Risk factors for damage accrual in primary antiphospholipid syndrome: A retrospective single-center cohort study.

BACKGROUND: Despite anticoagulant therapy, a antiphospholipid syndrome (APS) has a higher rate of recurrent events, which can lead to damage accrual and a negative impact on life quality. OBJECTIVES: To evaluate the risk factors and APS subsets associated with damage accrual. PATIENTS/METHODS: We conducted a retrospective single-center study. We reviewed the medical records of 282 APS patients, with a median age of 36 (IQR 30-46) years and a median of 195 (IQR 137-272) months. The primary endpoint was damage accrual during follow-up, defined as organ/tissue impairment present for at least six months or causing permanent loss. The secondary endpoints were early organ damage within six months of disease onset and death. RESULTS: Eighty (28.4%) patients presented damage accrual; 52.5% developed damage within six months of APS onset, and 41.3% had more than one organ involved. Neuropsychiatric involvement, affecting 38.8% of the patients, was the most frequent, followed by peripheral vasculopathy and renal involvement, 35% either. Death happened in 7 (2.5 %) patients; damage accrual was associated with a 6-fold risk of death [OR 6.7 (95% CI 1.3-35.1), p = 0.03]. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual with 5-fold and 4-fold higher risk, respectively [(OR 4.9 (95% CI 2.1-11.7), p < 0.0001 and (OR 3.8 (95% CI 1.5-10.1), p = 0.007]. The cumulative incidence of damage accrual increased by 5.7-fold and 3.6-fold in patients with microangiopathy and non-criteria manifestations. CONCLUSIONS: APS patients had a higher frequency of damage accrual. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual.

Antiphospholipid antibody carriers and patients with quiescent antiphospholipid syndrome show persistent subclinical complement activation.

OBJECTIVES: Complement activation has been advocated as one mechanism by which antiphospholipid antibodies (aPLs) can induce thrombosis. In patients with catastrophic aPL syndrome or re-thrombosis, enhanced complement activation was shown, even in quiescent phase of the disease. We aimed to assess complement activation and to investigate its association to clinical variables in aPL positive patients with a favorable disease course. METHODS: Subjects with at least two consecutive positive aPL antibody results obtained ≥12 weeks apart were enrolled. They were subjects without history of thrombosis or pregnancy morbidity (aPL carriers), patients with pregnancy morbidity alone (OAPS), and/or with arterial, venous, or small-vessel thrombosis (TAPS); all patients should have been free of symptoms for ≥2 years. Patients affected with systemic autoimmune diseases were excluded. Healthy age and sex-matched subjects were included as controls. Plasma C5a and C5b-9 levels were assessed by commercially available ELISA assays. Non-parametric Mann-Whitney test and Spearman's correlation were applied. RESULTS: Thirty-seven OAPS, 38 TAPS, 42 aPL carriers, and 30 healthy subjects were enrolled. Median C5a and C5b-9 levels were significantly higher in quiescent aPL positive patients (OAPS, TAPS, aPL carriers) compared with controls: C5a ng/ml 10.61 (IQR 6.87-15.46) vs 4.06 (2.66-7.35), p< 0.001; C5b-9 ng/ml 283.95 (175.8-439.40) vs 165.90 (124.23-236.8), p< 0.001. Similar C5a and C5b-9 levels were observed in OAPS and TAPS patients and aPL carriers. A positive correlation between C5b-9 median levels and the number of aPL positive tests was found (p= 0.002). CONCLUSIONS: The persistence of aPL antibodies is associated to a persistent subclinical activation of the complement cascade.

Predictors of disease activity in gout: a 12-month analysis of the ATTACk (Achieving improvement in the management of crystal-induced arthritis) multicentre cohort study.

