Antiphospholipid Patients Admitted in the Intensive Care Unit: What Must The Rheumatologist Know?

PURPOSE OF THE REVIEW: Antiphospholipid syndrome (APS) is a rare systemic autoimmune disorder that can escalate into a 'thrombotic storm' called the catastrophic antiphospholipid syndrome (CAPS), frequently requiring ICU admission for multiple organ failure. This review aims to offer insight and recent evidence on critically-ill APS patients. RECENT FINDINGS: The CAPS classification criteria define this condition as the involvement of at least three organs/systems/tissues within less than a week, caused by small vessel thrombosis, in patients with elevated antiphospholipid antibodies levels. These criteria do not encompass the full spectrum of critically-ill thrombotic APS patients and they need to be cautiously used for the bedside diagnosis of CAPS. Thrombocytopenia is the laboratory hallmark of CAPS, sometimes dropping below 20G/L, but a complete thrombotic microangiopathy pattern is infrequent. Anticoagulation is the pivotal treatment for APS and CAPS, associated with improved outcome. Triple therapy - the combination of anticoagulation, high-dose corticosteroids, and either plasma exchange or intravenous immunoglobulins - remains the standard treatment for CAPS patients. Eculizumab, an anti-C5 monoclonal antibody, may be useful in refractory patients. Despite significant progress, CAPS mortality rate remains high. Its diagnosis and management are complex, requiring a close multidisciplinary cross talk between APS specialists and intensivists.

Identification of new risk factors for hydroxychloroquine and chloroquine retinopathy in systemic lupus erythematosus patients.

BACKGROUND: Long-term hydroxychloroquine (HCQ) or chloroquine (CQ) intake causes retinal toxicity in 0.3-8 % of patients with rheumatic diseases. Numerous risk factors have been described, eg, daily dose by weight, treatment duration, chronic kidney disease, concurrent tamoxifen therapy and pre-existing retinal or macular disease. However, those factors cannot explain the entire risk of developing antimalarial retinopathy. OBJECTIVE: This study was undertaken to identify new risk factors associated with HCQ or CQ retinopathy (QRNP) in systemic lupus erythematosus (SLE) patients. METHODS: This case-control (1:2) study compared SLE patients with QRNP (cases) to those without (controls). Controls were matched for sex and known QRNP risk factors: HCQ and/or CQ treatment duration (±1 year) and age (±5 year) at SLE diagnosis. RESULTS: Forty-eight cases were compared to 96 SLE controls. Multivariable logistic-regression analysis retained the following as independent determinants significantly associated with QRNP: concomitant selective serotonin-reuptake inhibitor (SSRI) or serotonin- and norepinephrine-reuptake inhibitor (SNRI) intake (OR [95 % confidence interval] 6.6 [1.2 to 40.9]; p < 0.01); antiphospholipid syndrome (OR=8.9 [2.2 to 41.4] p < 0.01); blood hydroxychloroquine/desethylchloroquine concentration ([HCQ]/[DCQ]) ratio <7.2 (OR 8.4 [2.7 to 30.8]; p < 0.01) or skin phototype ≥4 (OR 5.5 [1.4 to 26.5]; p = 0.02), but not daily HCQ dose, blood [HCQ] or body mass index. CONCLUSION: The results of this case-control study identified blood [HCQ]/[DCQ] ratio, concurrent SSRI/SNRI therapy, skin phototype ≥4 and antiphospholipid syndrome as new risk factors for QRNP.

Systemic lupus erythematosus associated with HIV infection: a retrospective case-control study.

OBJECTIVES: The association of systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) remains scarcely described in the literature. Our objectives were to describe the characteristics of SLE in patients living with HIV (SLE-PLHIV) and compare it with SLE characteristics in patients without HIV infection. METHODS: We performed a retrospective study of 13 patients with SLE-PLHIV diagnosed between 1975 and 2020 in four different French hospitals. These patients were compared in a case-control study with a 1:5 ratio to age-, sex- and year of diagnosis- matched patients with SLE without HIV infection. RESULTS: Median (IQR) age at SLE diagnosis for patients with SLE and HIV infection was 43 years (36-53). There were 77% women. Main clinical manifestations were polyarthrtitis (84%), cutaneous lupus (69%), kidney disease (54%), serositis (15%) and autoimmune cytopenias (auto-immune haemolytic anaemia and/or immune thrombocytopenia) (31%). There were no neuropsychiatric manifestations. All patients had positive antinuclear antibody test with a titre ≥1:160. Anti-dsDNA antibodies were present in 75% of patients, and anti-Sm antibodies in 33%. SLE-PLHIV had more frequently renal manifestations (54 vs. 16%, p=0.006) and autoimmune cytopenia (31 vs 8%, p=0.04) than patients without HIV infection. CONCLUSIONS: SLE and HIV infection appear to be a rare association. Patients with SLE-PLHIV seem to have more renal manifestations and autoimmune cytopenias than patients with SLE without HIV infection.

