Thrombotic endocarditis and lupus anticoagulant. A pathogenetic possibility for idiopathic 'rheumatic type' valvular heart disease

Lupus anticoagulant and anti-phospholipid antibodies are well recognized as being associated with thromboembolic disorders in patients both with and without systemic lupus erythematosus (SLE). There have been recent reports of the association of lupus anticoagulant and antiphospholipid antibodies with severe valvular heart disease in patients with SLE and it has been suggested that organizing thrombus on the surface of the valve may be a cause of distortion and subsequent dysfunction. We describe two patients who did not have SLE, but who did have both lupus anticoagulant and antiphospholipid antibodies. Both had severe valvular heart disease, the pathology of which demonstrates valve distortion by layers of organizing thrombus identical to that of previously described patients with SLE. The gross appearance of these valves is similar to that of the valves in "rheumatic" heart disease. We suggest that in some patients with "rheumatic" heart disease, but without a history of rheumatic fever, the prothrombotic tendency associated with lupus anticoagulant and phospholipid antibodies may either contribute to, or be responsible for, the pathogenesis of "rheumatic" type valve deformities.     

Prevalence, morphologic types, and evolution of cardiac valvular disease in systemic lupus erythematosus

We performed echocardiography prospectively 4.9 +/- 0.7 years apart (mean +/- SD), in 74 patients with systemic lupus erythematosus. On the basis of the first study, the patients were distributed in four groups according to the type of valvular involvement: 7 patients had vegetations (Libman-Sacks endocarditis; group 1); 6 patients had rigid and thickened valves with stenosis, regurgitation, or both (group 2); 5 patients had miscellaneous forms of valvular involvement without valvular dysfunction (group 3), as did the 60 controls; and 56 patients had no valvular disease (group 4). The overall prevalence of clinically important valvular disease (groups 1 and 2) was 18 percent. Patients in group 1 were younger than those in group 2 (33.5 +/- 16.7 vs. 47.8 +/- 17.6 years; P less than 0.05), had a shorter mean duration of lupus (4.8 +/- 2.2 vs. 10.7 +/- 6.4 years; P less than 0.001), and had received a smaller cumulative dose of steroids (21.5 +/- 13.1 vs. 79.5 +/- 63.4 g of methylprednisolone or its equivalent; P less than 0.05). During the five-year follow-up, one patient in group 1 and five in group 2 required valve surgery, no patient in group 3 had valvular dysfunction, and five patients in group 4 had mild valvular lesions. We conclude that clinically important valvular involvement in systemic lupus is relatively frequent and sometimes requires surgery. Echocardiography can identify a subset of lesions (valvular thickening and dysfunction), other than verrucous (Libman-Sacks) endocarditis, that are prone to hemodynamic deterioration.     

Devic's syndrome and SLE: challenges in diagnosis and therapeutic possibilities based on two overlapping cases

Neuromyelitis optica (NMO, Devic's disease), an uncommon demyelinating neuro-immunological disease, can be associated with autoimmune diseases. In SLE associated forms anti-aquaporin-4 antibody positivity can help differentiating between SLE nerve system manifestation and NMO. In the literature rituximab, or immunoablative dose cyclophosphamide (CYC) was effective for the therapy resistant forms. Authors present 2 SLE overlapping NMO cases, one of them with SLE associated interstitial lung disease (ILD). In both cases neurological manifestations anticipated other SLE symptoms. Patients previously were treated with high dose corticosteroid therapy, plasmapheresis, and one of them with azathioprine, and the other one with oral CYC (which could not prevent flares). 0.5 g/m2 body-surface monthly parenteral inductive CYC therapy was administered, in one patient followed by quarterly maintenance therapy. This patient completed her 18 month maintenance treatment and has been in neurological remission, but required steroid pulse and plasmapheresis for lung symptoms. The second patient had urogenital infection after the induction phase, followed by an exacerbation, requiring plasmapheresis and high dose parenteral corticosteroid treatment. After it he refused CYC therapy and has been taking azathioprine. He has no new symptoms, only residual ones. In our two patients conventional dose CYC therapy proved to be effective for NMO/SLE overlap, required only transient supportive therapy.     

