Systemic Lupus Erythematosus - an overview (2023)

Treatment

Treatment of SLE is tailored to the individual and is based on specific disease manifestations and medication tolerability. For all patients, sunscreen and avoidance of prolonged direct sun exposure and other UV light may help control disease and should be reinforced at every visit with the patient.Hydroxychloroquine is recommended for all individuals with SLE when tolerated. In addition to treating mild SLE manifestations such as rash and mild arthritis, hydroxychloroquine prevents SLE flares, improves lipid profiles, and may improve mortality and renal outcomes. Potential toxicities include retinal deposition and subsequent vision impairment; therefore, annual ophthalmology exams are recommended for patients taking hydroxychloroquine, including automated visual field testing as well as spectral-domain optical coherence tomography (SD-OCT). Given that risk factors for ocular toxicity include duration of use and dose, hydroxychloroquine in SLE should never be prescribed at doses >6.5 mg/kg (maximum 400 mg daily), and newer ophthalmology guidelines recommend limiting maintenance dosing to 4-5 mg/kg.

Corticosteroids are a treatment mainstay for significant manifestations of SLE and work quickly to improve acute deterioration; side effects often limit patient adherence, especially in adolescence, and potential toxicities are worrisome. It is important to limit dose and length of exposure to corticosteroids whenever possible. Potential consequences of corticosteroid therapy include growth disturbance, weight gain, striae, acne, hyperglycemia, hypertension, cataracts, avascular necrosis, and osteoporosis. The optimal dosing of corticosteroids in children and adolescents with SLE remains unknown; severe disease is often treated with high doses of intravenous (IV) methylprednisolone (e.g., 30 mg/kg/day to a maximum of 1,000 mg/day for 3 days, sometimes followed by a period of weekly pulses) and/or high doses of oral prednisone (1-2 mg/kg/day). As disease manifestations improve, corticosteroid dosages are gradually tapered over months. For most patients it is necessary to introduce a steroid-sparing immunosuppressive medication to limit cumulative steroid exposure.

Steroid-sparing immunosuppressive agents for the treatment of pediatric SLE include methotrexate, leflunomide, azathioprine, mycophenolate mofetil (MMF), tacrolimus, cyclophosphamide, rituximab, and belimumab. Methotrexate, leflunomide, and azathioprine are often used to treat persistent moderate disease, including arthritis, significant cutaneous or hematologic involvement, and pleural disease. Cyclophosphamide, MMF, and azathioprine are appropriate for the treatment of lupus nephritis, whereas MMF and rituximab are often used for significant hematologic manifestations, including severe leukopenia, hemolytic anemia, or thrombocytopenia.

Cyclophosphamide, usually administered intravenously, is reserved for the most severe, potentially life-threatening SLE manifestations, such as renal, neurologic, and cardiopulmonary disease. Although cyclophosphamide is highly effective in controlling disease, the potential toxicities are significant, including cytopenias, infection, hemorrhagic cystitis, premature gonadal failure, and increased risk of future malignancy. Attention to adequate hydration can attenuate the risk of hemorrhagic cystitis. Fortunately, young girls are at much lower risk of gonadal failure than older women, and the use of gonadotropin-releasing hormone agonists, such as leuprolide acetate, may help prevent gonadal failure.

77.1 Introduction

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by autoantibody production, immune complex deposition, and heterogeneous clinical manifestations. Epidemiologic studies on the sibling risk ratio, familial aggregation of SLE and the disease concordance rate in monozygotic twins support a strong genetic contribution to the development of SLE (1). The inheritance of SLE is complex, following a polygenic model that common variations in a number of genes are involved, each contributing modestly to disease risk (2). As a genetically complex disease, SLE typically exhibits genetic heterogeneity, which has been demonstrated by genetic association analyses stratified by specific clinical features and ethnic backgrounds. In addition, epistasis, that is, interactions between genes or between genes and environmental factors, should be considered as potentially important determinants of disease risk.

