Efforts to Better Characterize "Antiphospholipid Antibody Nephropathy" for the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria: Renal Pathology Subcommittee Report.

OBJECTIVE: Antiphospholipid antibody (aPL) nephropathy (-N) can be challenging to recognize due to a lack of established classification or diagnostic criteria. As part of efforts to develop new antiphospholipid syndrome (APS) classification criteria (CC), the APS CC Renal Pathology Subcommittee aimed to better characterize the entity of aPL-N. METHODS: We used a 4-pronged approach that included (1) administering Delphi surveys to worldwide APS physicians to generate aPL-N terminology; (2) conducting a literature review to demonstrate the association of nephropathy with aPL and identify published aPL-N histopathological terminology and descriptions; (3) evaluating aPL-N terminology used in renal biopsy reports from an international patient registry; and (4) evaluating proposed kidney pathologic features for aPL-N by assessment of international Renal Pathology Society (RPS) members. RESULTS: After completing our metaanalysis demonstrating an association between nephropathy and aPL, we used Delphi surveys, a literature review, and international renal biopsy reports to develop a preliminary definition of aPL-N. The preliminary definition included include specific terms associated with acute (ie, thrombotic microangiopathy in glomeruli or arterioles/arteries) and chronic (ie, organized arterial or arteriolar microthrombi with or without recanalization, organized glomerular thrombi, fibrous and fibrocellular [arterial or arteriolar] occlusions, focal cortical atrophy with or without thyroidization, and fibrous intimal hyperplasia) lesions. Most RPS survey respondents agreed with this terminology and the importance of knowing aPL results for histopathological diagnosis. CONCLUSION: Our results support the inclusion of aPL-N in the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology APS CC, and provide the most widely accepted terminology to date for both acute and chronic pathologic lesions of aPL-N.

HPOSS: A hierarchical portfolio optimization stacking strategy to reduce the generalization error of ensembles of models.

Surrogate models are frequently used to replace costly engineering simulations. A single surrogate is frequently chosen based on previous experience or by fitting multiple surrogates and selecting one based on mean cross-validation errors. A novel stacking strategy will be presented in this paper. This new strategy results from reinterpreting the model selection process based on the generalization error. For the first time, this problem is proposed to be translated into a well-studied financial problem: portfolio management and optimization. In short, it is demonstrated that the individual residues calculated by leave-one-out procedures are samples from a given random variable ϵi, whose second non-central moment is the i-th model's generalization error. Thus, a stacking methodology based solely on evaluating the behavior of the linear combination of the random variables ϵi is proposed. At first, several surrogate models are calibrated. The Directed Bubble Hierarchical Tree (DBHT) clustering algorithm is then used to determine which models are worth stacking. The stacking weights can be calculated using any financial approach to the portfolio optimization problem. This alternative understanding of the problem enables practitioners to use established financial methodologies to calculate the models' weights, significantly improving the ensemble of models' out-of-sample performance. A study case is carried out to demonstrate the applicability of the new methodology. Overall, a total of 124 models were trained using a specific dataset: 40 Machine Learning models and 84 Polynomial Chaos Expansion models (which considered 3 types of base random variables, 7 least square algorithms for fitting the up to fourth order expansion's coefficients). Among those, 99 models could be fitted without convergence and other numerical issues. The DBHT algorithm with Pearson correlation distance and generalization error similarity was able to select a subgroup of 23 models from the 99 fitted ones, implying a reduction of about 77% in the total number of models, representing a good filtering scheme which still preserves diversity. Finally, it has been demonstrated that the weights obtained by building a Hierarchical Risk Parity (HPR) portfolio perform better for various input random variables, indicating better out-of-sample performance. In this way, an economic stacking strategy has demonstrated its worth in improving the out-of-sample capabilities of stacked models, which illustrates how the new understanding of model stacking methodologies may be useful.

Gout Prevalence, Practice Patterns, and Associations with Outcomes in North American Dialysis Patients.

