Manifestations, Complications, and Comorbidities of Lupus

Introduction

Systemic lupus erythematosus (SLE) is an exceptionally heterogeneous disease, characterized by a wide spectrum of constitutional and organ-specific manifestations, complications and comorbidities. Formally, the term “manifestations” signifies the signs and symptoms which occur as a direct result of SLE disease activity (the immunological dysfunction described in Pathogenesis and Pathophysiology), while “complications” signifies the processes that are only secondarily or indirectly caused by SLE disease activity, and “comorbidities” the medical conditions that co-exist with SLE but are not known to be causally related to SLE disease activity (although they may be causally linked to SLE, such as through a shared risk factor).

In a disease as complex and poorly understood as SLE, drawing boundaries between manifestations, complications and comorbidities is a challenge. Instead of attempting to sharply delineate and classify the various SLE-associated symptoms and conditions into these three semantic classes, in this module they are discussed in a causal relationship-agnostic manner, except where distinctions are pertinent to the treatment approach. Each subsection is focused on one organ or organ system, with the exception of the first (constitutional symptoms) and the last (covering infections, other immune disorders and malignancy).

Constitutional Symptoms

Constitutional symptoms are the most common group of symptoms in SLE; they include fatigue, fever, anorexia, lymphadenopathy and splenomegaly. Because constitutional symptoms are not specific, they are not normally included in SLE classification criteria, nor are they particularly useful on their own in diagnosis, although they may be used in the assessment of disease activity.

Fatigue affects up to 90% of patients with SLE. It may arise as a direct consequence of SLE activity, particularly in patients with neuropsychiatric lupus, because of comorbidities (e.g., autoimmune hypothyroidism or anemia), or associated psychosocial factors (e.g., mood disorders, perceived lack of social support) and other, unrelated factors (e.g., vitamin D deficiency, physical inactivity). Management of fatigue in SLE depends on the cause, but may involve treatment of active disease, treatment of associated comorbidity (anemia, hypothyroidism), exercise and cognitive behavioral therapy.

Fever is present in approximately 40-50% of patients with SLE, a proportion that has declined from the mid 20^th century values of 80% or more. Fever may occur as a direct result of SLE disease activity, but given the immune system dysfunction that characterizes SLE, it is often caused by a concomitant infection. The increased recognition of infectious etiology among physicians may be the main cause of the apparent reduction in fever prevalence in SLE. The management of fever depends on the underlying etiology: if partially infectious in origin, appropriate antimicrobial therapy is indicated; immunosuppressants and glucocorticoids (GCs) may be indicated depending on the severity of the SLE flare. In rare cases, fever in patients with SLE may be associated with malignancy.

Lymphadenopathy – changes in the size and consistency of lymph nodes – occurs in 5-7% of patients with SLE at disease onset and 12-15% of patients later in the disease course; however, it rarely develops more than a year into the disease course. Like fever, lymphadenopathy may be secondary to infection or malignancy. When caused by primary SLE disease activity, the lymph nodes may be soft, non-tender, mobile and variable in size; by contrast, cancer-associated lymphadenopathy is characterized by a progressive increase in lymph node size.

Splenomegaly – an increase in spleen size – can be seen in 10-45% of SLE cases, and is associated with active disease. It is often the result of increased lymphoid follicle size in the white pulp of the spleen, along with accumulation of macrophages and plasma cells around the arterioles and cells of the red pulp. Splenomegaly may have a non-SLE etiology, including malignancy, hepatic cirrhosis and infection.

Weight loss, anorexia, nausea and vomiting affect as many as 50% of patients with SLE. Although non-specific (like most constitutional symptoms), unexplained body weight loss of 5% or more may herald active SLE (e.g., nutrient malabsorption as a consequence of immune-mediated gastrointestinal tissue damage). Weight loss may also result from infection, malignancy, or as an adverse reaction to SLE drugs (e.g., mycophenolate mofetil [MMF]).

Musculoskeletal Complications

Musculoskeletal complications – arthritis/arthralgia, myositis/myalgia, osteonecrosis and osteoporosis – have a collective prevalence of >90% in patients with SLE. Although these symptoms may represent a manifestation of SLE, some – particularly osteonecrosis and osteoporosis – may result from medications used to treat SLE, such as GCs.