OBJECTIVES: Gout treatment is largely suboptimal in clinical practice. We aimed to assess the predictors of disease-activity at 12 months in a real-life setting. METHODS: Consecutive patients referred to Rheumatology Units for suspected acute crystal-induced arthritis were enrolled in a multicentre-cohort study. Only patients with clinical diagnosis of gout were eligible. Disease-activity was evaluated by the Patient Acceptable Symptom State (PASS) on a visual analogue scale (VAS, 0=unsatisfactory, 100=satisfactory) at 0 (T0) and 12 months (T12), and the composite score called Gout Activity Score (GAS) calculated on the number of arthritic attacks (flare count), serum uric acid (sUA), cumulative number of tophi, VAS (T12), PtGA (T12). Multivariate linear regression model was performed to assess predictors of gout disease-activity at T12 with PASS and GAS as outcomes. RESULTS: 201 patients had gout (diagnosis on synovial fluid in 45%, tophi in 26%, mean sUA 7.4±1.9 mg/L, 85% with urate-lowering therapy (ULT) in progress/initiated at T0); mean age 63±13 years, 88% men, median (interquartile range) disease duration 2.9 years (0.7-9.4). Follow-up visits were performed in 113 (56%) patients at T12. Mean PASS observed at T0 and at T12 were 38±27 and 74±23, respectively, whereas GAS at T12 was 10±8. A significant association was observed between the presence of tophi and PASS at T12 (-15.3, 95% CI -25.5, -5.2; p=0.003) and GAS at T12 (+4.0, 95% CI 0.6,7.4; p=0.02), adjusted for age, sex, disease duration, sUA <6 mg/dL, tender joint count, PASS at T0, ULT). CONCLUSIONS: The baseline presence of tophi may predict high disease-activity at T12, thus worsening GAS and patients' pain perception.

Impact of COVID-19 and COVID-19 vaccination on high-risk patients with antiphospholipid syndrome: a nationwide survey.

OBJECTIVES: Patients with APS and triple-positive for aPL are at high risk of recurrent events. As COVID-19 and COVID-19 vaccination may induce thrombotic complications, the objective of the study was to assess the course of COVID-19 and adverse events after vaccination in these patients. METHODS: This is a nationwide multicentre survey conducted in nine APS referral centres by means of a questionnaire. Included patients are thrombotic APS with triple-positive aPL confirmed 12 weeks apart. Reference specialist physicians used a four-graded scale of severity for COVID-19 [from 0 (asymptomatic) to 3 (hospitalization in intensive care unit)] and a six-graded scale for adverse reactions to vaccination [from 0 (transient local injection site sign/symptoms) to 5 (potentially life-threatening reactions)]. Outcomes were considered within a 30-day period. RESULTS: Out of 161 patients interviewed, 18 (11%) had COVID-19. All of them fully recovered without any progression to severe disease nor thromboembolic event. A total of 146 patients received the first (92%) and 129 (80%) the second dose of vaccine; side effects were minimal and, in most cases (83% after the first and 68% after the second vaccination) limited to a sore arm. Fifteen patients (9%) were unvaccinated. Most of them raised doubts on the need for vaccination, complained of poor safety and in general were reluctant about COVID-19 vaccination. CONCLUSION: Patients with triple-positive thrombotic APS did not suffer from severe COVID-19 outcomes. Importantly, COVID-19 vaccination was well tolerated. These data may reassure patients and physicians and contribute to reducing hesitancy in unvaccinated patients.

High plasma C5a and C5b-9 levels during quiescent phases are associated to severe antiphospholipid syndrome subsets.

