Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: associations with organ manifestations, immunolaboratory markers and disease activity indices

BACKGROUND: Some tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis. OBJECTIVES: We assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement. METHODS: TAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively. RESULTS: There were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6+/-1.7 vs 1.8+/-1.4 mg/l) and CA15-3 (22.9 +/- 1.8 vs 18.6 +/- 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls. CONCLUSION: The concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.     

Raised serum level of APRIL in patients with systemic lupus erythematosus: Correlations with disease activity indices

The aim of the present study is to assess serum APRIL levels in SLE patients versus rheumatoid arthritis (RA) patients and normal control and to correlate serum APRIL levels in SLE patients with disease activity indices. Serum APRIL levels was measured in 40 SLE patients, 20 patients with RA and 20 healthy volunteers who served as control group. Disease activity in SLE patients was assessed by the British Isles Lupus Assessment Group (BILAG) index and SLE disease activity index (SLEDAI), and results were correlated with serum APRIL levels. Significantly higher serum APRIL levels was observed in SLE patients compared to RA patients and normal controls (p = 0.003 and p ≤ 0.001, respectively). Positive correlations were found between serum APRIL levels and total BILAG index (r = 0.486 and p = 0.001), BILAG musculoskeletal score (r = 0.848 and p ≤ 0.001) and BILAG cardiorespiratory score (r = 0.326 and 0.04). Serum APRIL was higher in SLE patients compared to RA patients and normal control subjects and positively correlates with BILAG index and higher levels may be associated with musculoskeletal manifestations of the disease. APRIL antagonism could be a potential therapeutic target in SLE.     

Psychiatric manifestations in systemic lupus erythematosus

Psychiatric abnormalities are common in systemic lupus erythematosus (SLE) with a prevalence of 17% to 75%, reflecting different methods of patient selection and assessment, the different professional orientation of clinicians, and lack of an accepted consensus for diagnosing active neuropsychiatric lupus (NPSLE). The psychiatric syndromes included in the ACR Neuropsychiatric Lupus Nomenclature Committee criteria are cognitive dysfunction, acute confusional state (delirium), anxiety disorder, mood disorder, and psychosis. In SLE patients, identification of psychiatric phenomena and the generation of a differential diagnosis are crucial. Possible mechanisms include vascular injury and pathogenic antibodies. Treatment strategies are based on small case studies. The purpose of this review is to discuss clinical manifestations, pathogenesis and the present therapeutic options in psychiatric lupus.     

Vascular endothelial growth factor in systemic lupus erythematosus: relationship to disease activity,systemic organ manifestation,and nailfold capillaroscopic abnormalities

Introduction: The aim of the study was to evaluate whether vascular endothelial growth factor (VEGF) serum level is associated with systemic organ involvement, microvascular changes as determined by nailfold capillaroscopy, and disease activity of systemic lupus erythematosus (SLE). Materials and Methods: Serum levels of VEGF were determined by an enzyme-linked immunosorbent assay in 47 SLE patients and in 30 healthy controls. Nailfold capillaroscopy was performed in all patients and healthy subjects. Results: Morphological changes were observed by nailfold capillaroscopy in 45 of 47 (95.7%) SLE patients. Mild capillary changes were found in 16 (34%), moderate in 21 (44.7%), and severe in 8 (17%) SLE patients. All patients with systemic organ involvement showed severe or moderate changes in nailfold capillaroscopy. In comparison with the control group, a higher serum concentration of VEGF in SLE patients was demonstrated (p<0.05). Furthermore, significant differences in VEGF serum concentration between SLE patients with systemic involvement and controls were found (p<0.01). Comparison between patients with active and inactive SLE according to SLEDAI score showed a significantly higher concentration of VEGF in the sera of patients with active SLE (p<0.01). The SLE patients with severe and moderate changes in nailfold capillaroscopy showed significantly higher VEGF serum levels than SLE patients with mild changes (p<0.05) or healthy controls (p<0.01). Moreover, the VEGF serum level correlated significantly with ESR (r=0.580, p<0.0001) and CRP (r=0.512, p<0.005). Conclusions: Our data suggest that VEGF serum level may be a useful marker of disease activity and internal organ involvement in SLE patients. Abnormalities in nailfold capillaroscopy may reflect the extent of microvascular involvement and are associated with systemic manifestation in SLE.     