Data from clinical trials of SLE medication suggests that arthritis occurs in 60-65% of patients with SLE. Non-erosive, non-deforming inflammatory arthritis is the most common type of arthritis seen in SLE. Typically affecting hands, wrists and knees, it is characterized by joint erythema, tenderness and effusion. Uncommonly, SLE may be associated with erosive arthritis resembling rheumatoid arthritis (RA) and sometimes called “rhupus”. Patients with rhupus are often also positive for rheumatoid factor and cyclic citrullinated peptide (CCP) antibodies that characterize RA, and thus rhupus may represent an overlap syndrome. Synovitis, synovial proliferation, rheumatoid nodules and malalignment may occur, along with eponymous erosions, with the wrist preferentially affected. Jaccoud’s arthropathy, a rare joint disorder characterized by reducible (i.e., non-surgically correctable) deformities (Figure 6-1) without evidence of erosion on standard radiographs, may also occur in patients with SLE. Treatment of SLE-associated arthralgia or arthritis depends on the severity; for milder symptoms, nonsteroidal anti-inflammatory drugs (NSAIDs) or low dose GCs are typically sufficient. Immunosuppressive drugs may be required in case of persistent or more severe symptoms.

Fibromyalgia occurs in ~6% of patients with SLE, and is more common in patients with longer (>5 years) disease duration. Inflammatory myositis occurs in 3-19% of patients with SLE, and is more commonly seen in pediatric patients (8-19%) than patients with adult-onset SLE (4-6%). Lupus-associated myositis is normally indistinguishable from idiopathic inflammatory myositis, and is characterized by proximal muscle weakness and elevated muscle enzymes (e.g., creatine phosphokinase). Myopathic symptoms may be caused by SLE organ damage, and can also arise as an adverse reaction of GC and antimalarial therapy for SLE. The treatment of SLE-associated myositis, like that of arthritis, depends on disease severity. Glucocorticoids are typically the first-line agents, followed by classic immunosuppressants like azathioprine (AZA), methotrexate (MTX), or MMF. For refractory cases, rituximab (RTX) may be helpful.

Osteonecrosis – necrotic cell death in the bone which compromises its structural integrity – has a reported prevalence of 4-15% (symptomatic osteonecrosis) and 40-50% (silent/asymptomatic osteonecrosis) among patients with SLE, and is a significant contributor to pain and disability in SLE. The most commonly affected site is the hip, but about 50% of patients with SLE-associated osteonecrosis will have multi-site involvement. Osteonecrosis is believed to result from ischemic death of osteocytes. Risk factors include SLE activity and prolonged GC use. Mild osteonecrosis symptoms are typically managed by pain control medications, while more severe cases may require surgical treatment.

Osteoporosis – a decrease in bone density and strength – may have a prevalence as high as 23% among patients with SLE. In addition to the risk factors that apply to the general population, SLE disease activity and pharmacotherapy (primarily GCs) are additional factors that increase the risk of osteoporosis in patients with SLE. Cytokine-mediated inflammatory damage and indirect mechanisms (such as nephritis, inadequate sun exposure, and secondary reduction of mobility) both contribute to disease activity-related bone loss in SLE. Glucocorticoids inhibit bone formation and resorption, and negatively impact calcium metabolism. Bone loss management includes non-pharmacologic (e.g., exercise, monitoring of vitamin D levels, maintaining recommended calcium intake) and pharmacologic (e.g., bisphosphonates) options.