INTRODUCTION: Gout occurs frequently in patients with kidney disease and can lead to a significant burden on quality of life. Gout prevalence, and its association with outcomes in hemodialysis (HD) and peritoneal dialysis (PD) populations located in North America, is unknown. METHODS: We used data from North America cohorts of 70,297 HD patients (DOPPS, 2012-2020) and 5117 PD patients (PDOPPS, 2014-2020). We used three definitions of gout for this analysis: (1) having an active prescription for colchicine or febuxostat; (2) having an active prescription for colchicine, febuxostat, or allopurinol; or (3) having an active prescription for colchicine, febuxostat, or allopurinol, or prior diagnosis of gout. Propensity score matching was used to compare outcomes among patients with versus without gout. Outcomes included erythropoietin resistance index (ERI=erythropoiesis stimulating agent dose per week/(hemoglobin×weight)), all-cause mortality, hospitalization, and patient-reported outcomes (PROs). RESULTS: The gout prevalence was 13% in HD and 21% in PD; it was highest among incident dialysis patients. Description of previous history of gout was rare, and identification of gout defined by colchicine (2%-3%) or febuxostat (1%) prescription was less frequent than by allopurinol (9%-12%). Both HD and PD patients with gout (versus no gout) were older, were more likely male, had higher body mass index, and had higher prevalence of cardiovascular comorbidities. About half of patients with a gout history were prescribed urate-lowering therapy. After propensity score matching, mean ERI was 3%-6% higher for gout versus non-gout patients while there was minimal evidence of association with clinical outcomes or PROs. CONCLUSION: In a large cohort of PD and HD patients in North America, we found that gout occurs frequently and is likely under-reported. Gout was not associated with adverse clinical or PROs.

Increased risk of acute and chronic microvascular renal lesions associated with antiphospholipid antibodies in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Microvascular renal lesions have been described in patients with antiphospholipid antibodies (aPL), however their association with aPL is inconsistent among studies. Therefore, our objective was to investigate associations between microvascular renal lesions and aPL among systemic lupus erythematosus (SLE) patients. METHODS: Studies were selected if they included SLE patients with and without aPL positivity with a description of kidney biopsy identifying acute and/or chronic microvascular renal lesions as well as lupus nephritis. Data sources were Pubmed, Embase, Cochrane Library, hand search, congress abstracts, and reference lists of studies, without language restrictions. Risk estimates were independently extracted by 2 investigators. Pooled effect estimates were obtained by using the Mantel-Haenszel method (random effects). RESULTS: Of 1860 identified records obtained between 1991 and 2021, 35 published studies (10 cohorts, 7 case-control, 18 cross-sectional) met inclusion criteria, including 3035 SLE patients according to American College of Rheumatology criteria and 454 cases of microvascular renal lesions. Frequency of microvascular renal lesions in aPL-positive vs. aPL-negative SLE patients was 31.3% vs. 10.4%, respectively. The overall pooled odds ratios (OR) for microvascular renal lesions in aPL-positive vs. aPL-negative SLE patients was 3.03 (95% confidence interval [CI], 2.25-4.09). The risk of microvascular renal lesions was the highest for lupus anticoagulant (OR = 4.84 [95% CI, 2.93 to 8.02]) and IgG anticardiolipin antibodies (OR = 3.12 [95% CI,1.08-9.02]) while the association with anti-ß2-glycoprotein I antibodies (OR = 1.88 [95% CI, 0.25-14.14]) did not reach statistical significance. Furthermore, aPL were not associated with any classes of lupus nephritis. CONCLUSION: In SLE patients, aPL-positivity is associated with a significant 3- to 5-fold increased risk for specific microvascular renal lesions. This risk is mainly driven by lupus anticoagulant and IgG anticardiolipin antibodies. Our results support the inclusion of microvascular renal lesions as new criteria for definite antiphospholipid syndrome.

A multianalyte assay panel with cell-bound complement activation products demonstrates clinical utility in systemic lupus erythematosus.