Comparison of patients with isolated cutaneous lupus erythematosus versus systemic lupus erythematosus with cutaneous lupus erythematosus as the sole clinical feature: A monocentric study of 149 patients.

BACKGROUND: Cutaneous lupus erythematosus (CLE) may present as an isolated entity or be classified as Systemic lupus erythematosus (SLE) by the presence of laboratory abnormalities, including cytopenia, low complement levels, and/or autoantibodies (CLE with laboratory SLE). OBJECTIVE: To compare isolated CLE and CLE with laboratory SLE and to validate an existing 3-item score with age < 25 years (1 point), phototypes V to VI (1 point), antinuclear antibodies ≥ 1:320 (5 points) to predict the risk of progression from CLE to severe SLE (sSLE). METHODS: Monocentric cohort study including consecutive patients with CLE. CLE with laboratory SLE was defined by 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for SLE score of ≥10 points at baseline with CLE as the sole clinical feature. RESULTS: Of the 149 patients with CLE, 20 had CLE with laboratory SLE. The median follow-up duration was 11.3 years (IQR: 5.1-20.5). Ten patients (7%) had sSLE developed. In survival analysis, the risk of progression to sSLE was higher among CLE with laboratory SLE (hazard ratio = 6.69; 95% CI: 1.93-23.14, P < .001) compared to isolated CLE. In both groups, none of the patients with a risk score ≤ 2 had sSLE developed. LIMITATIONS: Monocentric study with a limited number of patients. CONCLUSIONS: CLE with laboratory patients with SLE have a higher risk of progression to sSLE than isolated CLE.

Prognostic value of hypermetabolic bone sarcoidosis observed by 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: Sarcoidosis is a multisystemic granulomatosis diagnosed mainly in young adults.18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) is useful in sarcoidosis cases to search for a biopsiable site or assess disease activity.18F-FDG PET-CT can reveal bone hypermetabolism in sarcoidosis patients, even in the absence of osteoarticular symptoms. The aim of this study was to describe metabolic bone involvement in sarcoidosis patients and to evaluate its prognostic impact. METHODS: This was an observational, comparative, retrospective, monocentric study. Inclusion criteria were a confirmed diagnosis of sarcoidosis according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria and at least one 18F-FDG PET-CT scan during follow-up. Metabolic bone involvement of sarcoidosis was defined as focal bone hypermetabolism with no argument for a differential diagnosis of bone 18F-FDG uptake. Patients with and without bone involvement were compared. RESULTS: Among the 175 included patients, 32 (18%) had metabolic bone involvement of sarcoidosis. The metabolic bone involvement was mainly axial and mostly without bone abnormalities on CT. Metabolic bone involvement was associated with intrathoracic and extrathoracic lymph node involvement and with a higher number of organs involved. Patients with metabolic bone involvement more frequently received corticosteroids, methotrexate and tumor necrosis factor (TNF)-α inhibitors and a higher number of treatments. Relapse of sarcoidosis occurred sooner in patients with metabolic bone involvement. CONCLUSION: These results suggest that metabolic bone involvement is associated with more diffuse and more severe sarcoidosis.

Type 1 interferons: A target for immune-mediated inflammatory diseases (IMIDs).

The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDs. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.

Is it safe to withdraw low-dose glucocorticoids in SLE patients in remission?

Glucocorticoids (GCs) remain a cornerstone of the treatment of Systemic Lupus Erythematosus (SLE). Numerous studies have emphasized the risk of damage accrual in SLE patient treated with GC, but currently, it is not possible to dissociate favorable and undesirable effects of GCs because their underlying mechanisms are entangled at the molecular level. Here, we review whether available data suggest that it is possible, feasible and desirable to taper and discontinue GC treatment in SLE. The main potential concern with GC withdrawal is the risk of SLE flare, which is strongly associated with increased organ damage, mortality, healthcare costs, decreased quality of life and work productivity. While most studies have assumed the cut off point for low doses (e.g. 7.5/mg/d) as the limit for safety, it is still controversial whether lower doses may influence damage accrual long-term. Also, a recent randomized trial has shown that a daily dose of 5 mg of prednisone in SLE patients in short-term remission can prevent up to 50-75% of flares, with an acceptable safety profile. However, this treatment is not mandatory for all patients. Yet, several observational studies highlight that discontinuation of GC is associated with lower damage accrual. Currently, we do not have a reliable method to identify patients who may require long-term low-dose GC. Therefore, further research is needed to identify a subgroup at high risk of relapse who would benefit from continuing prednisone. In the meantime, when considering the discontinuation of very low-dose prednisone, the decision must be individualized, as HCQ and conventional immunosuppressive agents are not without risk of side effects.