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Cutaneous Complications

Cutaneous manifestations are common in lupus, occurring in up to 80% of patients and representing the first sign of disease in ~25% of cases. Lupus-associated cutaneous manifestations exhibit a high degree of heterogeneity, with lupus-specific and lupus-non-specific features. Lupus-non-specific manifestations include cutaneous vascular lesions (e.g., periungual telangiectasia, red lunula, livedo racemosa, Raynaud's phenomenon, among others), papular mucinosis, calcinosis cutis, nonscarring alopecia,and erythema multiforme. The presence of these non-specific manifestations is associated with higher disease activity. Lupus-specific cutaneous manifestations associated with the three subtypes of cutaneous lupus (CLE) described in Types of Lupus: acute CLE, most often manifesting as a non-discoid malar rash (see Figure 2-2A), subacute CLE, commonly presenting with nonindurated psoriasiform and/or annular polycyclic rash (see Figure 2-2B), and chronic CLE (CCLE), in which discoid lesions are most common (see Figure 2-2C). In addition to discoid lesions, CCLE – the CLE type least likely to progress into SLE – may in rare cases manifest as lupus erythematosus profundus/panniculitis (LEP) and chilblain lupus erythematosus (CHLE). Indurated subcutaneous nodules or plaques characterize LEP; these lesions may develop into deep lipoatrophy or retracted scars (Figure 6-2). Cold, damp conditions may result in manifestation of CHLE, with itchy and painful bluish plaques/nodules reminiscent of chilblain frostbite (Figure 6-3). These lesions may also develop erosions or ulcerations. Another subtype of cutaneous lupus, lupus erythematosus tumidus (LET), was defined as a distinct entity relatively recently – in the past two decades. Generally associated with a more favorable prognosis, LET is typified by urticaria-like erythematous papules that often appear swollen (Figure 6-4).

A number of mechanisms contribute to the development of CLE, but it is often driven by interactions between external factors (often UV light exposure) and immunological dysfunction, including cytokine production and inappropriate infiltration of pro-inflammatory cells into the epidermis, a process potentiated by deficient clearance of apoptotic cells and interferon signaling. Approximately 60-80% of patients with SLE show photosensitivity, with reactions ranging from cutaneous lesions (triggered by UV radiation-driven local DNA damage and increased keratinocyte apoptosis) to systemic disease flares (driven by UV light-driven increase in autoantigen generation and accessibility).

The first-line treatment options for cutaneous manifestations include topical agents (including GCs and calcineurin inhibitors) and/or systemic agents (GCs and antimalarials). Second-line options include MTX, retinoids, dapsone and MMF. Prevention is also of crucial importance to patients with skin manifestations. Preventive strategies include the use of broad-spectrum sunscreens, UV-protective clothing, and – in severely photosensitive patients – avoidance of florescent lights.

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Hematologic Complications

Cytopenias commonly occur in patients with SLE, affecting either single blood cell lineages (e.g., leukopenia, thrombocytopenia, anemia) or a combination of two or more lineages. Cytopenias may occur because of SLE disease activity (e.g., autoantibodies directed against specific blood cell types or subtypes, decreased production because of damage in the bone marrow), or because of drug-related adverse events (Table 6-1).

Leukopenia, typically defined as a total white blood cell count below 4000/mm³ on at least two measurements, has a reported prevalence of 22-42% in SLE. Persistent leukopenia (i.e., leukopenia present in at least 75% of measurements) is rarer, with a reported prevalence of 13%. Neutropenia (absolute neutrophil count [ANC] of 1000-2500 mm³) is a common contributor to leukopenia (20-40% of SLE cases), while severe neutropenia (ANC of less than 1000 mm³) is rare (1-4% of SLE cases). Lymphocytopenia (lymphocyte count below 1500 mm³ on at least two occasions) is another common contributor to leukopenia, with a wide range of reported prevalence among SLE patients (15-82%). Lymphopenia is associated with increased disease activity, neurologic involvement, and organ damage.

Thrombocytopenia (platelet count below 150,000/mm³) affects between 10% and 40% of patients with SLE, and is most commonly mild to moderate (platelet count 50,000 to 100,000/mm³), but severe thrombocytopenia of <20,000 mm³ has been reported to occur in just over a quarter of patients with SLE. Thrombocytopenia is associated with increased mortality and organ damage.

Anemia (hemoglobin levels <12.0 g/dL [women] or <13.0 g/dL [men]) is common in patients with SLE, with a prevalence of ~50%. Anemia in SLE may be immune-mediated or non-immune-mediated. Immune-mediated forms include autoimmune hemolytic anemia (caused by direct autoimmune targeting of surface antigens on erythrocytes) which affects 3-8% of patients with SLE, and pure red cell aplasia (anemia caused by depletion of erythroid precursors in the marrow), which is rare in SLE. Non-immune-mediated forms include iron deficiency anemia (most common, ~33%), anemia of inflammation, microangiopathic hemolytic anemia and drug-induced anemia.

