Incomplete Lupus Erythematosus Research Articles

The Role of Clinical Features and Serum Biomarkers in Identifying Patients with Incomplete Lupus Erythematosus at Higher Risk of Transitioning to Systemic Lupus Erythematosus: Current Perspectives.

Discovery of antinuclear antibodies (ANA) enabled earlier diagnosis of systemic lupus erythematosus (SLE) and other ANA+ connective tissue diseases (CTD). Rheumatologists increasingly encounter high referral volume of ANA+ patients. It has been estimated that only a small percentage of these patients will eventually transition to either SLE or other specified CTD. Incomplete lupus erythematosus (ILE) has been defined as a subset of patients who have some SLE-specific clinical manifestations but do not meet currently accepted classification criteria for SLE. Several studies have been performed with the goal of identifying clinical features, serum and tissue biomarkers that can distinguish those patients with ILE at risk of transitioning to SLE from those who will not. Increased autoantibody diversity, presence of anti-double-stranded DNA (dsDNA) antibodies, high expression of type I and type II interferon (IFN)-gene products, increased serum levels of B-cell-activating factor of the TNF family (BAFF), and certain serum cytokines and complement products have been identified as markers with positive predictive value, particularly when combined together. Once this patient population is better characterized biochemically, clinical trials should be considered with the primary objective to completely halt or slow down the transition from ILE to SLE. Hydroxychloroquine (HCQ) appears to be a promising agent due to its good tolerability and low toxicity profile and open-label studies in ILE patients have already shown its ability to delay the onset of SLE. Other therapeutics, like those targeting abnormal type I and type II IFN-signatures, B-cell specific signaling pathways, complement activation pathways and high BAFF levels should also be evaluated, but the risk to benefit ratio must be carefully determined before they can be considered.

Controversies in Systemic Lupus Erythematosus: Are We Treating Our Patients Adequately?

Systemic lupus erythematosus (SLE) is characterized by great clinical heterogeneity. The objectives of its management are to make a timely diagnosis and to initiate treatment as promptly as possible so organ damage can be avoided while at the same time exposure to potentially toxic drugs is minimized so that its overall course and outcome improve. In reviewing the current literature, it became quite clear that there are specific topics in which controversies do exist. These include how to treat patients with incomplete lupus erythematosus, the real possibility of abandoning altogether the use of oral glucocorticoids, and the pros and cons of the use of cyclophosphamide and mycophenolate mofetil for the induction treatment of lupus nephritis. Herein we discuss different points of view regarding these still unresolved issues; these comments represent a debate that took place during the PANLAR Virtual Congress (Pan American League of Associations for Rheumatology) and that was organized by the PANLAR Lupus study group, GLADEL (Grupo Latino Americano De Estudio del Lupus) on September 19, 2020.

Mock Recruitment for the Study of Antimalarials in an Incomplete Lupus Erythematosus Trial.

Recruitment to randomized clinical trials is expensive and often falls short of goals, limiting achievement of measurable outcomes. To prepare for a trial in patients with incomplete forms of lupus, a mock recruitment protocol was carried out at 4 proposed study sites. The objective was to determine levels of interest in patients and to uncover potential barriers to enrollment. After obtaining institutional review board approval, study coordinators approached individuals who generally fit proposed criteria for the trial. A standardized script was followed in a structured interview. Levels of interest were determined and any reasons for concerns were collected with an open-ended format. A total of 45 subjects were interviewed, of which 73% expressed an interest in the trial, and 64% said they were likely to enroll. Concerns of those who were not interested included risk of hydroxychloroquine, desire not to receive placebo, and lack of time for participation. The mock recruitment suggests that the trial will be attractive to suitable patients. The concerns raised support other data indicating that provision of information is crucial to achieving enrollment goals. Mock recruitment of potential investigators should be considered also to address referral concerns.

Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE): study protocol for a randomized controlled trial

BackgroundOnset of systemic lupus erythematosus (SLE) is preceded by a preclinical phase characterized by expression of autoantibodies and nonspecific clinical symptoms. Hydroxychloroquine is a treatment for lupus that is widely used based on longstanding experience and a very good safety profile. Existing data suggest that treatment with hydroxychloroquine may postpone the onset of disease. However, prospective studies that prove and quantify the efficacy of hydroxychloroquine in the preclinical phase of lupus have not been done. This study will test the hypothesis that early hydroxychloroquine use can prevent accumulation of clinical abnormalities and modify immune responses that define SLE.MethodsA randomized, double-blind, placebo-controlled trial of hydroxychloroquine vs placebo will be conducted. Participants will have incomplete lupus erythematosus as defined by the presence of antinuclear antibody (ANA) positivity at a titer of 1:80 or greater, as well as one or two additional criteria from the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. The age range will be 15–45 years and the treatment phase will be 96 weeks. The primary endpoint will be the increase in the number of features of SLE defined by the 2012 SLICC classification schema. Secondary outcomes will include the proportion of participants who transition to a classification of SLE as defined by SLICC criteria.DiscussionA major challenge for improving therapies in patients with SLE is early detection of disease. The ANA test that is widely used to screen for SLE has low specificity and interpretation of its significance is challenging. The Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE) trial will provide insights into the appropriate target population for intervention, and will assess whether hydroxychloroquine can slow progression as measured by the accumulation of criteria. Ophthalmologic safety in this population will be assessed. The study will investigate candidate biomarkers that will guide treatment decisions and will accumulate a specimen biobank that will be available to the lupus research community for further in-depth mechanistic studies. This trial is a first step toward testing the feasibility of disease prevention strategies in SLE.Trial registrationClinicalTrials.gov, NCT 03030118. Registered on 24 January 2017.

Use of SLICC criteria in a large, diverse lupus registry enables SLE classification of a subset of ACR-designated subjects with incomplete lupus

ObjectiveSLE is traditionally classified using the American College of Rheumatology (ACR) criteria. The Systemic Lupus International Collaborating Clinics (SLICC) recently validated an alternative system. This study examined large cohorts of...

Preventing the development of SLE: identifying risk factors and proposing pathways for clinical care.

Although challenging, developing evidence-based approaches to an early and accurate diagnosis of systemic lupus erythematosus is a key approach to preventing disease and lupus-associated morbidity and mortality. Advances in our understanding of preclinical and incomplete lupus erythematosus have enabled the identification of risk factors that may predict disease and the development of potential strategies aimed at primary prevention. Emerging data support the notion that there is a temporal disease progression from initial asymptomatic autoimmunity (preclinical lupus) through early clinical features of the disease (incomplete lupus erythematosus) to finally becoming fully classifiable systemic lupus erythematosus (complete lupus erythematosus). Here, we review the demographic, clinical, biomarker as well as genetic and environmental features that are reported to increase the risk of disease progression. Based on these risk factors, we propose a clinical care pathway for patients with early disease. We envisage that such a pathway, through early identification of disease, may improve patient outcomes, while reducing health care costs.

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment.

Objective. The study goals were to evaluate performance of SLE classification criteria, to define patients with incomplete lupus erythematosus (ILE), and to probe for features in these patients that might be useful as indicators of disease status and hydroxychloroquine response. Methods. Patients with ILE (N = 70) and SLE (N = 32) defined by the 1997 American College of Rheumatology criteria were reclassified using the 2012 Systemic Lupus International Collaborating Clinics criteria. Disease activity, patient reported outcomes, and levels of Type I interferon- (IFN-) inducible genes, autoantibodies, and cytokines were measured. Subgroups treated with hydroxychloroquine (HCQ) were compared to patients not on this drug. Results. The classification sets were correlated (R2 = 0.87). ILE patients were older (P = 0.0043) with lower disease activity scores (P < 0.001) and greater dissatisfaction with health status (P = 0.034) than SLE patients. ILE was associated with lower levels of macrophage-derived cytokines and levels of expressed Type I IFN-inducible genes. Treatment of ILE with HCQ was associated with better self-reported health status scores and lower expression levels of Type I IFN-inducible genes than ILE patients not on HCQ. Conclusion. The 2012 SLICC SLE classification criteria will be useful to define ILE in trials. Patients with ILE have better health status and immune profiles when treated with HCQ.

Preclinical lupus.