OBJECTIVES: High plasma C5a and C5b-9 levels are considered a clear sign of complement activation. We aimed to evaluate the clinical significance of these two complement activation products during quiescent phases of thrombotic antiphospholipid syndrome (APS) by comparing their plasma levels in the different clinical subsets and relating them to the clinical characteristics and antiphospholipid antibody profile of the patients. METHODS: The three patient subsets studied were: i) thrombotic patients responsive to anti-vitamin K therapy (TAPS); ii) patients with refractory to vitamin K antagonists recurrent thrombosis (RAPS); iii) patients diagnosed with catastrophic APS (CAPS). Plasma C5a and C5b-9 levels were assessed using commercial ELISA assays. RESULYTS: Sixty-two quiescent APS patients were recruited: 40 were affected by TAPS, 13 by RAPS and 9 by CAPS. Data analysis showed that the TAPS patients had significantly lower levels of both complement activation products with respect to the RAPS and CAPS patients. In addition, C5a and/or C5b-9 significantly prevailed in the patients with small-vessel thrombosis, just as C5b-9 did in the triple antiphospholipid antibody positive patients. The ROC curve showed that the best cut-offs for C5a and C5b-9 levels had a higher sensitivity, specificity and likelihood ratio in the CAPS and RAPS groups than they did in the TAPS subset. CONCLUSIONS: These results suggest that the persistence of high plasma C5b-9 and C5a levels during quiescent phases identifies APS patients with more severe disease who may develop rethrombosis and benefit from complement inhibition treatment during an acute disease phase.

The first thrombotic event in purely obstetric antiphospholipid syndrome patients and in antiphospholipid antibody carriers: comparison of incidence and characteristics.

PURPOSE: The long-term risk of thrombosis after pregnancy in women with purely obstetric antiphospholipid syndrome (OAPS) is not well defined. The current study's primary outcome was to evaluate the incidence and characteristics of the first thrombotic event in OAPS, identifying the risk factors for thrombosis in OAPS was its secondary one. METHODS: Patients with purely OAPS were consecutively enrolled between September 1999 and September 2019. Subjects without a history of pregnancy morbidity or thrombosis but with persistent positivity for one or more antiphospholipid antibodies (aPL carriers) made up the control group. The study groups included 94 OAPS patients and 124 aPL carriers who were matched for clinical and laboratory parameters. RESULTS: An event rate of 0.49/100 patient years was registered in OAPS patients during a mean follow-up of 8.7 years ± 5.5 SD. Kaplan-Meier survival analysis revealed that the cumulative incidence of thromboembolic events was not significantly different in OAPS patients vs aPL carriers. Arterial thrombosis and cerebrovascular events were the more frequent types of vascular involvement in the two groups. As far as risk factors for thrombosis were concerned, the presence of lupus anticoagulant significantly prevailed in both thrombotic OAPS patients and thrombotic aPL carriers with respect to purely OAPS patients and aPL carriers who did not develop thrombosis (p = 0.01 and p = 0.00, respectively). CONCLUSION: Just as for aPL carriers, closer monitoring and possibly, a pharmacological prophylaxis should be reserved for OAPS patients at highest risk of developing the first thrombotic event.

Catastrophic antiphospholipid syndrome: Lessons from 14 cases successfully treated in a single center. A narrative report.

The study aimed to evaluate the clinical significance of laboratory findings in patients with catastrophic antiphospholipid syndrome (CAPS) and to report the effects of a well-defined treatment protocol in 14 consecutive cases. Thirteen patients (12 presenting one and one presenting two episodes of CAPS) were consecutively treated and monitored between 1986 and 2017. Antiphospholipid antibody (aPL) characteristics of the patients were compared with those of 64 matched controls (45 antiphospholipid syndrome patients and 19 aPL carriers) who did not develop CAPS during the same mean follow-up period (12 years ±â€¯9.9 SD). Triple aPL positivity (IgG/IgM anticardiolipin + IgG/IgM anti-ß2Glycoprotein I + lupus anticoagulants) significantly prevailed in the CAPS patients with respect to the controls (p = 0.003). IgG anticardiolipin and IgG anti-ß2Glycoprotein I mean antibody titers of the CAPS patients were significantly higher than those of the controls (p = 0.0018 and p = 0.003, respectively). Triple therapy (anticoagulation + plasma exchange + steroids) was administered to all the CAPS cases except for one. Beginning in 2009, intravenous immunoglobulin infusion has also been included in the triple therapy protocol (six patients). All the patients recovered from CAPS; five showed renal failure and one a I-II class New York Heart Association (NYHA) dilated cardiomyopathy. Long-term outcomes of CAPS included a gradual worsening of renal failure in one patient who required hemodialysis 30 years after the acute episode. Renal function improved in the other four patients. The patient affected with dilated cardiomyopathy worsened to a II class NYHA over a five year period. Currently all the patients are alive. A specific antiphospholipid antibody profile could be considered a risk factor associated to CAPS. Early use of a defined treatment protocol based on triple therapy either or not associated with IVIG was associated with recovery in all CAPS patients.