Impaired metabolism predicts coronary artery calcification in women with systemic lupus erythematosus.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) exhibit a high risk for cardiovascular diseases (CVD) which is not fully explained by the classical Framingham risk factors. SLE is characterized by major metabolic alterations which can contribute to the elevated prevalence of CVD. METHODS: A comprehensive analysis of the circulating metabolome and lipidome was conducted in a large cohort of 211 women with SLE who underwent a multi-detector computed tomography scan for quantification of coronary artery calcium (CAC), a robust predictor of coronary heart disease (CHD). FINDINGS: Beyond traditional risk factors, including age and hypertension, disease activity and duration were independent risk factors for developing CAC in women with SLE. The presence of coronary calcium was associated with major alterations of circulating lipidome dominated by an elevated abundance of ceramides with very long chain fatty acids. Alterations in multiple metabolic pathways, including purine, arginine and proline metabolism, and microbiota-derived metabolites, were also associated with CAC in women with SLE. Logistic regression with bootstrapping of lipidomic and metabolomic variables were used to develop prognostic scores. Strikingly, combining metabolic and lipidomic variables with clinical and biological parameters markedly improved the prediction (area under the curve: 0.887, p < 0.001) of the presence of coronary calcium in women with SLE. INTERPRETATION: The present study uncovers the contribution of disturbed metabolism to the presence of coronary artery calcium and the associated risk of CHD in SLE. Identification of novel lipid and metabolite biomarkers may help stratifying patients for reducing CVD morbidity and mortality in SLE. FUNDING: INSERM and Sorbonne Université.

Kidney dysfunction due to AA amyloidosis in a morbidly obese female.

Kidneys are commonly involved in systemic amyloidosis. Systemic AA amyloidosis is known to be associated with states of chronic inflammation such as autoimmune conditions, chronic infections, and malignancies. Obesity is increasingly recognized to be a risk factor for low-grade, chronic inflammation. We report a 48-year-old female with morbid obesity who presented with unexplained persistent mild kidney dysfunction and low-grade proteinuria. Attempt at evaluating the cause of kidney dysfunction included performing kidney biopsy despite technical challenges. Kidney biopsy showed AA amyloidosis with predominant vascular deposition, explaining the absence of nephrotic-range proteinuria. Evaluation for secondary causes of systemic AA amyloidosis was negative. While our patient was treated with sleeve gastrectomy for morbid obesity with reasonable response, it is likely that ongoing chronic inflammation, reflected by her laboratory markers, resulted in AA amyloidosis. Treatment with anakinra, an interleukin-1 antagonist, led to improvement in the laboratory markers in the next 6 months, and her kidney function remained stable. This report highlights an important cause of kidney dysfunction in morbid obesity, an atypical presentation of AA amyloidosis, and emphasizes the value of kidney biopsy in such patients.

Diagnostic yield, safety and therapeutic consequences of myocardial biopsy in clinically suspected fulminant myocarditis unweanable from mechanical circulatory support.