Systemic lupus erythematosus (SLE) is often preceded by immune dysregulation and clinical manifestations below the threshold for SLE classification. This review discusses current and evolving concepts about the preclassification period of SLE, including clinical and mechanistic observations, and potential avenues for early identification and intervention. Although incomplete lupus erythematosus (ILE) involves fewer clinical manifestations than SLE, ILE patients can suffer organ damage and early mortality. Common clinical features in ILE include antinuclear antibody seropositivity, polyarthritis, immunologic manifestations, and hematological disorders. Despite having lower disease activity and damage scores than SLE patients, ILE patients may develop pulmonary arterial hypertension, or renal, neurological, or peripheral vascular damage. The recently proposed Systemic Lupus International Collaborating Clinics SLE classification criteria could shift the period considered 'preclinical SLE'. Murine studies suggest that the balance of T-helper/T-regulatory cells, peroxisome proliferator-activated receptor γ activity, and plasmacytoid dendritic cell pathways may be valuable targets for early intervention. Advances in our understanding of early SLE, including stages before clinical features are fully developed, will improve our ability to identify individuals at high risk of classification for potential prevention trials, provide necessary information to improve diagnostic testing, and perhaps identify novel targets for directed therapeutics in clinical SLE.

A Case of Bad Prognosis for Membranous Nephropathy in a Patient with Mixed Connective Tissue Disease

Incidence of renal involvement in mixed connective tissue disease (MCTD) is low. In the presence of glomerulonephritis, membranous nephropathy (MN) in MCTD is common. A 47-year-old woman presented with hypothyroidism. She developed Raynaud’s phenomenon, arthralgia, and incomplete lupus erythematosus, diagnosed with MCTD. One year after then, the patient developed persistent proteinuria (1+) without hematuria. Following diagnosis with MCTD, her renal function began to deteriorate. The renal biopsy showed late stage MN. For the treatment of MN with mild proteinuria and MCTD, we prescribed an angiotensin II receptor blocker and 7.5 mg of methotrexate per week and 300 mg of hydroxychloroquine daily. The patient had a reduced estimated glomerular filtration rate of 55% for the subsequent eight years. The MN in MCTD is known to show good renal prognosis. Here, we report on a rare case of MN in MCTD in Korea with a bad prognosis. (J Rheum Dis 2015;22:260262)

Autoantibodies to C-Reactive Protein in Incomplete Lupus and Systemic Lupus Erythematosus

ObjectiveAnti-C-reactive protein (CRP) antibodies have been described in patients with systemic lupus erythematosus (SLE). We investigated the potential of the anti-CRP antibody as a marker for disease activity in SLE...

AB0194 HLA DRB1 alleles in incomplete lupus erithematosus

BackgroundSystemic lupus erythematous (SLE) represents a heterogeneous group of patients. Some of them are diagnosed with SLE with mild articular and cutaneous symptoms, while others present with severe organ damage....

Organ damage in high-risk patients with systemic and incomplete lupus syndromes

The objective of this study was to characterize organ damage in lupus patients enrolled in Dallas Regional Autoimmune Disease Registry (DRADR). Retrospective chart review was carried out on 99 patients with four or more diagnostic criteria for systemic lupus erythematosus (SLE) and 15 with less than four of these criteria, who were designated as having incomplete lupus erythematosus (ILE). The majority of patients (84 %) were African American or Hispanic/Latino; mean disease duration was 9.5 years. The mean damage score was 1.57 (range 0-8), and a damage score greater than 0 was present in 64 % of the patients. The ILE group had lower mean damage scores (0.67) than the SLE group (1.67; P = 0.04), explained in part by the shorter disease duration in the ILE patients (4.33 vs. 10.24 years; P = 0.003). The most prevalent damage category was renal, present in 24 % of patients. Malignancies occurred in individuals who were significantly older than those who had renal or peripheral vascular damage (P = 0.0007). The findings confirm clinical impressions that DRADR includes a high-risk lupus population. The ILE patients have less damage but also shorter disease duration, suggesting that this might represent an earlier disease stage. These results are consistent with the hypothesis that ILE patients include a subset that is likely to experience progressive organ damage. Longitudinal study of these patients has significant likelihood of tracking the changes that are correlated with disease progression to SLE.

