%) discontinued GCs at week-12. At week-24, other 12 patients (46%) withdrew GCs. The median prednisone dose decreased from 5 mg/day (interquartile range 5–10 mg) to 2.5 (0–5) mg/day at week 12 and 48 (p < 0.00001 vs baseline). At week 48, 12 out of 30 patients (40%) had discontinued prednisone. The percentage of patients achieving remission or low disease activity increased throughout the follow-up without any difference between patients who discontinued or not the GC. In this cohort of long-standing RA patients treated with tofacitinib, the discontinuation of glucocorticoids was achievable in up to 30% of patients. These results should encourage rheumatologists to consider GCs tapering and discontinuation of GCs, as suggested by the 2022 EULAR recommendations, an achievable goal

Cord entanglement

Cord entanglemen

Recurrent Pregnancy Loss Causes, Controversies, and Treatment cap. 8 The Etiology of the Antiphospholipid Syndrome

Phospholipids (PL), the basic components of all cell membranes, consist of two layers. The inner layer contains negatively charged anionic alcohol groups facing the cytoplasm, and the outer layer contains neutral or zwitterionic alcohol groups facing the extracellular fluid or bloodstream. In certain conditions such as ischemia, cell injury, or autoimmunity, negatively charged PLs can be exteriorized. The exteriorized PLs may be an antigenic stimulus for the production of antiphospholipid antibodies (aPL) or permit a number of serum proteins with procoagulant activity (\u3b22-glycoprotein I [\u3b22-GP1], prothrombin, protein C, protein S, and annexin V) to bind PL epitopes and be presented to the immune system in unique \u201cneoantigenic\u201d conformations, which may induce aPL formation [1]. aPL may recognize either the PL region of the complex or an epitope consisting of the portion of the PL and neighboring aminoacyls on the protein carrier, or may react with the protein alone. In pregnancy, placental tissues are continuously remodeled resulting in the externalization of inner surface PLs such as phosphatidyl serine (PS) [2]. aPL require a cofactor (apolipoprotein H or \u3b22GP1), a negatively charged phospholipid binding protein, to exert their effects. \u3b22GP1-dependent aPL are thought to recognize their antigen on placental tissue, inhibit growth and differentiation of trophoblasts, and cause inflammation, defective angiogenesis, and thrombosis, leading to impaired placentation

Haemoglobin discordances in twins: is "really" due to differences in timing of cord clamping? A consideration to Verbeek L and co-authors

Dear Editor, We read with interest the article by Verbeek L. et al [1], showing that the second-born twin has higher levels of hemoglobin (Hb) than first-born co-twins after vaginal delivery (VD; Hb differential effect does not occur in twins delivered by Caesarean section. Since Hb difference is present in both uncomplicated monochorionic (MC) and dichorionic (DC) twin pairs, authors focused on the time difference of umbilical cord clampings (UCC) for the two twins, rather than vascular anastomoses (absent in DC twins). Precise timing data unfortunately were not recorded. However, beside UCC timing, other factors should be taken into account for the VD management. Recent observations have provided compelling evidence demonstrating that UCC timing is not the only determinant of net placental -to-infant blood transfusion [2]; uterine contractions and lung aeration result to be determinant factors influencing umbilical artery and venous blood flows[2]. Specifically the uterine contractions during the third stage of labor significantly increase the placental-to-neonatal gradient and may facilitate 50% of placental transfusion [3]; such effect is also reported in single term neonates when the "two step" head-to-body delivery method is used [4]. In our opinion, uterine contractions can affect the placental transfusion more than UCC timing in the vaginally born twins: the second-born twin is exposed to the contractions that lead to the birth of the first twin! These additional contractions can increase the placental transfusion and the risk of polycithemia both in DC and MC twins; moreover, in second-born MC twin, contractions can determine acute inter-twin blood transfusion through placental vascular anastomoses. In agreement with authors [1], targeted studies in the twins delivered vaginally should be carried out to establish the optimal UCC timing; anyway we recommend evaluating also the effect of uterine contractions as well as medications administered to the mothers, such as oxytocin-like components

Is there any role for the Hydroxychloroquine (HCQ) in refractory obstetrical antiphospholipid syndrome (APS) treatment?