BACKGROUND: Fulminant myocarditis is a rare and severe disease whose definite and etiological diagnoses rely on pathological examination. Albeit, myocardial biopsy can be associated with significant morbidity and mortality, its therapeutic consequences are unclear. We conducted a study to determine the diagnostic yield, the safety and the therapeutic consequences of myocardial biopsy in patients with fulminant clinically suspected myocarditis unweanable from mechanical circulatory support (MCS). METHODS: Monocenter, retrospective, observational cohort study in a 26-bed French tertiary ICU between January 2002 and February 2019. Inclusion of all fulminant clinically suspected myocarditis patients undergoing in-ICU myocardial biopsy while being on MCS. The primary endpoint was the proportion of patients classified as definite myocarditis using Bonaca criteria before and after including myocardial biopsy results. RESULTS: Forty-seven patients (median age 41 [30-47], female 53%) were included: 55% died before hospital discharge, 34% could be bridged-to-recovery and 15% bridged-to-transplant. Myocardial biopsy was endomyocardial or surgical in 36% and 64% cases respectively. Tamponade requiring emergency pericardiocentesis occurred in 29% patients after endomyocardial biopsy. After adding the biopsy results in the Bonaca classification algorithm the percentage of definite myocarditis raised from 13 to 55% (p < 0.0001). The rate of biopsy-related treatments modifications was 13%, leading to patients' recovery in only 4% patients. CONCLUSIONS: In clinically suspected myocarditis unweanable from MCS, myocardial biopsy increased the rate of definite myocarditis but was associated with a low rate of treatment modification and a significant proportion of adverse events. We believe the benefit/risk ratio of myocardial biopsy should be more carefully weighted in these frail and selected patients than suggested by actual guidelines. Further prospective studies are now needed to determine its value in patients under MCS.

Systemic lupus erythematosus-related acute lung disease.

INTRODUCTION: Systemic lupus erythematosus (SLE) is non-organ specific autoimmune disease with mainly skin, joint, and kidney involvement. SLE-related acute lung disease (ALD) is rare, poorly investigated and can lead to acute respiratory failure. We conducted a retrospective study aiming to describe clinical features, treatments and outcome of SLE-related APD. METHODS: We retrospectively included all patients with SLE and ALD admitted from November 1996 and September 2018 to La Pitié-Salpêtrière Hospital, after exclusion of viral or bacterial lung infection, cardiac failure or any other alternate diagnosis. RESULTS: During the time of the study, 14 patients with 16 episodes were admitted to our center: female 79%, mean age ± SD at admission 24 ± 11 years. ALD was inaugural of the SLE in 70% cases. SLE main organ involvement were: arthritis 93%, skin 79%, serositis 79%, hematological 79%, kidney 64%, neuropsychiatric 36% and cardiac 21%. 11 episodes required ICU admission for a median time of 8 days. Chest CT-scan revealed mostly basal consolidation and ground-glass opacities. When available, bronchoalveolar lavage mostly revealed a neutrophilic alveolitis with alveolar hemorrhage in 67% cases. Symptomatic respiratory treatments were: oxygen 81%, high-flow nasal canula oxygen 27%, non-invasive ventilation 36%, mechanical ventilation 64% and venovenous extracorporeal membrane oxygenation 18%. SLE-specific treatments were: corticosteroids 100%, cyclophosphamide 56% and plasma exchange 25%. All patients but one survived to ICU and hospital discharge. Two patients had a relapse of SLE-related ALD but none had interstitial lung disease during follow-up. CONCLUSION: Systemic lupus erythematosus-related acute respiratory failure is a severe event, mostly occurring at SLE onset, typical harboring a basal consolidation pattern on chest CT-scan and alveolar hemorrhage on BAL pathological examination. Mortality in our cohort is lower than previously reported but these results needs to be confirmed in further larger studies.

Clinical and Prognostic Factors in Patients with IgG4-Related Kidney Disease.

BACKGROUND: IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related factors in patients with IgG4-related kidney disease are insufficiently defined. METHODS: We conducted an observational cohort study using data from 35 sites in two European countries. Clinical, biologic, imaging, and histopathologic data; treatment modalities; and outcomes were collected from medical records. Logistic regression was performed to identify the possible factors related to an eGFR ≤30 ml/min per 1.73 m 2 at the last follow-up. Cox proportional hazards model was performed to assess the factors associated with the risk of relapse. RESULTS: We studied 101 adult patients with IgG4-related disease with a median follow-up of 24 (11-58) months. Of these, 87 (86%) patients were male, and the median age was 68 (57-76) years. Eighty-three (82%) patients had IgG4-related kidney disease confirmed by kidney biopsy, with all biopsies showing tubulointerstitial involvement and 16 showing glomerular lesions. Ninety (89%) patients were treated with corticosteroids, and 18 (18%) patients received rituximab as first-line therapy. At the last follow-up, the eGFR was below 30 ml/min per 1.73 m 2 in 32% of patients; 34 (34%) patients experienced a relapse, while 12 (13%) patients had died. By Cox survival analysis, the number of organs involved (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.55) and low C3 and C4 concentrations (HR, 2.31; 95% CI, 1.10 to 4.85) were independently associated with a higher risk of relapse, whereas first-line therapy with rituximab was protective (HR, 0.22; 95% CI, 0.06 to 0.78). At their last follow-up, 19 (19%) patients had an eGFR ≤30 ml/min per 1.73 m 2 . Age (odd ratio [OR], 1.11; 95% CI, 1.03 to 1.20), peak serum creatinine (OR, 2.74; 95% CI, 1.71 to 5.47), and serum IgG4 level ≥5 g/L (OR, 4.46; 95% CI, 1.23 to 19.40) were independently predictive for severe CKD. CONCLUSIONS: IgG4-related kidney disease predominantly affected middle-aged men and manifested as tubulointerstitial nephritis with potential glomerular involvement. Complement consumption and the number of organs involved were associated with a higher relapse rate, whereas first-line therapy with rituximab was associated with lower relapse rate. Patients with high serum IgG4 concentrations (≥5 g/L) had more severe kidney disease.