Although comparatively rare, pancytopenia (low levels of all blood cells) may also occur in patients with SLE, and could be related to direct immune-mediated destruction of all three lineages in the periphery or hematopoietic suppression in the bone marrow. Treatment of hematological manifestations depends on the affected cell lineage(s) and the etiology of the abnormalities.

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Lupus Nephritis

Kidneys are often affected by SLE disease activity, and renal disease – lupus nephritis (LN) – is a significant contributor to the morbidity and mortality of SLE. Lupus nephritis occurs in approximately 50% of all patients with SLE and typically manifests in the first 3 years following diagnosis. The standardized mortality ratio (risk of mortality compared to the general population) is higher in SLE patients with LN (6-6.8) than those without (2.4), and disease control is of paramount importance for decreasing the risk of end-stage renal disease and mortality. Like SLE in general, LN usually involves cycles of increased activity and remission, during which kidney damage progressively accumulates.

The first steps in evaluating for LN involves urinalysis (dipstick and sediment), blood analysis (serum creatinine), and determination of spot urine protein:creatinine ratio. These tests may reveal proteinuria or evidence of impaired glomerular filtration rate (GFR). If either proteinuria (protein:creatinine ratio >0.5 in a 24h collection) or decreased GFR (serum creatinine above upper limit of normal or estimated GFR <60 mL/min/1.73m²) is confirmed and not attributable to another (non-SLE) cause, a kidney biopsy – the gold standard procedure for diagnosing LN – should be considered. Patients with SLE should be screened for LN by urine testing every 3-6 months. It is important to note that LN (or at least glomerular immune complex [IC] accumulation) may occur without a positive urine/serum finding; this is thought to represent the earliest stage of LN. The renal biopsy is typically performed by a nephrologist or interventional radiologist and interpreted by a nephropathologist in concert with the team; ideally, a minimum of 10 glomeruli should be examined, although 20 or more is preferred. In addition to diagnosing LN, a kidney biopsy is used to assess the extent of disease and to inform treatment.

To help standardize the identification of clinically relevant information from renal biopsy samples, several classification schemata have been developed. By far the most widely used is the 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) system, which categorizes LN into six classes (Class I-VI) reflective of disease extent. Biopsy examples for Classes I-V are shown in Figure 6-5. Class I LN appears essentially normal on light microscopy, but IC deposits in the mesangium can be seen as electron-dense regions on electron micrographs, or with immunofluorescence (IF) staining for IgG or complement components. In Class II LN (“mesangial proliferative LN”), light microscopy reveals mild mesangial cell proliferation. Class III (“focal”) LN may show segmental (as in Figure 6-5) or global endocapillary proliferation on light microscopy, subendothelial IC deposits on electron miscopy, and IgG signal along the glomerular capillary walls on IF microscopy. Class IV (“diffuse”) LN is characterized by diffuse segmental or global endocapillary or extracapillary proliferation visible on light microscopy; the example in Figure 6-5 also shows glomerular capillary necrosis. Diffuse subendothelial IC deposits can be seen on electron and IF micrographs. Class V (“membranous”) LN is characterized by subepithelial IC deposits visible on electron and IF micrographs; the light micrograph in Figure 6-5 is stained with silver to emphasize the glomerular basement membrane (in black). Class V LN can occur together with Class III or IV LN; less numerous subepithelial deposits are visible in the Class IV biopsy example in Figure 6-5, suggesting the co-existence of Class IV and V LN. Note that Class III, IV, and V LN may occur with or without mesangial alterations. Class VI LN (not shown in Figure 6-5) is characterized by scarring of more than 90% of glomeruli without active inflammatory lesions; it is the terminal, irreversible stage. The ISN/RPS system was updated in 2018 to make the classification more clinically useful. The updated classification system, slightly abbreviated, is presented in Table 6-2.