OBJECTIVE: To evaluate the clinical utility of the multianalyte assay panel (MAP), commercially known as AVISE Lupus test (Exagen Inc.), in patients suspected of SLE. METHODS: A systematic review of medical records of ANA-positive patients with a positive (>0.1) or negative (<-0.1) MAP score was conducted when the MAP was ordered (T0), when the test results were reviewed (T1) and at a later time (T2, ≥8 months after T1). Confidence in the diagnosis of SLE and initiation of hydroxychloroquine (HCQ) were assessed. RESULTS: A total of 161 patient records from 12 centres were reviewed at T0 and T1. T2 occurred for 90 patients. At T0, low, moderate and high confidence in SLE diagnosis was reported for 58%, 30% and 12% patients, respectively. Confidence in SLE diagnosis increased for the MAP positive, while MAP negative made SLE less likely. Odds of higher confidence in SLE diagnosis increased by 1.74-fold for every unit of increase of the MAP score (p<0.001). Using the MAP-negative/anti-double-stranded DNA-negative patients as reference, the HR of assigning an International Classification of Diseases, Tenth Revision lupus code was 7.02-fold, 11.2-fold and 14.8-fold higher in the low tier-2, high tier-2 and tier-1 positive, respectively (p<0.001). The HR of initiating HCQ therapy after T0 was 2.90-fold, 4.22-fold and 3.98-fold higher, respectively (p<0.001). CONCLUSION: The MAP helps increase the confidence in ruling-in and ruling-out SLE in patients suspected of the disease and informs on appropriate treatment decisions.

Use of synthetic and biologic DMARDs during pregnancy.

Introduction: Since most of the autoimmune diseases (AID) affect mostly women in their fertile years, and fertility is in general preserved, the use of disease-modifying antirheumatic drugs (DMARDs) during conception, pregnancy, and lactation has been a matter of concern in the treatment of women affected by AID. Areas covered: We performed a comprehensive review of the latest and most relevant research papers published in the field and discussed different aspects related to the use of synthetic and biologic DMARDs and immunosuppressants in the preconceptional period, during pregnancy and lactation in AID patients, both in males and females. Expert commentary: Active AID impose an increased risk for adverse maternal and fetal outcomes, such as preeclampsia, miscarriage, intrauterine growth restriction, prematurity, low birth weight, and stillbirth. Family planning with proper contraception and shared decision-making on the ideal time to conceive with treatment adjustment must be a rule. One of the main challenges when counseling and/or adjusting treatment of patients that are planning a pregnancy is to provide a medication that is at the same time efficacious and safe at the conceptional period and to developing the fetus.

Serum albumin at 1 year predicts long-term renal outcome in lupus nephritis.

OBJECTIVES: The study aimed to determine if serum albumin at 12 months predicts long-term renal outcome at 48 months. Data from the NYU SAMPLE (Specimen and Matched Phenotype Linked Evaluation) Lupus Registry were used to compare the performance of albumin, anti-double-stranded DNA, C3/C4, proteinuria and haematuria. METHODS: 82 patients with SLE with data at time of renal biopsy, at 12 months and at a second visit, and up to 48 months were included. The significance of each biomarker as a predictor of an adverse renal outcome (ARO), defined as doubling of serum creatinine, as creatinine >4 mg/dL if initial >2.5 mg/dL or ESRD, was evaluated in univariate and exploratory multivariable Cox proportional hazards models. Hazard ratios (HRs) for ARO with 95% CIs were generated. The receiver operating characteristic (ROC) curves at 48 months were used to identify the optimal cut-off point for albumin and proteinuria to predict ARO. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for albumin and proteinuria. RESULTS: Serum albumin and proteinuria had statistically significant HRs for ARO (0.140 and 1.459, respectively). The model with both albumin and proteinuria indicated no additional independent contribution of proteinuria to albumin alone. The ROC curves identified cut-offs of 3.7 g/dL for albumin and 0.964 urine protein to creatinine ratio for proteinuria. Albumin had a sensitivity of 94%, specificity of 87%, PPV of 64% and NPV of 98%. CONCLUSIONS: This study demonstrates serum albumin >3.7 g/dL is a predictor of a favourable long-term renal outcome. These results support the inclusion of albumin as an outcome in lupus nephritis trials and treat-to-target guidelines.

New and upcoming treatments in antiphospholipid syndrome: A comprehensive review.