Severe Libman-Sacks endocarditis complicating antiphospholipid syndrome: a retrospective analysis of 23 operated cases.

OBJECTIVE: Data on severe heart valve disease (HVD), including Libman-Sacks endocarditis, associated with SLE and/or APS requiring valvular surgery are scarce. We thus conducted a retrospective study, aimed at describing and clarifying clinical, laboratory, echocardiographic, histopathological and evolutional features of SLE and/or APS patients with severe associated-HVD. METHODS: An observational retrospective multicentric analysis of 23 adults with SLE and/or APS and HVD between 1996 and 2019 and available histopathological report evaluating long-term follow-up. RESULTS: Twenty-three individuals (20 females, median age 37 [range 17-76] years) were included. All had APS (thrombotic in 22, with an arterial phenotype in 15 and with catastrophic APS [CAPS] in six), and 11 (47%) had SLE. Systemic underlying disease had been diagnosed prior to HVD in 12 (52%). In 10 patients (43%), HVD was complicated by cerebral stroke prior to surgery. Twenty patients (87%) had only one pathological valve, the mitral valve in 18 patients (78%). Valvular thickening (n = 19) and valvular regurgitation (n = 19) were the most frequently reported lesions. Fifteen (62%) patients underwent mechanical valve replacement, six (26%) conservative valve repair (five were later re-operated after a median time of 1 [0-4] year), and two (9%) underwent biological valve replacement. Nine patients (39%) presented early-onset post-operative complications, including three CAPS immediately after surgery and one death. After surgery, 18 patients (78%) had normal postoperative valvular function, but almost half of the patients (43%) had post-operative neurological sequelae (median follow-up of 6 [2-20] years). CONCLUSION: Severe HVD leading to surgery was strongly associated with thrombotic APS, especially arterial phenotypes. Half of the reported patients presented cerebral stroke complicating the HVD. Valvular surgery carried a significant risk of CAPS.

Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

BACKGROUND: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement. RESEARCH QUESTION: What are the pleuropulmonary manifestations in VEXAS syndrome? STUDY DESIGN AND METHODS: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others. RESULTS: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort. INTERPRETATION: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis.

Risk factors of progression from discoid lupus to severe systemic lupus erythematosus: a registry-based cohort study of 164 patients.

BACKGROUND: No study has assessed the risk factors of progression from discoid lupus erythematosus (DLE) to severe systemic lupus erythematosus (sSLE) (defined as requiring hospitalization and specific treatment). OBJECTIVE: To identify the risks factors of and generate a predicting score for progression to sSLE among patients with isolated DLE or associated with systemic lupus erythematosus with mild biological abnormalities. METHODS: In this registry-based cohort study, multivariable analysis was performed using risk factors identified from literature and pruned by backward selection to identify relevant variables. The number of points was weighted proportionally to the odds ratio (OR). RESULTS: We included 30 patients with DLE who developed sSLE and 134 patients who did not. In multivariable analysis, among 12 selected variables, an age of <25 years at the time of DLE diagnosis (OR, 2.8; 95% CI, 1.1-7.0; 1 point), phototype V to VI (OR, 2.7; 95% CI, 1.1-7.0; 1 point), and antinuclear antibody titers of ≥1:320 (OR, 15; 95% CI, 3.3-67.3; 5 points) were selected to generate the score. Among the 54 patients with a score of 0 at baseline, none progressed to sSLE, whereas a score of ≥6 was associated with a risk of approximately 40%. LIMITATIONS: Retrospective design. CONCLUSION: In our cohort, an age of <25 years at the time of DLE diagnosis, phototype V to VI, and antinuclear antibody titers of ≥1:320 were risk factors for developing sSLE.