Detection of autoantibodies to the p200-epitope of SSA/Ro52 antigen. A comparison of two laboratory assays.

BACKGROUND: Anti-p200 antibodies have been receiving growing interest in view of findings associating their presence to risk of fetal autoimmune congenital heart block (CHB). The study compares and evaluates the performance of two assays currently being used for their detection. METHODS: One hundred and sixteen pregnant women positive for anti-SSA/Ro52 antibodies were considered as the study population. Fifty women negative for anti-SSA/Ro52 antibodies were considered as the control population. Anti-p200 antibodies were analyzed using two home-made ELISA assays: one with biotinylated antigen and the other with free antigen. RESULTS: The specificity of the p200-free assay was significantly higher with respect to that of the p200-biotin assay (p=0.023). Both methods showed a high area under curve (AUC), thus, a good accuracy. There was a significant prevalence of anti-p200 antibodies when the p200-free assay was used to analyze the sera of the pregnant women with CHB fetuses (p=0.007). Cohen's κ and Spearman's ρ coefficients showed a good concordance (0.71) and a high correlation (0.93), respectively. CONCLUSIONS: The p200-free assay with respect to the biotin-based method was more specific in detecting p200 antibodies in women positive for anti-SSA/Ro52 antibodies. In addition, only the p200-free method significantly found p200 antibodies in patients with fetal CHB.

Plasmapheresis, intravenous immunoglobulins and bethametasone - a combined protocol to treat autoimmune congenital heart block: a prospective cohort study.

OBJECTIVES: At the moment there are no standard guidelines for the treatment of autoimmune congenital heart block (CHB). We set out to carry out a prospective cohort study to evaluate the benefits, limits, and safety of a combined therapy protocol to treat antibody-related CHB. METHODS: Twelve consecutive pregnant patients positive to anti-SSA/Ro ± anti-SSB/La antibodies in whom CHB was detected were prospectively evaluated from 2009 to 2014. The treatment protocol consisted of: weekly plasmapheresis, fortnightly intravenous immunoglobulins (IVIG), and daily 4 mg betamethasone from CHB detection until delivery; IVIG was administered to the neonates soon after birth. RESULTS: At the time CHB was detected, six of the foetuses presented atrioventricular blocks of 2(nd) degree type and six of 3(rd) degree type. Two of the foetuses with a 2(nd) degree block reverted to a 1st degree block and one to a normal atrioventricular conduction. The condition was stable throughout the pregnancy in the other three cases of 2(nd) degree block. All six 3(rd) degree blocks were stable during pregnancy and confirmed at birth. After a mean of 37.6 months ± 19.6 SD post-birth, the infants with 1st, normal sinus rhythm, and 2(nd) degree blocks at birth were all found to be stable. During the follow-up (29 months ± 19.8 SD), pacemakers were implanted in three of the six infants with 3(rd) degree blocks. CONCLUSIONS: This combined therapy seems to be effective and safe in treating 2(nd) degree CHB, while its efficacy in treating 3rd degree CHB remains to be established.

The efficacy of adalimumab in psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis: a case report.

BACKGROUND: The overlap syndrome of primary biliary cholangitis (formerly called primary biliary cirrhosis) and primary sclerosing cholangitis is an extremely rare condition that has never been described in association with other immune-mediated diseases, including psoriatic arthritis. While treatment with anti-Tumour Necrosis Factor-alpha (TNF-α) agents has proved to be effective in inflammatory arthropathies such as psoriatic arthritis, they have been employed in only a limited number of patients with autoimmune hepatitis, and their effectiveness is unclear. CASE PRESENTATION: We report the case of a 51-year-old female affected with psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis in whom 28 months of adalimumab treatment improved the symptoms of the inflammatory arthropathy as well as those of both cholangiopathies. CONCLUSION: Our results suggest that further studies examining the therapeutic role of this particular TNF-α blocker are warranted in cholestatic autoimmune hepatitis patients, and in particular in those individuals in whom the disease is associated with inflammatory arthropathies.

