Systemic Lupus Erythematosus Patients In Remission Research Articles

The Role of Sinopharm BIBP COVID-19 Vaccine Immunization in Systemic Lupus Erythematous Flare-up

Background: This study aimed to investigate the incidence and clinical characteristics of flare-ups in patients with systemic lupus erythematosus (SLE) following immunization with inactivated SARS-CoV-2 vaccines. Methods: In this cross-sectional study at Imam Hossein Hospital's Rheumatology Clinic (Iran), we investigated 72 SLE patients in remission who received the Sinopharm BIBP inactivated COVID-19 vaccine. Their post-vaccination status was monitored for 3 months using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) checklist by an internal medicine specialist. Results: Fourteen patients (19.44%) experienced symptom flare-ups after vaccination. The most common symptoms were arthritis (64.29%) and skin rash (21.43%). Age, sex, organ involvement, and treatment regimen did not significantly differ between those with and without symptom recurrence (P > 0.05). The second vaccine dose led to more flare-ups compared to the first dose (12.12% vs. 8.33%, P < 0.001). However, the severity of symptom recurrence, measured by the SLEDAI-2K score (P = 0.763), and the interval from vaccination to symptom recurrence (P = 0.075) did not significantly differ between the 2 groups. Except for 2 patients, none of the participants required hospitalization, and flare-up symptoms were effectively managed by prednisolone dosage adjustments. For these 2 patients, the treatment regimen was changed, and the steroid dose was increased; one of them was admitted to the hospital, and the other one was managed on an outpatient basis. Conclusions: The incidence of flare-ups in SLE patients in remission following COVID-19 vaccination with Sinopharm BIBP vaccine was low; most of them were mild and did not require hospitalization, except for 1 patient who was hospitalized after the first dose of vaccination and received rituximab due to vasculitis flare. These findings highlight vaccine safety and underscore the importance of close monitoring, especially after the second dose.

Risk Assessment Model for Postpartum Venous Thromboembolism Prevention in Patients with Systemic Lupus Erythematosus.

This article assesses the application of the Royal College of Obstetricians and Gynaecologists (RCOG) venous thromboembolism (VTE) risk model on a cohort of postpartum patients with a history of systemic lupus erythematosus (SLE). This is a secondary analysis of an ongoing patient registry of women with SLE from 2016 to 2022. There were 49 SLE patients with 55 pregnancies using the Definitions of Remission in SLE (DORIS) criteria to determine SLE disease activity. RCOG risk assessment model scoring was calculated for each patient prior to and after delivery. The primary outcome was the qualification of "active SLE" by standard rheumatologic criteria and assessment of recommendations for VTE prophylaxis based on RCOG VTE risk assessment scoring. Data were analyzed using Fisher's exact test, chi-square test, and Mann-Whitney U test with significance defined as p < 0.05. In the study cohort, 34 pregnancies (61.8%) were in DORIS remission at delivery. Twenty-one pregnancies (38.2%) were not and scored 3 points on the RCOG VTE risk model. Of these pregnancies, only 19% (n = 4) were recommended for VTE prophylaxis by the obstetrical provider despite RCOG score ≥3. Only 35.7% (n = 5) of pregnancies in DORIS remission, but with 3 points for non-SLE-related VTE risk factors (n = 14), were recommended for VTE prophylaxis. Of the 20 pregnancies in remission with an RCOG score < 3 after assessing all risk factors, 15% (n = 3) were nevertheless recommended for VTE prophylaxis. No patients had a postpartum VTE regardless of therapy. These data reveal a need to improve upon providing postpartum VTE prophylaxis to SLE patients not in remission while also recognizing a diagnosis of SLE alone should not equate with active disease. Moreover, SLE patients in remission may still warrant VTE prophylaxis if other non-SLE-related risk factors are present. · Those with SLE are at increased risk for VTE postpartum.. · VTE prophylaxis should be instituted when clinically appropriate.. · Caution should be exercised in broadly assigning disease activity for SLE diagnosis only.. · This study supports VTE prophylaxis use in postpartum patients with SLE..