The best therapy regimen for refractory obstetrical antiphospholipid syndrome remains to be determined. Additional treatments with steroids, plasma exchanges and immunoglobulins failed to show any beneficial effect. We present a case of a woman who had a better pregnancy outcome after the administration of hydroxychloroquine (HCQ) as additional treatment. Furthermore, we highlighted that HCQ was able to dramatically reduce the antiphospholipid antibodies levels

Five-years drug survival of mycophenolate mofetil therapy in patients with systemic lupus erythematosus. comparison between renal and non-renal involvement

Objective: The EULAR recommendations underline the use of MMF for Lupus Nephritis (LN) but also for the treatment of moderate/severe non-renal manifestations (NLN). This study aims at evaluating the 5-years drug retention rate (DRR) of MMF in a SLE cohort in a real-life scenario. Secondly, we investigated the MMF influence to control chronic damage progression. Methods: We performed a longitudinal study including all the SLE patients starting MMF in our Lupus Clinic (from 2008 to 2020). The DRR was estimated using the Kaplan-Meier method. Results: We evaluated 162 SLE patients (M/F 22/140). The most frequent indications for prescribing MMF were LN (101 patients, 62.3%) and musculoskeletal manifestations (39, 24.1%) followed by NPSLE (10, 6.2%) and other manifestations (12, 7.4%). We registered a median treatment duration of 30 months (IQR 55). At 60 months follow-up we observed a DRR of 61.1% for LN patients, which was similar to that registered for patients without renal involvement (60.5%). The DRR was higher in the subgroup of patients with joint involvement (75.4%, p non-significant). During the overall observation period, 92 patients (59.2%) discontinued MMF. The main cause of withdrawal was the achievement of remission, observed in 20 patients (21.7%). Moreover, MMF resulted able to control chronic damage progression, as demonstrated by the lack of significant increase in the median SDI values (baseline: 0.6, IQR 1; last: 0.93, IQR 1). Conclusions: Our finding suggested that MMF is a safe and effective drug for SLE manifestation other than LN, especially for joint involvement. Moreover, it was able to reduce the chronic damage progression

HOW TO USE LUPUS ANTICOAGULANTS IN NEONATES BORN TO MOTHERS WITH ANTIPHOSPHOLIPID SYNDROME.

HOW TO USE LUPUS ANTICOAGULANTS IN NEONATES BORN TO MOTHERS WITH ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome: An update on risk factors for pregnancy outcome

Background: The optimal treatment of women with primary antiphospholipid syndrome (APS) is still debated. About 20\u201330% of women with APS remain unable to give birth to healthy neonates despite conventional treatment, consisting of prophylactic-dose heparin and low-dose aspirin. These cases are defined \u201crefractory obstetric APS\u201d. The early identification of risk factors associated with poor pregnancy outcome could be the optimal strategy to establish criteria for additional therapies, such as hydroxychloroquine, steroids, intravenous immunoglobulin, and plasma exchange. Purpose: The aim of the present study was to review current literature about risk factors for poor pregnancy outcome. Search methods: The PubMed database was used to search for peer-reviewed original and review articles concerning risk factors for pregnancy outcome in APS from 1st January 1990 to 15th January 2018. Outcomes: History of pregnancy morbidity and/or thrombosis, the association with SLE and/or other autoimmune diseases are well known history-based predictive factors for obstetrical complications, such as miscarriage, maternal venous thromboembolism, intrauterine foetal demise, preeclampsia, and neonatal death. Moreover, laboratory findings associated with poor pregnancy outcome are:triple antiphospholipid antibodies aPL positivity, double aPL positivity, single aPL positivity, false-positive IgM for CMV, and hypocomplementemia. Triple positivity is confirmed as the most significant risk factor by a large body of evidence. Furthermore, the abnormal uterine arteries Doppler velocimetry results are confirmed to be strongly associated with poor pregnancy outcomes in APS. The good performance of the uterine arteries velocimetry, as a negative predictive factor, was reported by different studies. On the contrary, in case of abnormal uterine arteries results, the relevance of a careful surveillance is highlighted for the high risk of maternal-foetal complications. Nevertheless, this tool is a late indicator to suggest any additional treatments. Conclusions: In order to prevent obstetrical complications and establish the optimal combination therapy, the knowledge at preconception or at the beginning of pregnancy of risk factors associated with poor pregnancy outcome could be a crucial step for management and treatment of APS. In addition, in the preconception assessment a regimen with low-dose aspirin, folic acid, and vitamin D supplementation should be offered, and a treatment strategy has to be established (conventional vs additional therapy). In fact, additional treatment has to be tailored for each patient