Apheresis in high risk antiphospholipid syndrome pregnancy and autoimmune congenital heart block.

In the first part a prospective cohort study was reported to evaluate the efficacy and safety of a treatment protocol including plasma exchange (PE) or PE plus intravenous immunoglobulins (IVIG) or immunoadsorption (IA) plus IVIG administered in addition to conventional therapy to 22 pregnant women with high-risk APS. The results indicate that PE or IA treatments administered along with IVIG and conventional antithrombotic therapy could be a valuable and safe therapeutic option in pregnant APS women with triple antiphospholipid antibody positivity along with a history of thrombosis and/or one or more severe pregnancy complications. In the second part the efficacy and safety of PE combined with IVIG and steroids were evaluated for the treatment of 10 patients with autoimmune congenital heart block (CHB) by comparing maternal features, pregnancy outcome and side effects with those of 24 CHB patients treated with steroids only. The patients treated with the combined therapy showed a statistically significant regression of 2nd degree blocks, an increase in heart rate at birth and a significantly lower prevalence of pacing in the first year of life. Moreover, no side effects were observed except for a few steroid-related events. If these results are confirmed by large-scale studies, the apheretic procedures could lead to improved outcomes in the treatment of these devastating diseases.

Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study.

OBJECTIVES: To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. METHODS: Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. RESULTS: We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. CONCLUSIONS: Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

Prevalence and adverse consequences of delayed diagnosis and misdiagnosis in thrombotic antiphospholipid syndrome. An observational cohort study and a review of the literature.

OBIECTIVES: This study aims to prospectively evaluate the frequency and adverse consequences of diagnostic delay and misdiagnosis in a cohort of patients with thrombotic antiphospholipid syndrome (TAPS). In addition, a systematic review of the literature concerning the diagnostic delay and misdiagnosis of TAPS was carried out. METHODS: Patient enrollment occurred between 1999 and 2022. The study group was formed by TAPS patients whose diagnosis was delayed and those who were misdiagnosed. The control group was made up of patients who were timely and correctly diagnosed with TAPS. RESULTS: The literature review showed 42 misdiagnosed patients, 27 of them were in one retrospective cohort study and 15 in 13 case reports. One hundred sixty-one out of 189 patients (85.2%) received a timely, correct diagnosis of TAPS; 28 (14.8%) did not. The number of patients with diagnostic issues was significantly higher for the first period (1999-2010), and the number of patients with a correct diagnosis was significantly higher for the second one (2011-2022). When the clinical and laboratory characteristics of the patients with delayed diagnosis were compared with those with misdiagnosis, there was a significantly higher number of severe adverse consequences characterized by permanent disability or death in the latter group. The two most common types of misdiagnoses were systemic lupus erythematosus (6 cases, 46.1%) and cardiovascular diseases (4 cases, 30.8%). CONCLUSIONS: The study demonstrates that although knowledge about TAPS has improved over time, diagnostic delays and errors remains to be addressed as they are strongly associated to adverse consequences. Key Points •Although knowledge of thrombotic antiphospholipid syndrome has improved over time, it is still limited. •Diagnostic delay and misdiagnosis are still an important issue that remains to be addressed as they are strongly associated to adverse consequences. •The three more frequent misdiagnoses are multiple sclerosis, systemic lupus erythematosus and cardiovascular diseases.

Short and long-term outcomes of children with autoimmune congenital heart block treated with a combined maternal-neonatal therapy. A comparison study.