Current therapeutic recommendations for thrombosis prevention in patients with antiphospholipid syndrome (APS) are limited to anticoagulation with vitamin K antagonists (VKA) or heparins and to anti-platelet aggregating agents. Maintaining optimized anticoagulation to prevent recurrent thrombosis or bleeding remains a therapeutic challenge. Although there are important ongoing trials with direct oral anticoagulants, they still aim the same target. New insights about pathophysiology in APS have revealed a myriad of potential pathways to be investigated as treatment targets. A radical shift from a hematological/coagulative approach to an immunological one will probably represent the near future of APS treatment. We reviewed the therapeutic trends and potential future treatments.

Antiphospholipid antibodies can identify lupus patients at risk of pulmonary hypertension: A systematic review and meta-analysis.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening condition that may affect outcomes in patients with systemic lupus erythematosus (SLE). The role of antiphospholipid antibodies (aPL) on the risk of PH is controversial. Therefore our objective was to estimate the risk of PH (WHO groups 1-5) including associated pulmonary arterial hypertension (APAH, WHO group 1 only) related to aPL in patients with SLE. METHODS: Systematic review and meta-analysis were performed: MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched through 2015. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (PH including APAH). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. PROSPERO registration number: CRD42015016872. RESULTS: Of 984 identified abstracts, 31 primary studies (five cohorts, 13 case-control, 13 cross-sectional) met inclusion criteria, including 4480 SLE patients. Prevalence of PH in aPL-positive vs. aPL-negative SLE patients was 12.3% vs. 7.3%, respectively. The overall pooled odds ratio (OR) for PH was 2.28 (95% CI, 1.65 to 3.15) (I2=39%). The risk of APAH was also significantly increased (OR=2.62 [95% CI, 1.11-6.15]). The risk of PH was the highest for lupus anticoagulant (OR=1.96 [95% CI, 1.31-2.92]) and IgG anticardiolipin antibodies (OR=2.64 [95% CI, 1.30-5.36]) while other antibodies were not significantly associated with PH. CONCLUSIONS: Among SLE patients, aPL can identify patients at risk for PH and APAH. These findings warrant implementation of effective screening and early treatment strategies.

Assessment of the independent associations of IgG, IgM and IgA isotypes of anticardiolipin with thrombosis in SLE.

OBJECTIVE: The Sydney classification criteria for antiphospholipid syndrome include lupus anticoagulant or moderate-to-high titre anticardiolipin IgG or IgM. We explored the association of all anticardiolipin isotypes, lupus anticoagulant and the combination with venous and arterial thrombosis. METHODS: Patients with systemic lupus erythematosus (SLE) in a large clinical cohort seen quarterly were repeatedly tested by protocol for anticardiolipin antibodies and lupus anticoagulant. Subgroups of patients were defined based on the geometric mean titres of IgG, IgM, IgA anticardiolipin and lupus anticoagulant expressed in dilute Russell's viper venom time (RVVT) seconds for each patient across all cohort visits. These subgroups were compared with respect rates of thrombosis since diagnosis with SLE. Rate ratios were estimated using Cox Proportional Hazards models. RESULTS: Of the 1390 cohort members included, there were 284 thrombotic events observed over 17 025 person-years since diagnosis for a rate of 1.7 events per 100 person-years. Those with a geometric mean titre of IgG anticardiolipin >20 had a significantly elevated rate of thromboses (rate ratio 1.8, p=0.0052), whereas there was no evidence of an association between thromboses and elevated IgM geometric mean (rate ratio 1.2, p=0.40). There were relatively few cohort members with elevated IgA geometric mean but the rate of thromboses in that group was elevated (rate ratio 1.7, p=0.23). The associations between anticardiolipin antibodies and thromboses were strongest when considering venous thromboses. Those with two or more elevated anticardiolipin isotypes or those with both IgG anticardiolipin and RVVT did not appear at higher risk than those with a single elevated marker. CONCLUSION: This study supports previous observations that IgG anticardiolipin and lupus anticoagulant are associated with higher rates of thromboses. Our power to study IgA anticardiolipin was limited due to small number of patients with elevated IgA.