Risk Assessment Model for Postpartum Venous Thromboembolism Prevention in Patients with Systemic Lupus Erythematosus

Background Patients with Systemic Lupus Erythematosus (SLE) may be at increased risk for developing a venous thromboembolism (VTE), particularly in the postpartum period. The Royal College of Obstetricians and Gynaecologists (RCOG) guideline for postpartum VTE prophylaxis is often used to triage which patients should get VTE prophylaxis. In this RCOG guideline, a score ≥ 3 drives a formal recommendation for postpartum anticoagulation. RCOG is unique in its inclusion of “active SLE” as an actionable VTE risk factor (adding 3 points). We sought to determine if a cohort of postpartum patients with a known history of SLE a) qualify as having “active” SLE by standard rheumatologic criteria b) have other risk factors for VTE c) received the recommended prophylaxis based on RCOG VTE risk assessment scoring and d) had a postpartum VTE. Objective To assess the application of the RCOG venous thromboembolism (VTE) risk model on a cohort of postpartum patients with a history of Systemic Lupus Erythematosus (SLE). Study Design This is a secondary analysis of an ongoing patient registry of women with SLE from 2016-2022. There were 49 SLE patients with 55 pregnancies using Definitions of Remission in SLE (DORIS) criteria to determine SLE disease activity. RCOG risk assessment model scoring was calculated for each patient prior to and after delivery. The primary outcome was the qualification of “active SLE” by standard rheumatologic criteria and assessment of recommendations for VTE prophylaxis based on RCOG VTE risk assessment scoring. Data were analyzed using Fisher’s Exact test, chi-square test, and Mann-Whitney U test with significance defined as p&lt;0.05. Results In the study cohort, 34 pregnancies (61.8%) were in DORIS remission at delivery. Twenty-one pregnancies (38.2%) were not and scored 3 points on the RCOG VTE risk model. Of these pregnancies, only 19% (n=4) were recommended for VTE prophylaxis by the obstetrical provider despite RCOG score ≥ 3. Only 35.7% (n=5) of pregnancies in DORIS remission, but with 3 points for non-SLE related VTE risk factors (n=14), were recommended for VTE prophylaxis. Of the 20 pregnancies in remission with an RCOG score &lt; 3 after assessing all risk factors, 15% (n=3) were nevertheless recommended for VTE prophylaxis. No patients had a postpartum VTE regardless of therapy. Conclusion These data reveal a need to improve upon providing postpartum VTE prophylaxis to SLE patients not in remission while also recognizing a diagnosis of SLE alone should not equate with active disease. Moreover, SLE patients in remission may still warrant VTE prophylaxis if other non-SLE-related risk factors are present.

MRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients.

Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 polymorphism) in a cohort of SLE patients compared to healthy controls. This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing. CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of CD44 was associated with higher level of global CD44 mRNA (p = 0.04) but not with the variant isoforms. In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

Which patients with systemic lupus erythematosus in remission can withdraw low dose steroids? Results from a single inception cohort study.

A progressive tapering until withdrawal of glucocorticoids (GC) is considered one of the main goals of Systemic Lupus Erythematosus (SLE) management. However, which patient may be a candidate for safe GC withdrawal has not been determined yet. This study aimed to evaluate the rate of low-dose GC withdrawal in SLE patients in remission and to identify predictors of flares. Eligible patients were SLE patients in prolonged clinical remission defined by a cSLEDAI = 0 for at least 2 years and on a stable SLE treatment (including daily 5 mg prednisone). Flares were defined by SELENA-SLEDAI Flare Index. Predictors of flares after GC withdrawal were analyzed by Cox regression. We selected 56 patients in whom a GC withdrawal was attempted. 98 patients were in the prednisone maintenance group. The proportion of patients experiencing a flare was not significantly lower in the maintenance group than in the withdrawal group (p = 0.81). However, among the withdrawal group, the rate of flares was significantly higher in serologically active clinically quiescent (SACQ) patients (p < 0,0001). At Cox regression analysis, duration of hydroxychloroquine (HCQ) therapy and ≥5 year remission at withdrawal were protective factors, while a SACQ disease and history of lupus nephritis increased the risk of disease flare. GC withdrawal is an achievable target in SLE and may be attempted in patients in complete remission.However, it might underline a caution in patients with SACQ disease who may be at greater risk forflare when GCare discontinued. HCQ therapy and durable remission can significantly reduce the risk.