Proper classification of LN is of crucial importance because it informs treatment. A proposed LN treatment algorithm is shown in Figure 6-6. Class I and II LN have mild clinical manifestations and are associated with a low risk of progressive renal disease; therefore, therapy is generally focused on supportive measures and the treatment of extra-renal SLE manifestations. Class III and IV LN require prompt treatment to reduce further disease progression and mortality risk. Induction therapy typically consists of high-dose glucocorticoids followed by oral prednisone, and either cyclophosphamide (CYC) or MMF for induction therapy. Induction therapy is followed by maintenance therapy, usually consisting of prednisone with an immunosuppressive agent (CYC, MMF, or potentially AZA if the patient cannot tolerate CYC or MMF). For refractory cases, calcineurin inhibitors (CNI) or belimumab may be added to MMF and the addition of rituximab may be considered. In Class V LN that is sub-nephrotic, most practitioners start with immunosuppressive therapy (GCs plus MMF with or without CNI); in patients with nephrotic syndrome that is severe with potential signs of anasarca or gut edema, a non-oral immunosuppressant (CYC) can be used. Like in Class III or IV LN, the role of AZA in Class V LN is limited to patients with contraindications to other immunosuppressive therapies. Belimumab may also be considered as an add-on to MMF and/or CNI. Class VI LN is irreversible; supportive therapy is indicated, as is renal replacement therapy – ideally, kidney transplantation.

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Cardiovascular Manifestations and Complications

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with SLE, with a standardized mortality ratio (SMR) of approximately 2.2. Both atherosclerotic CVD and non-atherosclerotic CVD is more common in patients with SLE than in the general population. The increased burden of CVD in SLE is likely a result of an interaction between SLE disease activity-dependent organ/tissue damage (e.g., inflammatory damage to the cardiac muscle or inflammation-mediated vascular endothelium dysfunction, which potentiates atherosclerotic plaque formation) and increased prevalence of traditional CVD risk factors (diabetes, hyperlipidemia, smoking, hypertension, etc.) in the SLE population.

Non-atherosclerotic manifestations of CVD include symptomatic pericarditis (which affects ~25% of SLE patients at some point in the disease course and is part of all SLE classification criteria), myocarditis (~9% of SLE cases), valvular abnormalities (rare, but 2.5 times more common than in the general population), pericardial tamponade (2% of SLE cases) and heart failure (rare, but 2.7 fold more common than in the general population, and often myocarditis-associated).

Atherosclerotic CVD is also common in patients with SLE. Coronary artery events have an estimate prevalence range of 6-10% in cohorts of patients with SLE. Subclinical atherosclerosis is concerningly common in SLE, with autopsy studies showing the prevalence of atherosclerotic plaques of 50% in young patients with SLE.

The primary and secondary prevention of atherosclerotic CVD does not differ in patients with and without SLE, although SLE is recognized as an independent risk factor and therefore may inform the choice of statin initiation. Treatment of acute CVD manifestations depends on their type and etiology.

Neuropsychiatric Lupus

Systemic LE can have an adverse effect at any level of the nervous system, from single nerves to the entire brain. The SLE-related mechanisms that can damage neurons and supporting neural cells are diverse, including direct immune attack and comorbidity- or pharmacotherapy-related damage. These mechanisms can act in both the peripheral nervous system (PNS) and the central nervous system (CNS) to cause neuropsychiatric (NP) SLE, a complex, heterogeneous disease that is still inadequately understood. Symptoms common in NP SLE include cognitive impairment (estimated prevalence 7-80%), mood disorders (7-65%), anxiety disorder (6-40%), headache or migraine (12-28%), seizure disorders (7-20%), cerebrovascular disease including stroke (8-15%), psychosis (1-11%), acute confusional state (1-7%), mononeuropathy (1-7%), polyneuropathy (2-5%), myelopathy (1-4%), demyelinating syndrome (1-3%), aseptic meningitis (<3%), cranial neuropathy (1%), movement disorder (1%), autonomic disorder (<1%), Guillain–Barré syndrome (acute inflammatory demyelinating polyradiculopathy; <1%), myasthenia gravis (rare) and plexopathy (rare).