Native valve endocarditis caused by an organism resembling Corynebacterium striatum.

An organism resembling Corynebacterium striatum was isolated from the blood of a patient with acute aortic valvular insufficiency and no history of valvular heart disease. At autopsy, histopathologic examination of the aortic valve revealed pleomorphic gram-positive bacilli and destruction of valvular tissue. Our isolate differed from other nondiphtherial corynebacteria, including the type strain of C. striatum (ATCC 6940), in its ability to reduce nitrite. Nitrite reduction may be useful for distinguishing strains of corynebacteria.     

Production and analysis of IgG monoclonal anti-DNA antibodies from systemic lupus erythematosus (SLE) patients.

This study compares recently devised methods for producing IgG anti-DNA MoAbs from patients with SLE and analyses the antibodies generated from one patient at different phases of disease. Lymphocytes from SLE patients were transformed with Epstein-Barr virus(EBV) and/or fused with a heteromyeloma cell line, CB-F7. Direct fusion with CB-F7 resulted in the highest proportion of IgG-secreting lines, whereas EBV transformation resulted in a high percentage of IgM-secreting lines. Using direct fusion, five IgM anti-DNA antibody-secreting hybridomas were generated using lymphocytes from a patient with relatively inactive SLE. Six months later when the disease was active, only IgG anti-DNA antibodies were produced. The antigen-binding patterns of the MoAbs were analysed. Only one of the IgM anti-DNA antibodies reacted with dsDNA by ELISA and none by Crithidia immunofluorescence, whereas two of the IgG antibodies reacted with dsDNA by ELISA and Crithidia but did not bind to ssDNA. Only the two IgG high affinity anti-dsDNA antibodies bound to histones, and this was enhanced by added DNA, whereas three IgM antibodies bound to cardiolipin. This study supports the notion that MoAbs derived from a patient with SLE represent those found in the serum of SLE patients at different stages of disease activity. The binding to histones by the two IgG anti-dsDNA antibodies supports the recently expressed view that antibodies binding DNA/histone may be important in the pathogenesis of SLE.     

Increased production of the third component of complement (C3) by monocytes from patients with systemic lupus erythematosus.

We measured in vitro C3 production by peripheral blood monocytes from patients with systemic lupus erythematosus (SLE), and found it to be significantly greater than that from normal controls. We also found that monocytes from SLE patients with active disease produced a markedly larger amount of C3 than those from SLE patients with inactive disease. Production of C3 by monocytes correlated with serum levels of anti-dsDNA antibodies and inversely correlated with serum C3 levels in SLE patients. Serial measurement of C3 in the culture supernatant from each SLE patient showed that C3 production by monocytes fell in parallel with a decrease of disease activity. The effect of corticosteroids was ruled out as there was no relation between the level of C3 production by monocytes and the dose of prednisolone. This seems to be the first study in which the C3 production was assayed at a cellular level in SLE patients, and this study suggests that the local C3 production is increased in SLE patients.     

Severe valvular and aortic arch calcification in a patient with Gaucher's disease homozygous for the D409H mutation

Gaucher's disease is an autosomal recessive inherited defect of the lysosomal enzyme glucocerebrosidase, which leads to glucocerebroside accumulation in the reticuloendothelial system. Homozygosity for the D409H mutation has been associated with cardiovascular valvular disease. We present a case of a 17-year-old Palestinian patient who presented with severe aortic and mitral valvular calcification, as well as calcification of the ascending aorta, the aortic arch and the ostia of his coronary arteries. The patient was confirmed to be homozygous for the D409H mutation in the glucocerebrosidase gene. The patient's enzyme assay for glucocerebrosidase activity was 5 nm/h/mg protein (normal 13-22 nm/h/mg). The patient presented with symptoms of dyspnea and chest pain. He had a 6-year history of documented aortic valve calcification by echocardiogram after two of his older brothers died of congestive heart failure and severe valvular calcification. Cardiac catheterization showed a severely calcified aorta with almost no motion of the aortic valve leaflets and severe calcification of the mitral valve and the mitral valvular apparatus. The patient underwent extensive cardiac surgery with aortic and mitral valve replacements and intraoperative findings confirmed calcification of the entire aortic root. Electron microscopy of the valves confirmed the presence of Gaucher's cells. Enzyme therapy with imiglucerase was initiated. The patient is in stable condition, 20 months post-operatively.     