IgM on the surface of T cells: a novel biomarker of pediatric-onset systemic lupus erythematosus.

Children with systemic lupus erythematosus (SLE) frequently have kidney involvement. Lupus nephritis sometimes presents alone, without systemic SLE features, representing the so-called full-house nephropathy (FHN). Distinguishing patients with SLE or FHN has therapeutic and prognostic implications. In this retrospective observational study, we determined the presence of IgM on the surface of T cells (T cell IgM) by flow cytometry and characterized its ability in distinguishing SLE and FHN patients in a large pediatric cohort (n = 84). Fifty-seven patients with SLE (≥ 4 SLICC criteria at disease onset or during the follow-up) and 27 patients with FHN (3 or less SLICC criteria) were enrolled. Elevated T cell IgM levels were found in 24/25 SLE patients in active phase of disease and in 29/45 SLE patients in remission. In contrast, among FHN patients, only 1/9 presented this characteristic in active phase of disease and 0/20 in remission. Compared with standardized SLICC laboratory parameters, i.e., autoantibody titers and hypocomplementemia, T cell IgM positivity showed an extremely high sensitivity and specificity for the diagnosis of SLE, with the highest area under the curve (0.97, p < 0.001) by receiver operating characteristic analysis, similar to ANA (0.96, p < 0.001) and anti-dsDNA (0.90, p < 0.001) autoantibodies. Altogether, our data indicate that T cell IgM intensity may be a useful tool to correctly classify patients with lupus nephritis as SLE or FHN since disease onset.

SAT0162 WITHDRAWAL OF LOW-DOSE STEROIDS IN SYSTEMIC LUPUS ERYTHEMATOSUS IN REMISSION: PREDICTORS OF FLARES AND DIFFERENCE IN OUTCOMES IN SEROLOGICALLY ACTIVE CLINICALLY QUIESCENT PATIENTS

Background:According to the recent recommendations for Systemic Lupus Erythematosus (SLE), a progressive tapering until withdrawal of glucocorticoids (GC) is considered one of the main goals of SLE management (1). However, which patient may be a candidate for safe GC withdrawal has not been determined yet and a proportion of patients are kept on long-term low-dose prednisone despite clinical remission.Objectives:to evaluate the rate of low-dose GC withdrawal in SLE patients in remission and to identify predictors of flares.Methods:Eligible patients were SLE patients according to the ACR criteria (2) who were in prolonged clinical remission defined by a cSLEDAI=0 for at least 2 years and on a stable SLE treatment (immunosuppressive drugs and/or hydroxychloroquine (HCQ) and daily 5 mg prednisone). A SACQ period was defined as at least 1-year period with persistent serologic activity without clinical manifestations. Flares were defined by SELENA-SLEDAI Flare Index (3). Damage was assessed by SLICC damage index (SDI). Data were compared by the unpaired student’s t test or chi-squared test as appropriate. Predictors of flares after GC withdrawal were analyzed by Cox regression.Results:Out of 246 SLE patients registered in the Naples Lupus Clinic database, 132 eligible patients were identified. Among them, we selected 57 (43%) patients in whom a GC withdrawal was attempted. 75 (57%) patients were in the prednisone maintenance group.There were no significant differences between the two treatment groups (table 1). The proportion of patients experiencing a flare was not significantly lower in the maintenance group than in the withdrawal group (15/75 vs 16/57; p=0.28). Moreover, the proportion of patients who had an increase in the SDI at the end of follow up was similar between the two groups (14/75 vs 8/57; p=0.48). However, among the withdrawal group, the rate of flares was significantly higher in SACQ patients (10/22 vs 6/35; p=0.02), while the majority of serologically inactive patients (82%) successfully stopped GCs without subsequent flares. At Cox regression analysis (Table 2), duration of HCQ therapy and &gt;4 year remission at withdrawal were protective factors, while a SACQ disease and history of lupus nephritis (LN) increased the risk of disease flare.Table 1.Baseline characteristics of 132 patients at study entryCharacteristicsWithdrawal group (n=57)Maintenance group (n=75)p-valueFemale, no. (%)54 (94)70 (93)0.73Age, years26.7±10.128.5±11.70.37Disease duration, years8.5±2.99.1±12.90.73History of lupus nephritis, no. (%)13(22)22(29)SDI score0.40±0.70.57±0.80.26Immunosuppressive drugs, no. (%)31 (54)33(44)0.16HCQ, no. (%)52 (91)66 (88)0.06Low C3, no. (%)28 (49)41(54)0.52Increased dsDNA Ab, no. (%)11 (19)19 (25)0.41Table 2.Factors predicting lupus flares during follow-up at Cox regression analysisVariablesHR95% CIp valueSACQ2.991.08 – 8.250.03Age0.970.93 – 1.020.29Disease duration0.990.94 – 1.040.84History of LN3.381.22-9.330.01SDI score1.130.63 – 2.010.66Immunosuppressive drugs2.390.86 – 6.620.09HCQ, ever2.920.43 – 35.20.95Duration of HCQ0.840.72 – 0.980.035years remission0.120.04 – 0.390.0003Conclusion:GC withdrawal is an achievable target in SLE and may be attempted in patients in complete remission. In SACQ patients, maintenance of 5mg prednisone is superior to its withdrawal in order to prevent flares. Long-term HCQ therapy and prolonged remission can significantly reduce the risk of disease relapse after GC withdrawal.