Undifferentiated CTD: A wide spectrum of autoimmune diseases

The existence of systemic autoimmune diseases not fulfilling classification criteria for defined connective tissue diseases (CTDs) is a common clinical experience. These conditions have been variably defined as incomplete lupus erythematosus, early undifferentiated connective tissue diseases and undifferentiated connective tissue diseases (UCTDs). However, the definition of UCTD includes a wide spectrum of diseases ranging from 'organ-dominant' conditions (e.g., idhiopatic non-specific interstitial pneumonia) to simplified conditions (stable UCTD), to early CTDs or mild forms of CTDs. In the present article, the literature data on undifferentiated diseases and their clinical spectrum as well as the importance of the definition of new classificative criteria are discussed.

Breast cancer in lupus

The purpose was to evaluate the frequency of breast cancer (BC) in patients with either systemic (SLE) or incomplete lupus erythematosus (ILE), and possibly to find out immunological differences in patients with and without cancer. 133 consecutive female patients with lupus were included. The records were retrospectively analysed with respect to both malignant disease and routine laboratory parameters (e.g. autoantibodies, white blood cell counts). BC was the most common malignancy that was detected in 50% of female lupus patients with concomitant oncological disease. Other malignancies were significantly less ( p < 0.001) frequent. Only ILE-patients had BC or other oncological diseases. The proportion of ILE-patients with SSA- and SSB-autoantibodies was significantly higher ( p < 1.5 × 10 −10 and 9.1 × 10 −17) in those with malignancies than without. The presented data suggest that BC is the most common malignancy in patients with ILE. SLE is no prerequisite to acquire an oncological disease. Immunological disturbances (e.g. SSA- and SSB-autoantibodies) could play a role in the oncogensis.

Interferon signature gene expression is correlated with autoantibody profiles in patients with incomplete lupus syndromes

Interferon (IFN) signature genes have been shown to be expressed highly in peripheral blood of patients with systemic lupus erythematosus (SLE), especially in the presence of active disease. However, the expression of this gene signature in individuals with incomplete forms of lupus and the pathogenic relationship between IFN signature genes and autoantibody production have not been explored fully. In the present study, we examined the gene expression and autoantibody profiles of patients diagnosed with incomplete lupus erythematosus (ILE) to determine correlations of the gene expression signature with autoantibody production. Gene expression analysis was carried out on the 24K Illumina Human Refseq-8 arrays using blood samples from 84 subjects, including patients with SLE (n = 27) or ILE (n = 24), first-degree relatives (FDR) of these patients (n = 22) and non-autoimmune control (NC) individuals (n = 11). Autoantibody expression was measured using standard immunoassays and autoantigen proteomic arrays. Up-regulation of a set of 63 IFN signature genes was seen in 83% of SLE patients and 50% of ILE patients. High levels of IFN gene expression in ILE and SLE showed significant correlations with the expression of a subset of IgG autoantibodies, including chromatin, dsDNA, dsRNA, U1snRNP, Ro/SSA, La/SSB, topoisomerase I and Scl 70, while low IFN levels were correlated with immunoglobulin (Ig)M autoreactivity. These studies suggest that in patients with ILE the IFN gene expression signature may identify a subset of these individuals who are at risk for disease progression. Furthermore, high levels of alpha IFN may promote autoantibody class-switch from IgM to the more pathogenic IgG class.

Defining undifferentiated connective tissue diseases: a challenge for rheumatologists