Numerous genetic studies on SLE have been performed. Before 2007, the main approaches to explore genes predisposing to disease risk are (1) targeted and genome-wide linkage studies using multiplex families and (2) candidate gene association studies, usually performed using unrelated cases and ethnically matched control individuals. In the past four years (2007–2011), genome-wide association (GWA) studies that represent an important step beyond the two aforementioned methods have revolutionized the search for genetic influences on SLE susceptibility with more than 30 disease-associated loci identified and confirmed in large datasets. Efforts in delineating functional variants underlying SLE-associated signals and rare variants that may have strong impact in risks for SLE are underway. Results from these studies will help elucidate the molecular mechanisms and cellular pathways modulated by robust genetic associations with SLE, and should provide new targets for more focused therapies.

General Rx

1 Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a broad range of clinical manifestations. It is characterized by an immune system dysregulation resulting in the production of various autoantibodies and is considered a multifactorial disease with evidence of genetic susceptibility [1]. SLE affects several organ systems and leads to significant morbidity and mortality. Gastrointestinal (GI) manifestations caused by the disease per se or aggressive treatment regimens are not rare in SLE patients [2], but are seldom reported, likely being masked by other, more salient clinical features such as renal or central nervous system abnormalities. The incidence of GI symptoms attributable to the disease itself varies widely, ranging from 1.3% to 27.5% in the literature. Chronic intestinal pseudoobstruction (CIPO), protein-losing gastroenteropathy, and intestinal vasculitis are the most common identifiable SLE-related GI manifestations [3], which seem to occur more commonly in Asian populations. No specific autoantibodies associated with SLE-related gastroenteropathy have been identified to date. In this chapter, we describe the GI manifestations occurring in SLE patients. The liver manifestations of the disease are beyond the scope of this chapter and will be reviewed elsewhere.

Renal System

Kidney involvement in SLE (Chapter 113) is common, with 74% of patients being affected at some time in the course of disease, and is a poor prognostic indicator. Renal pathology is generally attributed to the deposition of circulating immune complexes or in situ formation of these complexes in glomeruli and results in the activation of complement and subsequent recruitment of inflammatory cells. In addition to glomerular inflammation, necrosis, and scarring, renal pathology is characterized by vascular lesions, including thrombotic microangiopathy and extraglomerular vasculitis. Tubulointerstitial disease, including infiltration of the interstitium with mononuclear cells, tubular atrophy, and interstitial fibrosis, is increasingly recognized as associated with a poor prognosis for persistent nephritis and renal survival.¹⁷ Hypertension may be a consequence of significant renal involvement.

Most cases of lupus nephritis present a complex immunopathologic picture, but in general, the pattern of renal disease reflects the site of deposition of immunoglobulins and the quality of the effector mechanisms they induce. Mesangial deposition of immunoglobulin induces mesangial cell proliferation and is associated with microscopic hematuria and mild proteinuria (Fig. 250-3). Subendothelial deposition of immune complexes results in proliferative and exudative inflammation, together with hematuria, mild to moderate proteinuria, and reduced glomerular filtration rate. Subepithelial deposition of immune complexes adjacent to podocytes and along the glomerular basement membrane can result in membranous nephritis with nephrotic-range proteinuria. In addition, antiphospholipid antibodies may support the development of thrombotic or inflammatory vascular lesions within or external to glomeruli.