OBJECTIVE: The short and long-term outcomes of children with anti-Ro/La-related congenital heart block treated with a combined maternal-neonatal therapy protocol were compared with those of controls treated with other therapies. STUDY DESIGN: Sixteen mothers were treated during pregnancy with a therapy consisting of daily oral fluorinated steroids, weekly plasma exchange and fortnightly intravenous immunoglobulins and their neonates with intravenous immunoglobulins (study group); 19 mothers were treated with fluorinated steroids alone or associated to intravenous immunoglobulins or plasma exchange (control group). RESULT: The combined-therapy children showed a significantly lower progression rate from 2nd to 3rd degree block at birth, a significant increase in heart rate at birth and a significantly lower number of pacemaker implants during post-natal follow-up with respect to those treated with the other therapies. CONCLUSION: The combined therapy produced better short and long term outcomes with respect to the other therapies studied.

Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study.

OBJECTIVES: To assess risk factors for a first thrombotic event in confirmed antiphospholipid (aPL) antibody carriers and to evaluate the efficacy of prophylactic treatments. METHODS: Inclusion criteria were age 18-65 years, no history of thrombosis and two consecutive positive aPL results. Demographic, laboratory and clinical parameters were collected at enrolment, once a year during the follow-up and at the time of the thrombotic event, whenever that occurred. RESULTS: 258 subjects were prospectively observed between October 2004 and October 2008. The mean ± SD follow-up was 35.0 ± 11.9 months (range 1-48). A first thrombotic event (9 venous, 4 arterial and 1 transient ischaemic attack) occurred in 14 subjects (5.4%, annual incidence rate 1.86%). Hypertension and lupus anticoagulant (LA) were significantly predictive of thrombosis (both at p<0.05) and thromboprophylaxis was significantly protective during high-risk periods (p<0.05) according to univariate analysis. Hypertension and LA were identified by multivariate logistic regression analysis as independent risk factors for thrombosis (HR 3.8, 95% CI 1.3 to 11.1, p<0.05, and HR 3.9, 95% CI 1.1 to 14, p<0.05, respectively). CONCLUSIONS: Hypertension and LA are independent risk factors for thrombosis in aPL carriers. Thromboprophylaxis in these subjects should probably be limited to high-risk situations.

Predictive factors for switching in patients with psoriatic arthritis undergoing anti-TNFα, anti-IL12/23, or anti-IL17 drugs: a 15-year monocentric real-life study.

OBJECTIVES: We aimed to evaluate the (a) potential predictors of first biological disease-modifying anti-rheumatic drug (bDMARD) failure and (b) factors associated with failure of multiple therapies in psoriatic arthritis (PsA). MATERIALS AND METHODS: We enrolled consecutive PsA patients attending our unit and undergoing bDMARDs during 2004-2020. Disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were recorded. Disease activity and functional and clinimetric scores were recorded at baseline and yearly and were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Effectiveness was evaluated over time with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of response and failure of multiple bDMARDs. Kaplan-Meier curves were used to assess differences in time-to-first bDMARD discontinuation. Infections and adverse events were recorded. RESULTS: Two hundred sixty-four patients were included (117 (44.32%) females, mean age 56 years, mean PsA duration 15 years); 117 (44.32%) switched bDMARDs at least once. Switchers were mostly females, with higher Psoriasis Area and Severity Index and worse Health Assessment Questionnaire at baseline. Mean time-to-first bDMARD discontinuation was 72 months; 2-year and 5-year retention rates were 75% and 60%, respectively. Survival curves for anti-TNFα/anti-IL12/23/anti-IL17 were similar (p = 0.66). Main reasons for switching were inefficacy (67.52%) and adverse events (25.7%). Female sex was associated with a higher risk of first bDMARD discontinuation (HR = 2.39; 95% CI: 1.50-3.81) and failure of multiple bDMARDs (OR = 1.99; 95% CI: 1.07-3.69); initiating therapy before 2015 was protective (HR = 0.40; 95% CI: 0.22-0.73). CONCLUSIONS: Survival rate was good for anti-TNFα and other bDMARDs. Female sex was a predictor of first bDMARD discontinuation, unlike mechanism of action, comorbidities, and BMI. Key Points • Drug survival in PsA patients was confirmed be greater for the first bDMARD administered. • In case of failure of the first bDMARD, switching/swapping proved a good treatment option, as reflected by a persistent satisfactory effectiveness with second-line bDMARDs and so subsequent switches. • Female sex may constitute a predisposing risk factor for flare and therapeutic switches. • Discontinuation or switching of biologics due to mechanism of action, comorbidities tolerability and BMI did not seem to impact first bDMARD withdrawal.