Thrombotic events in patients with antiphospholipid syndrome treated with rivaroxaban: a series of eight cases.

The current treatment for antiphospholipid syndrome (APS) with thrombotic manifestation is long-term anticoagulation. Vitamin K antagonists (VKA) are usually the agents of choice. However, VKA limitations, such as unpredictable anticoagulation effects due to interaction with diet and other drugs, require regular monitoring. This may impact on patients' quality of life. Since the approval of new oral anticoagulants (NOAC) for non-valvular atrial fibrillation and deep vein thrombosis prevention, much has been speculated about its use in APS patients. We report here a series of eight APS patients with failure of thrombotic prevention during rivaroxaban use. All patients had venous thrombosis as the initial manifestation of APS, and two of them also had arterial manifestations. Three patients had triple antibody positivity. Five patients developed arterial events during the treatment with rivaroxaban. Until the results of ongoing trials of rivaroxaban for APS are presented, NOAC should not be recommended to APS patients. Our preliminary experience as well cases previously reported in the literature suggest that there is a high-risk group that is less protected with rivaroxaban, namely those with previous arterial thrombosis or triple positivity. VKA remains to be the mainstay treatment for thrombotic APS.

The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features.

The purpose of this task force was to critically analyze nine non-criteria manifestations of APS to support their inclusion as APS classification criteria. The Task Force Members selected the non-criteria clinical manifestations according to their clinical relevance, that is, the patient-important outcome from clinician perspective. They included superficial vein thrombosis, thrombocytopenia, renal microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis, which were reviewed by this International Task Force collaboration, in addition to the seronegative APS (SN-APS). GRADE system was used to evaluate the quality of evidence of medical literature of each selected item. This critical appraisal exercise aimed to support the debate regarding the clinical picture of APS. We found that the overall GRADE analysis was very low for migraine and seizures, low for superficial venous thrombosis, thrombocytopenia, chorea, longitudinal myelitis and the so-called seronegative APS and moderate for APS nephropathy, heart valve lesions and livedo reticularis. The next step can be a critical redefinition of an APS gold standard, for instance derived from the APS ACTION registry that will include not only current APS patients but also those with antiphospholipid antibodies not meeting current classification criteria.

Acute Renal Failure and Jaundice without Methemoglobinemia in a Patient with Phenazopyridine Overdose: Case Report and Review of the Literature.

Phenazopyridine is a commonly used urinary analgesic available throughout the United States. Ingestion of large quantities can lead to methemoglobinemia, hemolytic anemia, jaundice, and acute renal failure. We report a case of a 78-year-old male with previously normal renal function who developed acute renal failure and jaundice without methemoglobinemia or hyperbilirubinemia after taking nearly 8 g of phenazopyridine over the course of 4 days. Initially presenting with oliguria, the urine output began to increase by day 2 of his admission, and the creatinine peaked 11 days after he began taking phenazopyridine, and he was discharged safely soon after. To our knowledge, this is the first such case of renal failure and jaundice without methemoglobinemia or hemolytic anemia in an adult patient with normal renal function.

The respiratory tract and juvenile rheumatic diseases.

Respiratory tract disorders in the juvenile rheumatic diseases are not infrequent and can have different clinical features when compared with those in the adult diseases. The purpose of this review article is to show the main manifestations of the respiratory tract, with an emphasis on lung involvement, in the most frequent juvenile rheumatic diseases.

O aparelho respiratório e as doenças reumáticas da infância e da adolescência / The respiratory tract and juvenile rheumatic diseases

Distúrbios do aparelho respiratório nas doenças reumáticas que acometem a faixa etária pediátrica não são raros e podem apresentar características clínicas diferentes quando comparados ao quadro clínico de adultos. Este artigo de revisão procura mostrar as principais manifestações do aparelho respiratório, com ênfase no acometimento pulmonar, nas principais doenças reumáticas da infância e adolescência.

Respiratory tract disorders in the juvenile rheumatic diseases are not infrequent and can have different clinical features when compared with those in the adult diseases. The purpose of this review article is to show the main manifestations of the respiratory tract, with an emphasis on lung involvement, in the most frequent juvenile rheumatic diseases.