A World Health Organization classification of lupus nephritis lesions was first published in 1975, with subsequent revisions. These classifications were reviewed and rigorously reexamined in the revised International Society of Nephrology and Renal Pathology Society classification criteria for lupus glomerulonephritis (GN) published in 2004, with additional review in 2018.¹⁸ (Table 113-7 inChapter 113, and alsoE-Table 250-2). Class I and II GN involves mesangial deposition of immune complexes (class I without and class II with mesangial hypercellularity); class III describes focal GN involving less than 50% of total glomeruli; class IV includes diffuse GN involving 50% or more of glomeruli; class V designates membranous lupus nephritis; and class VI is characterized by advanced sclerotic lesions. Classes III and IV have subdivisions for active and sclerotic lesions, and class IV currently also has subdivisions for segmental and global involvement. Recent recommendations from these societies include elimination of the IV-S and IV-G subdivisions and replacement of the active and chronic designations for class III/IV lesions with application of activity and chronicity indices for all classes. They also suggest eliminating the term “endocapillary proliferation” and are considering a more appropriate definition of endocapillary hypercellularity. Validation of candidate revised classification criteria is planned by these groups. Pathologic diagnosis should include descriptions of tubulointerstitial and vascular disease as well as glomerular involvement. Several renal pathologic lesions seen in SLE patients that are not encompassed in the classification scheme for lupus GN include lupus podocytopathy, collapsing glomerulopathy, and thrombotic microangiopathy, the latter often associated with antiphospholipid syndrome.

Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune rheumatic disorder with a diverse presentation and clinical course. It is most prevalent in females of childbearing age with a female:male ratio of 9:1 in this population. The prevalence of SLE is also higher in certain ethnicities, reflected in prevalence rates of ∼40/100000 persons in Northern European cohorts in comparison with rates of 200/100000 persons in studies of patients of African-American descent (Johnson etal., 1995). In addition to the higher disease frequency in this population, patients of Afro-Caribbean and Hispanic origin have also been observed to have an adverse clinical course. Recent studies also support the need for closer monitoring in patients with a juvenile onset of disease and males with SLE, both phenotypic factors that portend the potential for an adverse clinical course (Amaral etal., 2014).

Despite marked improvements in the therapeutics of SLE, there remains a significantly increased mortality in patients diagnosed with SLE. While in the 1970s a standardized mortality rate (SMR, which defines how many persons, per thousand of the population, will die in a given year)of 12.6 was noted in one large study of a cohort with SLE, reassessment of the same population within the last decade reported an SMR of 3.46 (Bernatsky etal., 2006). Although this indicates significant therapeutic advances, it should be highlighted that SLE is a condition that tends to affect a young female population making this statistic all the more clinically relevant. Further understanding of the pathophysiology of the disease with the ultimate goal of identifying unique therapeutic targets is required to further improve the prognosis of individuals withSLE.

1 Introduction

Systemic lupus erythematosus (SLE) is a chronic, multisystemic, autoimmune disease with a highly heterogeneous pattern of clinical and serological manifestations. It is found in approximately 9–10 times as many women as men. It usual occurs in women during the child bearing years. It is more common, and often more severe, in black, hispanic and Chinese populations compared to caucasians. The disease may commence with one or two symptoms, however, multi-organ involvement is characteristic of SLE. Clinical manifestations vary significantly in different patients and in different periods of the disease. Although the individual's form of the disease is often established in a given patient during the 5years after diagnosis, great long term vigilance is required, as additional features (even renal disease) may appear after more than 10years. In the past four decades, major efforts have been made to define disease activity and damage, using standardized scales. These tools are essential to get international agreement about disease progression and prognosis especially in the era of new biological treatment.

The aetiopathogenesis of SLE is complex and involves an interplay of environmental, hormonal and immunological factors, although precisely how these interactions come about and the invariable, but subtle differences between individuals, remains obscure. A key factor in lupus development is the failure of the efficient removal of dead/dying cells. This normal process is known as apoptosis (the program of cell death) and inefficient removal of “cell debris” results in the undue persistence of nuclear fragments. This process ultimately leads to the development of the antinuclear antibodies, which characterize this disease, together with a reduction in complement levels and patterns of interferon expression.