Relationship between disease activity,organ damage and health-related quality of life in patients with systemic lupus erythematosus: A systemic review and meta-analysis

ObjectivesSystemic lupus erythematosus (SLE) is a common systemic autoimmune disease that may lead to considerable physical, psychological, and socioeconomical burden. In previous studies, inconsistent results were reported for the association of disease activity and organ damage with health-related quality of life (HRQoL). This paper aimed to explore the relationship between disease activity, organ damage, and HRQoL measured by SF-36, EQ-5D, LupusQoL, and LupusPRO and investigate whether the correlation is region-specific.MethodsWe systematically searched for studies reporting the association between SLE disease activity, organ damage, and HRQoL in MEDLINE, EMBASE, PsycINFO, World of Science, the Cochrane Library, and CINAHL from inception to December 2019. A meta-analysis and region subgroup analysis were performed with a random-effects model to estimate pooled correlation coefficients and heterogeneity.ResultsForty articles were included representing of 6079 adult SLE patients. The meta-analysis of SF-36 and LupusPRO studies revealed mild to moderate negative correlations between disease activity and domains of these HRQoL measurements (correlation coefficient r ranging from ?0.27 to ?0.07). Likewise, negative correlations were found between organ damage and domains of SF-36 and LupusPRO (r ranging from ?0.25 to ?0.08). The pooled correlation coefficient is relatively higher in physical functioning related domains than mental health. In the region subgroup analysis, disease activity had strong negative correlations with SF-36 domains in African and European SLE patients, while organ damage had the strongest negative correlation with SF-36 domains in Asian SLE patients (p < 0.010).ConclusionThis study provides the first comprehensive assessment of the relationship between disease activity, organ damage, and four popular HRQoL instruments, which provides useful insight into the target therapy in SLE management.     

Neuropsychiatric manifestations in Thai patients with systemic lupus erythematosus

Neuropsychiatric (NP) manifestations in patients with systemic lupus erythematosus (SLE) [NPSLE] and prognostic factors were studied in 91 patients. There were 98 NP episodes, of which 78 (79.6%) occurred within the first year of the disease. Twenty-six patients (6.7%) had NPSLE as an initial presentation of the disease. There were seizures in 53 episodes (54.1%), psychosis in 13 (13.3%), acute confusion state in 11 (11.2%), abnormal consciousness in 6 (6.1%), transverse myelitis in 6 (6.1%), peripheral neuropathy in 5 (5.1%), cerebral infarction in 2 (2.0%) and aseptic meningitis in 2 (2.0%). Most forms of NPSLE responded well to high dose corticosteroids. Anti-convulsant therapy could be discontinued within a median duration of 3 months after the SLE activity was under control, and without significant recurrence of seizures. The 5-year and 10-year survival rates of patients with NPSLE were 75.9% and 50.6%, respectively. Patients with NPSLE had significantly more cutaneous vasculitis and less arthritis than those without.     

Atypical manifestations in a patient with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease associated with the production of various autoantibodies and involvement of multiple organs. Necropsy findings in a 65 year old woman with SLE who had multiple aortic aneurysms and dissections, as well as other unusual manifestations, are described. The case illustrates the occurrence of and the difficulties encountered in the diagnosis of several diseases, namely aortic aneurysm, aortic dissection, acute pancreatitis, and Penicillium marneffei infection.     

Increased level of serum HLA class I antigens in patients with systemic lupus erythematosus. Correlation with disease activity

Abstract: The level of soluble pYn-assoriated HLA Class I heavy chains (sHLA-I) and of soluble β₂-μ-free HLA Class I heavy chains (sHLA-FHC) was found to be significantly higher in sera from 58 patients with systemic lupus erythematosus (SLE) than in those from 82 age and sex-matched controls. The level of serum sHLA-I in patients with SLE was significantly correlated to disease activity. Western blotting analysis showed that the 44-kDa isoform represents the major component in the antigens immuno-precipitated by anti-β₂-μ mAb NAMB-1 and by anti-β₂-μ-free HLA Class I heavy chain mAb HC-10 from sera of patients with SLE. These results suggest that the increased serum levels of sHLA-I and of sHLA-FHC in patients with SLE reflect their increased shedding from cell membrane. In view of the ability of sHLA-I and of sHLA-FHC to induce apoptosis of activated T cells, it is suggested that their increased serum levels in patients with SLE is triggered by dysregulation of the immune system leading to T-cell activation. The increased serum levels of sHLA-I and of sHLA-FHC may be used by the immune system to control the pool of activated T cells by inducing apoptosis. If this possibility is proven to be correct, modulation of the serum level of sHLA-I and of sHLA-FHC may be utilized to develop strategies to treat SLE.     

Hodgkin's disease associated with systemic lupus erythematosus

We report on the rare association of Hodgkin's disease with systemic lupus erythematosus. Two years after the diagnosis of systemic lupus erythematosus, the patient developed upper abdominal pain, jaundice, splenomegaly, and fever of unknown origin. He had a rapidly fatal clinical course, despite being treated for systemic lupus erythematosus, cholecystitis, and possible sepsis. Autopsy revealed Hodgkin's disease, lymphocyte-depletion type, involving lymph nodes, liver, spleen, and bone marrow. The awareness of the association of Hodgkin's disease with systemic lupus erythematosus and its modes of presentation will help in the early diagnosis and management of such patients.     