Proper management of NP SLE requires distinguishing the “primary” manifestations (i.e., those NP events caused by immune-mediated damage, whether to the neural tissue itself or associated vasculature) from NP events caused by comorbidities (e.g., hypertension, depression) and SLE therapy (e.g., infections caused by pharmacological immunosuppression). Autoantibodies are the key mediators of tissue damage in primary NP SLE. Antiphospholipid antibodies and ICs are associated with ischemic disruption of intracranial vessels, which can cause focal (stroke) or diffuse (vascular cognitive impairment) outcomes. SLE-associated inflammation (autoantibodies, cytokines and complement) can also damage the endothelial cells of the blood-brain barrier, allowing circulating autoantibodies (e.g., anti-ribosomal P and anti-NR2) to disrupt neuronal function in the brain.

Strategies to differentiate primary NP SLE from potential mimics should include consideration of factors favoring primary NP SLE (e.g., type and chronology of manifestation consistent with primary NP SLE, presence of non-neurological SLE activity, presence of antiphospholipid antibodies, distinctive neuroimaging abnormalities and findings in the cerebrospinal fluid [CSF] obtained through lumbar puncture) and factors favoring alternative explanations (e.g., CSF findings indicative of infection, presence of malignancy or other comorbidities). Examination of CSF for the presence of proinflammatory cytokines, anti-NR2, or anti-ribosomal P antibodies may become diagnostically useful in clinical practice after further research and development. Advances in magnetic resonance imaging (MRI) may also improve the diagnostic yield of neuroimaging. Primary NP SLE may involve cerebral white matter hypoperfusion that is invisible on conventional MRI (cMRI); this hypoperfusion may be revealed if cMRI is combined with dynamic susceptibility contrast MRI to measure blood flow in the semioval center (the central area of white matter) of the brain. Once the diagnosis of primary NP SLE is established, the treatment depends on the etiology. The diagnostic and management strategies are summarized in Table 6-3. Immunosuppressive therapy (GCs, AZA, MMF, CYC, or B cell-targeted therapy) is used for NP SLE of a primarily inflammatory etiology, while anticoagulation/antiplatelet therapy is used for NP SLE of thrombotic or embolic origin; if both inflammatory and ischemic causes are suspected, these therapeutic approaches should be combined. Cognitive and behavioral rehabilitation of function, including computer-based cognitive retraining methods, should also be considered. Unfortunately, NP SLE remains understudied and there is at present a dearth of data on the efficacy of most treatment strategies.

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Depression

Mood disorders, including major depression and mood disorder with depressive features, are common in patients with SLE; the high variability of reported prevalence (7-65%) may be due to differences in definitions and instruments used in different studies. Data from cross-sectional studies suggest a prevalence of ~15% for depression in patients with SLE. Regional variability also exists, with prevalence rates in East Asia being on the lower end of the spectrum – a fact that may have both biological and cultural causes.

Although often considered causally linked with NP SLE, depression in individual patients with SLE can arise from a complex interaction of a number of contributing factors, including medication use and the burden of living with a chronic disease. The putative biological basis for depression in SLE patients is poorly understood. Some reports have linked specific markers, including type I IFN, anti-ribosomal P antibodies, and anti-NR2 antibodies with mood disorders, while others have failed to uncover a link. Mood disorders have been liked to NP SLE in 38% of patients with SLE; however, no association was found between global SLE disease activity, cumulative organ damage and SLE-related autoantibodies, suggesting a more complex etiology. Depression may also be associated with immunosuppressive medications. An inconsistent link with high-dose prednisone has been reported, and in clinical trials of belimumab the frequency of depression and severe depression was higher with belimumab (5% and 0.4%, respectively) than with placebo (4% and 0.1%).

Depression has a negative impact on health-related quality of life in patients with SLE that is independent of disease activity, organ damage and medication use. It is also associated with reduced adherence to pharmacological, behavioral and lifestyle therapy, negatively impacting disease management. This makes it crucial to promptly address; depending on the etiology, effective treatment of depression in SLE patients may include both SLE-specific (immunosuppressive) and non-SLE-specific (antidepressant) therapies.

Pulmonary Complications

Pulmonary disease associated with SLE includes pleural, airway, parenchymal and pulmonary vascular manifestations. Common pulmonary symptoms include chest pain, dyspnea and cough; however, it is important to note that these symptoms may also have non-pulmonary etiologies.