Undifferentiated connective tissue diseases: distinct clinical entities? Classification criteria have been developed by the scientific community to improve communication and facilitate clinical studies. In clinical practice, however, it is not unusual to come across systemic autoimmune diseases that do not meet the existing classification criteria. These diseases have been variously termed as incomplete lupus erythematosus, undifferentiated connective tissue diseases (UCTD) or undifferentiated connective tissue syndromes. 1–18 However, a review of the literature shows that a broad range of conditions including transitory diseases, the initial phases of defined CTD, incomplete forms of defined CTD, and conditions that cannot be classified or diagnosed based on the clinical findings have been classified as UCTD. 4,9,15,19–24 Studies demonstrate that a certain proportion of UCTD patients will eventually develop defined CTD, generally systemic lupus erythematosus (SLE), but others develop conditions such as systemic sclerosis (SSc), Sjogren’s syndrome, mixed connective tissue diseases, rheumatoid arthritis (RA), systemic vasculitis and polydermatomyositis. 2–4,6–9,11–15 The marked discrepancy in the reported rates of such an evolution – ranging from 10% to 70% – may be attributable to the characteristics of the patients recruited in different studies, in particular their disease duration. Higher incidences have been reported during the first 3– 5 years of the disease, and, therefore, studies that include patients with recent onset UCTD are likely to see a larger number evolving to a CTD. In contrast, UCTD of long duration is much less likely to develop into a defined CTD. At the same time, a distinct subgroup of patients can be identified who will maintain an undefined profile during follow-up. 4,6–8,11–15 Their disease can be termed stable UCTD, a condition with low disease activity, a low incidence of flares (7% in our patient population over 1 year; unpublished data) and the absence of severe organ involvement (e.g. pulmonary fibrosis, kidney or neurological impairment). The most common clinical manifestations are non-erosive arthritis; Raynaud’s phenomenon without swollen hands, sclerodactily or nailfold capillaroscopic abnormalities suggestive of SSc; sicca symptoms (but negative salivary gland biopsy and ocular test results) and leucopenia. The serological profile is positive for antinuclear antibodies (ANA), generally with a single autoantibody specificity (anti-Ro/SSA or anti-RNP) and only rarely disease-specific autoantibodies (usually anti

Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT).

Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE. Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up. Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE. A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

Clinical outcome and predictors of disease evolution in patients with incomplete lupus erythematosus.

To determine the outcome and identify risk factors for evolution into systemic lupus erythematosus (SLE) in a population of incomplete lupus erythematosus (ILE) patients, we studied the clinical and serologic manifestations in a cohort of 87 ILE patients. ILE patients had at least one but less than four of the American College of Rheumatology (ACR) classification criteria of SLE and did not present distinctive clinical features or meet classification criteria of other connective tissue diseases. The patients that remained with ILE were compared with patients that evolved into SLE and with a cohort of 94 SLE patients. The mean disease duration and follow up of ILE patients were 4.4 +/- 4.1 and 2.2 +/- 2.4 years respectively. Eight patients evolved into SLE, but none presented major organ damage. At baseline, patients that remained with ILE were less likely to have photosensitivity, elevated anti-dsDNA and decreased C3 complement than patients that evolved into SLE. At the end of the study, malar rash and oral ulcerations were also less frequent in the ILE group. Compared with all SLE cases, ILE patients were less likely to have photosensitivity, malar rash, oral ulcers, Raynaud's phenomenon, arthritis, low C3, low C4, positive anti-dsDNA, anti-Sm, anti-RNP, anti-Ro and anti-La antibodies at baseline. Hazard analyses showed that malar rash, oral ulcers, elevated anti-dsDNA and decreased C4 were associated with SLE occurrence. In conclusion, this study suggests that ILE represents a mild spectrum of lupus in which mucocutaneous and serological abnormalities are associated with progression into SLE.

Incomplete Lupus Erythematosus

Thirty-eight patients with incomplete lupus erythematosus (ILE) (defined as the presence of fewer than four of the criteria of the American College of Rheumatology for systemic lupus erythematosus [SLE]) were identified and compared with 42 patients with SLE. Both groups were comparable with respect to age, sex, and race. Patients with ILE had symptoms for an average of 38 months before seeking rheumatologic care and were followed up for a mean of 19 months; patients with SLE averaged 9 months with symptoms before their diagnosis was made and were followed for a mean of 30 months. Characteristic clinical features of patients with ILE included positive antinuclear antibody titers (83%), polyarticular nonerosive arthritis (47%), and cutaneous findings (61%). These were comparable with findings in the the SLE group. However, patients with ILE had significantly fewer systemic manifestations than did those with SLE. Patients with ILE were treated with nonsteroidal anti-inflammatory drugs more frequently (47%) than were patients with SLE, while the latter group received more topical and oral corticosteroids and immunosuppressives. Only two of the patients with ILE went on to have typical SLE. Thus, ILE may be frequent, mild, and relatively stable or benign, apparently evolving slowly if at all into SLE or other rheumatic disease.