The efficacy and safety of second-line treatments of refractory and/or high risk pregnant antiphospholipid syndrome patients. A systematic literature review analyzing 313 pregnancies.

OBJECTIVE: The most efficacious strategy to manage pregnant patients with antiphospholipid syndrome (APS) refractory to conventional heparin/low-dose aspirin treatment or at high risk of adverse pregnancy outcomes has not been determined with any degree of certainty. The study set out to evaluate the efficacy and safety of the second-line treatments most frequently used in addition to conventional therapy, and the data were analyzed to identify which is/are associated to the best pregnancy outcomes. METHODS: A systematic review of the literature on studies concerning second-line treatments for refractory and/or high risk pregnant APS women published between February 2006 and February 2020 was conducted. The records were retrieved by searching Medline via Pubmed, the Web of Science platform, the Cochrane library database and clinicaltrials.gov. RESULTS: Fourteen studies met the eligibility criteria of the review: six retrospective cohort studies, one case-control, one case-series and six case reports. The results of single treatment protocols based upon hydroxychloroquine (HCQ), low-dose steroids (LDS), intravenous immunoglobulins (IVIG), plasma exchange (PE) or pravastatin and of combination protocols based upon HCQ+LDS, IVIG+LDS, PE+LDS and PE+IVIG used during 313 pregnancies in 303 APS women were analyzed and compared. The second-line treatments produced 261/313 (83.4%) live births; severe pregnancy complications were registered in 75/313 (24%) pregnancies. Drug side-effects were observed in 3/313 (0.9%) pregnancies. Statistical analysis identified a significantly higher live birth rate and/or a significantly lower number of severe complications in the pregnancies treated with IVIG, HCQ, pravastatin, PE+IVIG and PE+LDS. CONCLUSION: Our results suggest using low-dose IVIG (< 2 g/Kg/month) or HCQ 400 mg/day starting before pregnancy in women with APS refractory to conventional therapy, while high-dose IVIG (2 g/Kg/month) associated with PE or alone in those with high risk±refractory APS.

Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies.

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers' pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

Upgrading Therapy Strategy Improves Pregnancy Outcome in Antiphospholipid Syndrome: A Cohort Management Study.

The current study evaluates the efficacy and safety of different treatment strategies for pregnant patients with antiphospholipid syndrome. One hundred twenty-seven consecutive pregnancies were assessed; 87 (68.5%) with a history of pregnancy morbidity alone were treated with prophylactic low molecular weight heparin (LMWH) + low-dose aspirin (LDA, 100 mg) (group I) and 40 (31.5%) with a history of thrombosis and/or severe pregnancy complications with therapeutic LMWH + LDA (group II). LMWH doses were increased throughout the pregnancies depending on the patients' weight gain, and treatment was switched to a more intensive one at the first sign of maternal/fetal complications. The study's primary outcome was live births. There were no significant differences in live birth rate between group I (95.4%) and group II (87.5%). Even fetal complication rate was similar in the two groups; group II nevertheless had a higher prevalence of maternal and neonatal complications (p = 0.0005 and p = 0.01, respectively) and registered a significantly lower gestational age at delivery and birth weight (p = 0.0001 and p = 0.0005, respectively). Two patients in group I switched to group II therapy, six patients in group II switched to a more intensive treatment strategy (weekly plasma exchange + fortnightly intravenous immunoglobulins in addition to therapeutic LMWH + LDA). The multivariate analysis uncovered that triple antiphospholipid antibodies positivity was an independent factor leading to a more intensive therapy. All eight switched patients achieved a live birth. Study results revealed that adjusted LMWH doses and switching therapy at first signs of severe pregnancy complications led to a high rate of live births in antiphospholipid syndrome patients.