Choroidal thickness in lupus nephritis.

This study aimed to compare choroidal thickness between patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) in complete renal remission to that of patients with SLE without LN. This was a retrospective case-control study of 23 SLE patients meeting either the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria and followed at Washington University School of Medicine Rheumatology or Nephrology, and Ophthalmology outpatient clinics. The diagnosis of LN was based on renal pathology, and complete renal remission was defined as proteinuria <500 mg/daily and serum creatinine at baseline. Extra-renal flare status was determined using modified Fortin criteria. Choroidal thickness was measured using spectral-domain optical coherence tomography and read by blinded reviewers. In SLE patients without extra-renal flare, choroidal thickness of LN patients was 281 ± 78 µm compared to 288 ± 70 µm in non-LN SLE patients (p = 0.766) at the fovea. Choroidal thickness was not different in patients with LN in remission compared to non-LN SLE patients in remission. Additional studies are needed to examine choroidal thickness in patients with SLE with active LN.

Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse

ObjectivesMaintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has...

Quality of life among female patients with systemic lupus erythematosus in remission.

The objective is to assess quality-of-life (QoL) parameters among Indian female systemic lupus erythematosus (SLE) patients with durable remission. Indian female SLE patients in remission determined by the European consensus criteria and age-matched female control participants were included in the study. All included participants underwent measurements of QoL [Medical Outcomes Study Short-Form-12 (SF12)], Fatigue Severity Scale, and structured interview with a clinical psychologist. The population comprised of 126 female SLE patients [median age: 27.5years [interquartile range (IQR): 11]; median disease duration: 36months (IQR 26)] and 110 female controls [median age 30years (IQR 9)]. Clinical remission was seen in 65.9% (83/126) and complete remission in 34.1% (43/126). Significant fatigue was present in 18.3% (23/126). Both SF-12 physical component summary (PCS) and mental component summary (MCS) were similar between SLE patients and controls [median PCS: 50.3 (IQR: 16.2) vs. 48.6 (IQR: 11.6); median MCS: 57.2 (IQR: 4.8) vs. 57.9 (IQR: 7.6)]. In generalised linear modelling, PCS was associated with fatigue [odd's ratio (OR) 0.012, 95% confidence interval (CI) 0.006-0.025, p < 0.001], disease duration ≥ 5years (OR 23.16, 95% CI 1.548-346.58, p = 0.023), and complete remission (OR 33.16, 95% CI 4.43-248.15, p = 0.001); MCS with fatigue (OR 0.53, 95% CI 0.34-0.84, p = 0.007) and absence of depression (OR 3.65, 95% CI 1.07-12.44, p = 0.038). Patients with SLE in remission report significant fatigue in 18.3% of subjects. Both PCS and MCS scores are similar to healthy controls. Better PCS was associated with less fatigue, longer disease duration, and complete remission. Better MCS was associated with less fatigue and absence of depression.

Functional mannose binding lectin levels in patients with pediatric onset systemic lupus erythematosus in remission.