The outlook for patients with SLE is much better than 50years ago with a current prognosis of about 85% 15year survival. However, the mortality rate remains too high, especially as many SLE patients are under 40. Common causes of death in SLE patients include infection, atherosclerosis and cancer. Death from severe active disease per se is now very uncommon. Morbidity is another major concern for SLE patients. As well as profound fatigue (almost universal among patients), fever and lymphadenopathy, which must be distinguished from infection and malignancy respectively, are often prominent. Longer term problems include atherosclerosis, which is increased in SLE, osteoporosis and avascular necrosis both linked to the corticosteroids widely used to treat the disease, and other concomitant autoimmune diseases (present in approximately one third of SLE patients).

The current conventional therapies notably hydroxychloroquine, corticosteroids and immunosuppressives together with adjunctive drugs (e.g., anti-hypertensives, statins and vitamins D) and some major interventions such as dialysis and transplantation, have lead to the improved prognosis for SLE patients. However, analogous to the improved outlook for patients with diseases like rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis brought about by the biologic drugs, many attempts have been made to treat SLE with these newer approaches. In contrast to the great successes seen in these other conditions, SLE has proved a much “tougher proposition.” Indeed to date, only benlysta (which blocks a B cell activating factor) and B cell depletion (induced by anti CD20 monoclonals like rituximab and its biosimilars) have receive any kind of formal approval. However, many other attempts to block molecules involved in the immune response are on going. Linked to this, is an appreciation that much of the damage (i.e., permanent change) observed in SLE is due to the excessive use of corticosteroids. Thus, there are major attempts, also on going, to try and reduce the amounts of corticosteroids used to treat SLE patients. This article will now describe the clinical features, serological abnormalities, key pathological aspects, current and possible future treatment of SLE in some detail.

Basic Information

1 SLE Is a Chronic Autoimmune Disease With Challenging Therapies

Systemic lupus erythematosus (SLE) is a heterogeneous chronic multisystem autoimmune inflammatory disorder with a prevalence of 40–70 out of 100,000 people. It is believed that genetic predisposition and environmental factors (e.g.,UV exposure, infection, and stress), or a combination of the two, may contribute to the development of SLE [1]. Despite the different initiating factors involved, the final pathway leads to aberrations in immune cells, including Tcells, B cells, and monocytic lineage cells that result in Tcell deficiencies, polyclonal B cell activation, autoantibody production, and immune complex formation [2].

The initial flare of SLE can be controlled by conventional immunosuppressive therapy. However, a definitive cure is rarely achieved and lifelong immunosuppression is often required. Positive response to therapy ranges from20% to 100% at 6months, depending on the criteria used to define improvement, the extent of visceral damage, and the patient's ethnic origin and socioeconomic profile. First-line validated standard therapies, used to induce remission in the first 6–9months of a disease flare, are efficacious and well tolerated and combine corticosteroids with either (1) cyclophosphamide (CYC), using the classic National Institutes of Health regimen or the Eurolupus regimen with lower doses for shorter periods of time (3months) [3,4] or (2) mycophenolate mofetil (MMF) [5].

Despite a paucity of validated therapeutic targets and inability to conclusively demonstrate efficacy, monoclonal antibodies (e.g., rituximab) against T or B cell receptors (e.g., CD20) or adhesion molecules and costimulatory signals involved in T or B cell interactions have been used to treat the renal and extrarenal manifestations of SLE [6]. In 2011, belimumab, a monoclonal antibody against B cell-activating factor (BAFF) (also known as B-lymphocyte stimulator [Blys]) was the first targeted therapy that demonstrated efficacy in mild to moderate SLE in a randomized clinical trial [7]. Despite early diagnosis and treatment with immunosuppressive agents, as well as tight control of hypertension and infection, there is still a subgroup of SLE patients that don't respond to treatment and have a 10-year mortality of 10% [8]. In addition, early death from rapidly progressive atherosclerosis in SLE suggests that the subclinical inflammatory disease promotes endothelial damage and plaque formation and prolonged treatment with corticosteroids and immunosuppressive drugs leads to further damage beyond the SLE itself.