The most common pulmonary complication in SLE is pleural disease (pleuritis), estimated to affect 18-40% of patients with SLE at some point. Pleural effusions are present in ~33% of patients with pleuritis. Pleuritis is associated with increased SLE activity and other organ involvement. It can typically be managed pharmacologically (NSAIDs, antimalarials, GCs). By contrast, airway disease (obliterative bronchiolitis) is rare, but often refractory to pharmacological treatment and may require a lung transplant. Parenchymal manifestations include diffuse alveolar hemorrhage (a life-threatening complication seen in 0.5-4% of patients with SLE), acute lupus pneumonitis (occurring in 1-5% of patients with SLE but also life-threatening, with a mortality rate of 30-50%), interstitial lung disease (~3% of SLE patients) and cryptogenic organizing pneumonia (rare). Most parenchymal manifestations can be pharmacologically treated with GCs, and if needed, immunosuppressants. Vascular pulmonary manifestations include pulmonary hypertensions (treated depending on the cause) and pulmonary embolism (treated with anticoagulation agents and, in cases of hemodynamic instability, thrombolysis); the relative risk of the latter in SLE patients is 10-20 fold greater than in the general population.

Other Common Complications of Lupus

Patients with SLE are at an increased risk for acute and chronic infections because of both disease activity –dysfunction in both the innate and adaptive immune system – and treatment-related factors – chronic immunosuppression. Additionally, accumulated organ damage can cause functional hyposplenism and reticuloendothelial system disruption. Among patients hospitalized for infection, the most common infections include pneumonia, sepsis, skin infections, urinary tract infections and opportunistic infections; all are estimated to be at least 12 time more common in patients with SLE than in the general population. The spectrum of causative bacterial pathogens is the same in SLE as in the general population, but viral, fungal and parasitic opportunistic infections are more common. Because of the variable state of immunosuppression in patients with SLE, suspected infections should be treated with appropriate antimicrobial agents without delay. Prevention is of even greater importance, and patients should routinely update their vaccinations against influenza, pneumococcus, COVID, tetanus, herpes zoster and human papillomavirus as directed by current vaccination guidelines.

Systemic LE can also be associated with other autoimmune diseases, most commonly Sjögren syndrome (SjS) and antiphospholipid syndrome (APS). Sjögren (or Sjögren’s) syndrome is a systemic, inflammatory autoimmune disease that typically targets exocrine glands (predominantly salivary and lacrimal glands), causing mucosal surface dryness (predominantly in the mouth and eyes). The term “secondary” SjS is used when SjS occurs together with another systemic autoimmune disorder. The prevalence of secondary SjS in patients with SLE is estimated at 9-33%, with more recent analyses estimating 14-18%. Antiphospholipid syndrome is a systemic autoimmune disorder characterized by the presence of anti-phospholipid antibodies (aPLs) in association with thrombosis and/or obstetric morbidity (embryofetal deaths, prematurity and preeclampsia). Other manifestations of APS may include livedo reticularis, cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, hemolytic anemia, migraines and headaches and cognitive impairment. Like SLE and SjS, APS is an inflammatory disease; however, thrombosis plays a key role in APS pathology. The prevalence of aPL seropositivity in individuals with SLE is 30-40%; of these, 20-50% experience thrombotic events, so the prevalence of APS proper is lower in SLE than the mere presence of aPLs.

Finally, a variable risk for malignancy has been reported in patients with SLE, with an increased risk of hematological, lung, thyroid, liver, cervical and vulvovaginal cancer and a reduced risk of breast, endometrial and possibly ovarian cancer. The overall cancer risk in patients with SLE is slightly (~14-18%) elevated compared to the general population. The relative risk is highest for hematological cancer (~3 fold), especially for non-Hodgkin lymphoma (~4 fold). The relative risk for breast cancer is about 25% decreased across several studies, while many (but not all) studies also report a lower risk for endometrial, ovarian and prostate caner. The mechanism behind these differences in malignancy risk are unknown, but immunosuppressive therapy, clinical factors, viruses and genetics, among other factors, may play a role. Physicians should be aware of the increased risk for hematological malignancy and should monitor their patients for significant signs and symptoms.