Complement system plays a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Excessive activation of complement causes tissue injury and SLE occurrence is typically associated with congenital deficiencies of the early components of the classical complement pathway. Mannose-binding lectin (MBL) is recognized as important causative factor in the etio-pathogenesis of SLE and MBL-2 gene has evolved as a candidate gene for SLE susceptibility. This study was done to assess the functional MBL (fMBL) level in SLE patients in remission and its co-relation with disease severity and outcome. Functional MBL levels were compared with age and sex matched healthy controls and were correlated with duration of illness,complement levels and anti-double- stranded DNA antibody levels. Mean fMBL level in patients was found to be 696.19±408.98U/mL and 579.52±393.87U/mL in the control group. Four children had very low fMBL levels (<40U/mL). Functional MBL levels were higher in patients with SLE even when the disease was in remission as compared to healthy controls, although not statistically significant. Large variation exists in fMBL levels in patients with SLE even when in remission. Very low fMBL levels were found in some children with younger age of onset of SLE, multisystem involvement and severe course of the disease. Positive correlation of MBL levels with anti-ds DNA titers suggest that its values vary with activity and could be a potential biomarker of the disease.

EPA-1252 – Cognitive decline correlates with anticardiolipin antibodies and anti-dsdna in patients with systemic lupus erythematosus

Introduction Cognitive dysfunction (CD) affects 10-36% of patients with systemic lupus erythematosus (SLE). Its pathogenesis comprise direct neurocytoxicity, vasculopathy, thrombosis, hipercholesterolemia and atherosclerosis. The aim of this study was to evaluate CD in SLE patients and to investigate whether it is influenced by selected immunological and cardiological parameters. Methods Thirty-two SLE patients in remission were enrolled. Anti-cardiolipin and anti-dsDNA antibodies were estimated using immunoenzymatic techniques. Transthoracic echocardiography was performed using Acuson CV70. Since at least some tests proposed by the American College of Rheumatology for neuropsychological evaluation have Polish language version, we have used the Cambridge Neuropsychological Test Automated Battery (Cantab) that employs non-verbal stimuli and requires non-verbal responses. The following Cantab tests were used: Motor screening (MOT); Big little circle (BLC); Paired associated learning (PAL); Stockings of Cambridge (SOC); Graded naming test (GNT). Results In SLE results obtained in BLC, PAL, SOC PSMM, and GNT were lower than those of controls. SOC Mean initial thinking time correlated with ACL IgG (r=0.42; p=0.42) and anti-dsDNA antibodies (r=0.47, p=0.23) and, also, with aorticdiameter (r=0.48; p=0.036). SOC Mean subsequent thinking time negatively correlated with Left-ventricular-end-systolic diameter (r=-0.5; p=0.02). GNT correlated positively with posterior-wall-systolic-diameter (r=0.45; p=0.049) and interventricular-septum-systolic diameter (r=0.61; p=0.005). Conclusions SLE patients are cognitively compromised. Immunological and cardiological correlates may indicate underlying vascular brain damage. Biological explanation of the observed correlates is, however, unclear and possible causality needs further studies to become elucidated.

Persistent expression of autoantibodies in SLE patients in remission

A majority of the antibodies expressed by nascent B cells in healthy humans are self-reactive, but most of these antibodies are removed from the repertoire during B cell development. In contrast, untreated systemic lupus erythematosus (SLE) patients fail to remove many of the self-reactive and polyreactive antibodies from the naive repertoire. Here, we report that SLE patients in clinical remission continue to produce elevated numbers of self-reactive and polyreactive antibodies in the mature naive B cell compartment, but the number of B cells expressing these antibodies is lower than in patients with active disease. Our finding that abnormal levels of self-reactive mature naive B cells persist in the majority of patients in clinical remission suggests that early checkpoint abnormalities are an integral feature of SLE.