Refractory disease in systemic lupus erythematosus

There is no definition or guidelines for refractory disease (RD) in Systemic Lupus Erythematosus (SLE). However, new therapies have been tested mainly in refractory patients. The concept, like the disease, is complex and implies deeper knowledge on the disease pathogenesis and patients' subsets. RD is not included in current activity indices of the disease, what raises the question of how are we monitoring its response to new drugs. In this paper, we analyse some concepts considered important for the global definition of RD in SLE and in some specific organ involvements, excluding lupus nephritis. Management issues will be addressed also. Finally, we review therapeutic options in particular subsets of the disease, namely, cutaneous, articular, haematological and neuropsychiatric lupus. Crucial to the management of a patient suspected to be refractory is an accurate diagnosis, assuring that the persistent clinical manifestations are derived primarily from SLE and not from a concomitant or alternative process. Likewise, certainty about the patient compliance with the therapy prescribed is a frequent unrecognized problem that erroneously might lead to a classification of RD. Therapy of RD for SLE, in general and in most particular involvements, is currently based mainly on the clinician's own experience and judgement, with few randomized trials effectively addressing the issue. In such a heterogeneous disease, consideration of approval of drugs for single-organ indications may pave the way for new therapies. Better biomarkers are needed to add accuracy to the currently used activity indices in order to monitor RD and consolidate its definition. Prospective studies directed to RD in the main SLE involvements are needed to improve our understanding on the management of the disease and foster the development of targeted new drugs.     

Caveats and pitfalls in defining low disease activity in systemic lupus erythematosus

The treat-to-target strategy has been recently suggested in the management of Systemic Lupus Erythematosus (SLE). Lupus Low Disease Activity State (LLDAS) and Definitions Of Remission In SLE (DORIS) remission were outlined as two concentric targets. The achievement of LLDAS was shown to be associated with lower frequency of SLE flare, decreased damage progression, better quality of life, and reduced mortality. In addition, LLDAS has successfully been tested in post-hoc analyses of a number of randomized controlled trials. However, it has been recently underlined that LLDAS includes a high proportion of patients in remission, raising the question if these endpoints are sufficiently distinct to consider their separation clinically relevant. Some studies suggest that the protective effect of LLDAS on damage might be due to the inclusion of patients who are in remission. Notably, clinical low disease activity (LDA) seems to be uncommon in SLE due to the relapsing-remitting pattern of the disease, in which low level of activity only occurs transiently. Moreover, since the domains included in LLDAS have several limitations, such as the use of a binomial disease activity index, the exclusion of some mild manifestations and the consideration of items subjected to variability (physician global assessment and glucocorticoids dose), not all patients in LDA are adequately represented by LLDAS.     

Correlation of clonal T cell expansion with disease activity in systemic lupus erythematosus

It has been proposed that T cell activation may play an important role in the pathogenesis of systemic lupus erythematosus (SLE). In order to examine this hypothesis, we assessed the whole degree of clonal accumulation of T cells using RT-PCR and subsequent single-strand conformation polymorphism (SSCP) analysis. The analysis of the beta chain of the TCR revealed little clonotypic T cell expansion in the peripheral blood of lupus patients in remission, whereas in patients with active disease many dominant T cell clonal expansions without any distinct V beta bias were observed. The alteration in the number of T cell clones correlated well with disease activities, since these T cell expansions decreased as patients had improved. Furthermore, similar but more intense accumulations of T cell clones were found in pleural and pericardial effusions of patients with lupus serositis. Some of these identical expanded clonotypes were observed irrespective of the lesions and the times of sampling, and some of them were identical to those observed in the peripheral blood. These results suggest that the T cell clonal expansions correlate with the disease activities and that the expansion might contribute to the pathogenic lesion formation in SLE.      

Serum adenosine deaminase activity is increased in systemic lupus erythematosus patients and correlated with disease activity

Adenosine deaminase (ADA) has been found to be involved in autoimmune disease progression. To assess the potential application of serum ADA activity in diagnosing systemic lupus erythematosus (SLE) and evaluating SLE disease activity, we investigated the serum ADA activity of 120 SLE patients and 120 healthy controls in the present study. The results showed that serum ADA activity in SLE patients was significantly increased (median (IQR)?=?14 (11–19) U/L) compared with that in healthy controls (median (IQR)?=?8 (7–10) U/L). Based on a receiver operating characteristic curve analysis, the optimal cut-off value for using serum ADA activity to diagnose SLE patients was 10.5 U/L (specificity, 84.2%; sensitivity, 78.3%). The diagnostic performance of serum ADA activity for SLE patients was better than that of other conventional haematology markers. Moreover, serum ADA activity displayed an increasing trend with increasing SLE disease activity. Spearman’s correlation analysis showed that serum ADA activity was positively correlated with SLE disease activity. These findings suggest that serum ADA activity could be a diagnostic marker for SLE; moreover, measuring serum ADA activity may be helpful for evaluating and monitoring the disease activity of SLE patients.