Antinucleosome antibodies in SLE: a two-year follow-up study of 101 patients

We prospectively analyzed the diagnostic sensitivity and specificity as well as the clinical relevance of antinucleosome antibodies in SLE. One hundred and one consecutive SLE patients were followed for 3 years. Three serial serum samples from each patient were tested for antinucleosome antibodies by ELISA (optimum cut-off value 10 U/ml), and for anti-dsDNA antibody (by ELISA and IIF on Crithidia luciliae), and anti-dsDNA avidity (by Scatchard plot analysis). Sera from 100 healthy individuals (HI), 35 patients with systemic sclerosis (SSc), 30 with primary Sj?gren's syndrome (SS), 20 with rheumatoid arthritis (RA) and 48 with infectious diseases (ID), were assayed as controls. SLE activity and damage were evaluated using the ECLAM score and the SLICC/ACR index. At baseline, antinucleosome antibodies were found in 87 patients with SLE (86.1%), in 8 patients with SSc (22.8%), in 2 HI (2%), and in 1 ID (2.1%). The sensitivity and specificity of antinucleosome testing for SLE were 86.1% and 95.3%, respectively. The prevalence of antinucleosome antibodies in SLE was significantly higher than that of anti-dsDNA antibodies, with a correlation between them. No relevant relationship was found between antinucleosome antibodies and disease features, including renal involvement, disease activity, and disease damage. During follow-up, no significant variation was observed in antinucleosome level, nor in anti-dsDNA antibody level or avidity. We conclude that antinucleosome antibodies are commonly found in SLE. Low antibody levels can be detected in SSc, whereas medium/high levels are highly specific for SLE. Their clinical relevance during the disease course and utility for monitoring the individual patient seem to be poor.     

Graves' disease complicated with systemic lupus erythematosus (SLE): a case report

A 25 year old man had been subjected to subtotal thyroidectomy under the diagnosis of Graves' disease. About a year later the patient developed systemic lupus erythematosus (SLE). Reports on cases of Graves' disease complicated with SLE have barely been observed so far. Consequently, the authors reckoned, with reference to the other literatures on the subject, our case worth reporting.     

Characterization of ribosomal P autoantibodies in relation to cell destruction and autoimmune disease

Autoantibodies against the ribosomal P proteins are related to cell death and tissue destruction and are frequently exhibited in patients with systemic lupus erythematosus (SLE). In an attempt to explore the effect of tissue destruction on the induction of anti-P autoantibodies, we searched for anti-P autoantibodies by enzyme-linked immunosorbent assay in 201 antinuclear antibody (ANA)-positive individuals, in 10 patients with treated kidney SLE and in 45 acute leukaemia patients undergoing intensive chemotherapy. The autoantibody reactivity was further characterized using one- and two-dimensional immunoblot analysis and immunofluorescence. Anti-P were detected in 5.5% (11/201) of ANA-positive individuals, but not in kidney-affected SLE patients or in patients with leukaemia. Seven of 11 anti-P-positive patients had SLE (3/11), primary Sj?grens's syndrome (1/11) and other autoimmune diseases (3/11). A relation between disease activity and anti-P was suggested by follow-up examinations in one SLE patient, supported by the absence of anti-P autoantibodies in the 10 treated kidney SLE patients. Anti-P autoantibodies were detected by immunoblot in one patient with SLE indicating anti-P2 predominance and in the patient with Sj?grens's syndrome indicating anti-P1 predominance. Diverging humoral responses in these ANA- and anti-P-positive patients were further illustrated by immunofluorescence, elucidating varying nuclear reactivity and anti-P pattern. The observation of anti-P in individuals with active autoimmune disease, but not in patients with chemotherapy-induced cell damage, suggests that anti-P antibodies are part of a specific disease process, and not elicited as a response to cell destruction per se.     

Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus

Natural killer (NK) cells belong to the innate immune system but can also affect adaptive immune reactions. This immune regulatory function is often ascribed to the CD56(bright) subpopulation of NK cells that is prevalent in secondary lymphoid tissues and has potent cytokine-producing ability. The NK cells have been described as affecting autoimmune disease and stimulating B-cell production of antibodies, but their role in systemic lupus erythematosus (SLE) pathology has not been extensively studied. We have studied NK cells in SLE, a B-cell-driven systemic autoimmune disease, and phenotypically characterized peripheral blood NK cells in comparison to NK cells from patients with immunoglobulin A nephritis, rheumatoid arthritis and healthy individuals. We have found an increased proportion of CD56(bright) NK cells in SLE, regardless of disease activity. We detected a somewhat increased expression of the activating receptor NKp46/CD335 on NK cells from SLE patients, although neither the percentage of NK cells of all lymphocytes nor the expression of other NK receptors analysed (LIR-1/CD85j, CD94, NKG2C/CD159c, NKG2D/CD314, NKp30/CD337, NKp44/CD336, CD69) differed between patient groups. We show that type I interferon, a proinflammatory cytokine known to be abundant in SLE, can cause increases of CD56(bright) NK cells in vitro. We confirmed that serum levels of interferon-alpha were increased in active, but not in inactive, disease in the SLE patient group. In conclusion, we found an increased proportion of CD56(bright) NK cells in the blood of SLE patients, although it remains to be examined whether and how this relates to the disease process.     

初发SLE病人Th1/Th2及调控因子IL-18基因研究

目的：探讨未经药物治疗初发狼疮病人Th1/Th2细胞亚群分布及其调控细胞因子、细胞因子受体基因表达的差异，试图揭示系统性红斑狼疮发病的免疫紊乱机理。方法：运用三色荧光标记法流式细胞术检测42例未经药物治疗初发狼疮病人细胞亚群分布，并以10例正常人作对照；ABI7700 real-time PCR法同时检测 38例未经药物治疗初发狼疮病人和 28例正常人IL-18及其受体mRNA表达水平的差异。结果：①初发狼疮病人Th1较正常人明显减低（P<0．05），但Th1/Th2无显著性改变。②与正常组相比，SLE组病人IL-18 mRNA及其受体表达较正常人明显降低（P<0．05）；③面部红斑组病人Th1/Th2较正常人明显降低（P<0．05）；④关节炎组SLE病人较无关节炎病人IL-18表达降低。结论SLE是一种以Th1细胞下降，Th2细胞相对占优势的免疫介导的自身免疫性疾病，源于诱导向Th1细胞分化的IL-18及其受体减少和细胞因子间失衡所致。     

The curiously suspicious: infectious disease may ameliorate an ongoing autoimmune destruction in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, which can arise from a combination of genetic and environmental factors. In the past, infections (Epstein Barr virus, parvovirus B-19) have been indicated to play a causative role in the development of autoimmune diseases, such as SLE. On the other hand, with the emergence of the "hygiene hypothesis" infections have also shown to play a protective role in autoimmune diseases. Two case studies are presented which provide clinical evidence of SLE patients with severe, long-term disease, despite immunosuppresive therapy. The course of both diseases changed remarkably after they experienced infections with multiple microbes (bacterial, viral and fungal). Surprisingly, their clinical and laboratory signs of SLE normalized and they are now symptom-free after 5 and 3year follow-ups. The second patient has even had a normal pregnancy, which was a trigger factor for disease flare in the past. The infections presumably changed the host immune systems and the mechanisms of their protective effects are most likely multifactorial. Our cases illustrate that infections could be beneficial in SLE patients and re-directing research toward novel innate-based SLE therapy should be explored.     