Serum C4 levels in patients with systemic lupus erythematosus in remission

Twenty-six patients with systemic lupus erythematosus (SLE) showing systemic lupus activity measure (SLAM) and SLE disease activity index (SLEDAI) scores ≤2, as well as a lower C4 concentration than the mean C4 levels of healthy controls, were selected to evaluate the C4 levels of SLE patients in remission. Serum complement (CH50), complement components (C4, C3, and B), complement split products (C4d, iC3b, and Bb), phenotypic expression of C4 allotype, C4 production by peripheral blood monocytes, peripheral blood lymphocyte subpopulation, and interferon-gamma (IFN-γ) production were examined. In patients with SLE in remission, the C4 consumption (C4d/C4) was found to increase, and this was considered to be the most important factor for determining the serum concentration of C4. However, the relevance of the C4 allotypic expression was minimal. The IFN-γ-stimulated production of C4 by peripheral blood monocytes in SLE patients in remission was also less than that of the healthy controls. The IFN-γ-stimulated production of C4 in SLE patients in remission correlated with the peripheral blood CD4-positive cells. Less IFN-γ was produced by lymphocytes of SLE in remission than by those of healthy adults. We conclude that the serum C4 levels in SLE patients in remission reflect the degree of C4 consumption as well as the disease state, rather than genetic influences such as a C4A defect.

Serum C4 levels in patients with systemic lupus erythematosus in remission

Twenty-six patients with systemic lupus erythematosus (SLE) showing systemic lupus activity measure (SLAM) and SLE disease activity index (SLEDAI) scores ≤2, as well as a lower C4 concentration than the mean C4 levels of healthy controls, were selected to evaluate the C4 levels of SLE patients in remission. Serum complement (CH50), complement components (C4, C3, and B), complement split products (C4d, iC3b, and Bb), phenotypic expression of C4 allotype, C4 production by peripheral blood monocytes, peripheral blood lymphocyte subpopulation, and interferon-gamma (IFN-γ) production were examined. In patients with SLE in remission, the C4 consumption (C4d/C4) was found to increase, and this was considered to be the most important factor for determining the serum concentration of C4. However, the relevance of the C4 allotypic expression was minimal. The IFN-γ-stimulated production of C4 by peripheral blood monocytes in SLE patients in remission was also less than that of the healthy controls. The IFN-γ-stimulated production of C4 in SLE patients in remission correlated with the peripheral blood CD4-positive cells. Less IFN-γ was produced by lymphocytes of SLE in remission than by those of healthy adults. We conclude that the serum C4 levels in SLE patients in remission reflect the degree of C4 consumption as well as the disease state, rather than genetic influences such as a C4A defect.

Impairment of CD8+ T suppressor cell function in patients with active systemic lupus erythematosus.

Alteration of T cell suppression function has been recognized in patients with systemic lupus erythematosus (SLE). Recently, CD8(+) T suppressor lymphocytes (CD8(+) Ts) have been generated in vitro by incubating purified CD8(+) T cells with IL-2 and GM-CSF. Using this method, we generated CD8(+) Ts from patients affected by SLE. No major differences were found in the CD8(+) Ts phenotype between SLE patients and healthy subjects. CD8(+) Ts from SLE patients with active disease did not inhibit the anti-CD3 mAb-induced proliferation of autologous PBMC, whereas CD8(+) Ts from SLE patients in remission exerted an inhibitory activity comparable to normal subjects. The inhibitory effect of CD8(+) Ts cells was neither mediated by cytotoxic activity nor by apoptosis induction. Two cytokines, IFN-gamma and IL-6, were found to be responsible for the function of CD8(+) TS: In fact, counteraction of CD8(+) Ts suppression activity was obtained by blocking IFN-gamma with a specific Ab or by inhibiting CD8(+) Ts-mediated IL-6 secretion by an antisense oligonucleotide. Interestingly, CD8(+) Ts from SLE patients showed a peculiar cytokine pattern characterized by an impaired secretion of IL-6 and an increased secretion of IL-12. Thus, it appears that an altered balance between inhibitory (IL-6) and stimulatory (IL-12) cytokines might be responsible for the functional impairment of CD8(+) Ts in SLE patients.