Treatment of drug-resistant SLE with allogeneic/autologous hematopoietic stem cell transplantation (HSCT) was the first application of stem cell–based therapy for lupus. In 1997, Marmont etal. in Genova, Italy, performed the first autologous HSCT for SLE [9] using a peripheral CD34⁺ stem cell source after mobilization with CYC and granulocyte colony stimulating factor. Since that time, phase 1/2 prospective and retrospective studies have demonstrated a very favorable and prolonged clinical response with autologous HSCT in severely affected lupus patients [10]. Five-year follow-up data from 50 patients in the Center for International Blood and Marrow Transplant Research (CIBMTR) database showed an overall survival of 84%, probability of disease-free survival of 50%, and treatment-related mortality of 4% [11]. More recently, data from the European Group for Blood and Marrow Transplantation (EBMT) showed that 5-year overall survival was 81±8% and disease-free survival was 29±9%, with a nonrelapse mortality of 15±7% [12], suggesting that HSCT for lupus patients was a satisfactory and efficacious therapy. However, the biggest challenge for autologous HSCT is the high rate of disease relapse and the serious side effects of the conditioning therapy [13]. Jayne etal. reported that although 66% of patients achieved clinical remission by 6months, 32% of these patients subsequently relapsed, and transplant-related mortality (TRM) was 12% at 1year [14]. Unlike autologous HSCT, allogeneic HSCT appears to offer curative potential in that the auto-aggressive “old” immune system is replaced by a “new” one [15]. EBMT data contained two SLE patients who underwent allogeneic HSCT; however, one patient died of infection at 2.9months and the other patient's disease progressed after being followed for 3years. The clinical use of HSCT for severe autoimmune disease has been limited as TRM remains at about 20% [16] and the risk of graft versus host disease is high [17]. Clearly, a more effective and less toxic treatment regimen for SLE patients is urgently needed.

Classification and Clinical Features

Systemic lupus erythematosus (SLE or lupus) is a potentially fatal systemic autoimmune disease that predominantly affects women of childbearing age (Bertoli and Alarcon, 2007). Although the pathogenesis of SLE remains poorly understood, there is clearly widespread immune dysfunction encompassing both the innate and adaptive immune pathways. The immunological hallmark of SLE is the production of high-affinity autoantibodies directed against ubiquitous intracellular antigens, particularly double-stranded DNA and nucleoprotein complexes (Rahman and Isenberg, 2008). The clinical features of lupus are notoriously heterogeneous, with symptoms related to immune-mediated dysfunction of the kidney, skin, central nervous system, blood, and other organs. Accelerated cardiovascular disease is an important late-stage complication (Elliott et al., 2007; Urowitz et al., 1976).

Although considerable progress has been made in the management of lupus over the last 10 years (recent estimates suggest an 80–90% 10-year survival rate), it remains an incurable disease (Ramsey-Goldman and Gladman, 2007). The current therapeutic options of corticosteroids, small-molecule immunosuppressants, and even targeted biological agents all really fail to address fundamental disease mechanisms in SLE. As a consequence, treatment regimens remain suboptimal both in terms of therapeutic efficacy and unwanted side effects.

Perhaps the key motivation for studying lupus genetics is that it has the potential to highlight fundamental disease pathways that are part of the causative pathogenic process – pathways that will then be amenable to therapeutic intervention. However, we are also aware that demonstrable immunological dysfunction precedes the development of clinical lupus, often by many years, and it is during this window of opportunity that we perhaps have the best chances of intervening with targeted therapeutics to prevent the onset of overt disease (Arbuckle et al., 2003). The identification of genetic variants contributing to disease susceptibility may also eventually allow us to identify individuals who are at high risk of developing the disease and who can therefore be targeted for preventative, or pre-clinical treatment strategies. Whether we can utilize our genetic knowledge further, to predict disease manifestations or to guide therapeutic decisions, is more speculative and dependent on further research (Rhodes and Vyse, 2010).