Increased Level of Soluble HLA Class I Antigens in Systemic Lupus Erythematosus: Correlation with Anti-DNA Antibodies and Leukopenia

The concentration of soluble HLA class I (sHLA-I) was measured by ELISA in serum samples from 30 well-characterised SLE patients at high and low disease activity states and from 100 healthy controls. HLA-A allotypes in the patients were analysed by a PCR-based typing technique. A higher level of sHLA-I was found in SLE patient sera both at high and low disease activity than in controls (P< 0.001). The sHLA-I level was further increased during active disease (P< 0.01). Concentrations of sHLA-I correlated with anti-dsDNA antibodies at high disease activity, but not with disease activity as analysed by a modified SLEDAI. Numbers of leukocytes and lymphocytes, as well as levels of C1q and C3 correlated inversely with sHLA-I concentration. In five serial samples from ten patients the sHLA-I level co-varied with disease activity. Presence of HLA allotype A9 was associated with higher sHLA-I levels in both patients (P< 0.001) and controls (P< 0.001). We conclude that the increased sHLA-I concentration in SLE patients was related to several laboratory parameters reflecting disease activity suggesting that sHLA-I molecules are connected with the disease process. Increased sHLA-I level due to HLA-A allotype was not a disease susceptibility factor for SLE.     

系统性红斑狼疮患者骨髓间充质干细胞细胞因子分泌及其与病情活动的相关性研究

目的 探讨系统性红斑狼疮（SLE）患者骨髓间充质干细胞（MSCs）细胞因子分泌及其与疾病活动的相关性.方法 采用密度梯度离心和贴壁分离法对11例SLE患者和6例正常人骨髓MSCs进行分离培养,流式细胞术鉴定MSCs.取P2代细胞,半定量RT-PCR检测SLE患者骨髓MSCs白细胞介素-6（IL-6）,IL-7,IL-11,巨噬细胞集落刺激因子（M-CSF）和干细胞因子（SCF）的表达.结果 SLE患者MSCs均表达CD29、CD44和CD105,不表达CD14、CD34、CD45和HLA-DR.两组P2代MSCs均表达IL-6、IL-7、IL-11、M-CSF和SCF.SLE患者组MSCs IL-6、IL-7表达降低（P＜0.01）,IL-7的表达和SLE的活动评分（SLEDAI）呈负相关（r=-0.891,P＜0.05）.结论 SLE患者MSCs细胞因子分泌异常,可能与SLE血液系统损害及病情活动相关.     

Successful treatment of refractory thrombocytopenia with mycophenolate mofetil in a patient with systemic lupus erythematosus

While mild thrombocytopenia in systemic lupus erythematosus (SLE) is frequently seen in the context of active disease, severe thrombocytopenia causing significant bleeding is not that common. Corticosteroids are considered the first line therapy for severe thrombocytopenia in SLE. Second-line therapeutic agents or splenectomy have been reported to be effective for patients who fail to respond to steroids or those who require moderate doses of steroids to maintain the platelet counts. Recent randomized controlled studies have shown that mycophenolate mofetil (MMF) is an efficacious and safe therapeutic agent in patients with proliferative forms of lupus nephritis. However, little information has been available regarding the role of MMF in the treatment of immune thrombocytopenia complicated with SLE. Hereby I describe a patient with SLE in whom thrombocytopenia was refractory to corticosteroids, intermittent intravenous cyclophosphamide, azathioprine, cyclosporine, intravenous gamma globulin, danazol, and splenectomy, and whose platelet counts eventually normalized during therapy with MMF. In this patient, thrombocytopenia is initially thought to be associated with active SLE involving major organ. However, after immunosuppressive agents were given, the refractory nature of thrombocytopenia seems to be an isolated phenomenon, independently of SLE activity.     