Defective early T and T-dependent B cell activation in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by autoantibody production of unknown origin. Since T-B cell interaction is a key event to produce antibodies, we investigated this interaction through study of CD69, CD40 ligand (CD40L) and CD23 expression (three very early activation antigens). Peripheral blood mononuclear cells (PBMC) from inactive lupus patients were studied following culture with either medium alone, anti-CD3 monoclonal antibody (mAb), recombinant interleukin-4 (rIL-4) or phorbol myristate acetate (PMA)+/-ionomycin. Analysis of CD23 expression on lupus B cells in basal conditions and after anti-CD3 challenge of PBMC, a reflection of cognate interaction between T and B cells, was clearly defective. Conversely, CD23 expression on lupus B cells following non-cognate T cell signals (rIL-4) was preserved. CD69 and CD40L expression was also impaired in lupus T cells following anti-CD3 challenge. Nonetheless, activation by means of PMA and/or ionomycin was preserved both in T cells (CD69 and CD40L expression) and in B cells (CD23 expression). These results indicate that B cells from inactive lupus patients display a normal early response to direct B-cell stimuli. Conversely, T-dependent B-cell stimuli are clearly defective in SLE patients in remission. These results indicate that T-B cognate interaction related to defective T cell activation located between surface membrane and protein kinase C (PKC)/ionomycin function is an intrinsic characteristic of these patients.

In vitro inhibition of anti-DNA producing cells from systemic lupus erythematosus patients by autologous anti-F(ab′) 2 antibodies

We have previously documented an inverse relationship between serum levels of anti-F(ab′) 2 antibodies and disease activity in systemic lupus erythematosus (SLE). The present study focused on the specific in vitro inhibition of anti-DNA producing cells from SLE patients by autologous anti-F(ab′) 2 antibodies. Peripheral blood lymphocytes (PBL) from eleven inactive SLE patients with no apparent disease activity were cultured in vitro to evaluate anti-DNA antibody secretion. Low levels of synthesis of anti-DNA antibody were detected in 3 of 11 SLE patients using unstimulated PBL; on the contrary, pokeweed mitogen stimulation of cultured cells increased production of anti-DNA in all SLE subjects. Parallel cultures were also performed in the presence of heterologous and autologous anti-F(ab′) 2 antibodies and results on production of anti-DNA evaluated. Lymphocytes from SLE patients in remission showed inhibition of synthesis of anti-DNA antibodies when autologous anti-F(ab′) 2 antibodies were added to the cultures, whereas production of anti-tetanus toxoid IgG by the same cells was not significantly altered under the same conditions. These data suggest that a functional anti-idiotypic role may be assigned to anti-F(ab′) 2 antibodies during clinical remission of SLE.

Effects of interferon-α on the expression of a lupus idiotype in normal humans

Interferon (IFN) has extensive immunoregulatory effects but its role in systemic lupus erythematosus (SLE) remains obscure. The observations that a high proportion of patients with active SLE have increased IFN levels in their sera, and that IFN injected to lupus-prone mice aggrevates their disease, led us to examine the effects of IFN on the production of 16 6 —a high-frequency idiotype of monoclonal anti-DNA antibodies produced by human-human hybridomas derived from SLE patients. Peripheral blood mononuclear cells (PBMC) of healthy donors or of patients with SLE were incubated with IFN and pokeweed mitogen (PWM). Seven-day supernatants were assayed for total IgM, for IgM with 16 6 idiotype, and for IgM anti-DNA activity. PWM-stimulated PBMC of all healthy donors examined produced the 16 6 idiotype (mean 2.5 ng/ml). A significant increase of 16 6 in normals (above the level with PWM alone) was noted with 10–100 u/ml of IFN-α but not with 500 u/ml. In 3 10 normals the addition of IFN-α resulted in detectable anti-DNA activity. The IFN-induced increase in 16 6 idiotype was significantly more than the increase in IgM (335% vs 47% above baseline, with 10 u/ml of IFN). These effects of IFN could not be demonstrated in the absence of PWM nor in T-cell-depleted preparations. Recombinant IFN-γ had no augmenting effect on 16 6 production. Three SLE patients in remission had elevated levels of 16 6 in their PBMC supernatant (15–200 ng/ml) which could not be further augmented by IFN. Thus, we have demonstrated the potential of PWM-stimulated normal lymphocytes to generate a “lupus” idiotype and shown that production of this idiotype requires T cells and is preferentially enhanced by IFN-α. Further studies of the effects of IFN on the expression of anti-DNA antibodies may clarify a postulated role of IFN in autoimmune diseases.