Quality of life in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a pervasive disease with wide-ranging effects on physical, psychological and social well-being. As such, a comprehensive assessment of SLE should include several different outcomes, such as quality of life (QoL) and economic costs, in addition to measures of disease activity and damage. In fact, disease effects on QoL are often considered of greater overall importance to patients. Two approaches have been used in the measurement of QoL: generic questionnaires and disease-specific questionnaires. Generic questionnaires are designed to be used across various conditions and populations, whereas disease-specific questionnaires are designed to measure outcomes in one specific disease or condition. The most commonly used measure of QoL is the Medical Outcomes Study Short Form 36 (SF-36), which is a generic measure that is applicable in a variety of conditions, including SLE. Recently, SLE-specific measures have been developed that may prove to be more responsive than generic measures. The hope is that improved outcome measures will allow for better assessment of SLE and eventually facilitate drug development and improve patient care.     

Anti-mannose binding lectin antibodies in sera of Japanese patients with systemic lupus erythematosus

Mannose-binding lectin (MBL) is a key element in innate immunity with functions and structure similar to that of complement C1q. It has been reported that MBL deficiency is associated with occurrence of systemic lupus erythematosus (SLE). We hypothesized that anti-MBL antibodies, if present, would affect the occurrence or disease course of SLE, by reduction of serum MBL levels, interference of MBL functions, or binding to MBL deposited on various tissues. To address this hypothesis, we measured the concentration of anti-MBL antibodies in sera of 111 Japanese SLE patients and 113 healthy volunteers by enzyme immunoassay. The titres of anti-MBL antibodies in SLE patients were significantly higher than those in healthy controls. When the mean + 2 standard deviations of controls was set as the cut off point, individuals with titres of anti-MBL antibodies above this level were significantly more frequent in SLE patients (9 patients) than in controls (2 persons). One SLE patient had an extremely high titre of this antibody. No associations of titres of anti-MBL antibodies and (i) genotypes of MBL gene, (ii) concentrations of serum MBL, or (iii) disease characteristics of SLE, were apparent. Thus, we have confirmed that anti-MBL antibodies are indeed present in sera of some patients with SLE, but the significance of these autoantibodies in the pathogenesis of SLE remains unclear.     

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.     

The homogeneous multiplexed system--a new method for autoantibody profile in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method. We analyzed the presence of elevated titers of anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Jo1, anti-centromere, anti-Scl-70, anti-histone, and anti-dsDNA antibodies in 199 serum samples (113 SLE patients, 86 healthy donors). We compared the type, level and number of autoantibodies and the correlation between the autoantibody profile and disease severity utilizing the SLEDAI score. Elevated titers of at least one autoantibody were detected in 48% of 42 SLE patients. Elevated titers of anti-Ro antibodies were most commonly detected. The distribution of specific autoantibodies was: anti-Ro- 23.8%, anti-dsDNA- 19%, antihistone- 19%, anti-RNP- 14.2%, anti-La antibodies- 11.9%, anti-Sm- 7.1%, anti-Scl 70-4.7%, and anti-centromere- 2.4%. Utilizing ROC analysis, the sensitivity and specificity of anti-DNA antibodies at a cutoff value of 34 IU/ml were 87.1% and 79.4% respectively. Elevated titers of anti-Jo1 antibody were not detected. There was a correlation with the titer of anti-Ro antibodies and disease activity by the SLEDAI score. Seven patients harbored one autoantibody only, 15 patients harbored 2-3 autoantibodies, 3 patients harbored 4-5 autoantibodies, and one patient harbored 6 autoantibodies. A correlation between the number of autoantibodies per patient and disease severity was found. One patient with a multitude of autoantibodies had severe lupus and a myriad of clinical manifestations. In conclusion, the multiplex system is specific and sensitive, provides an autoantibody profile in a single test, and may be useful as a diagnostic test for SLE. Elevated anti-Ro antibodies are associated with severe disease. An autoantibody load may be indicative of more severe disease.