Genetics and epigenetics

SLE occurs when a genetically susceptible individual encounters an environmental trigger, most likely an infective agent, which is responsible for inducing antinuclear antibodies (ANA). After a variable lag of time from the appearance of ANA, deposits of immune material can be found in tissue without concomitant inflammatory lesions (11).

SLE is a multigenic disease. A combination of genome-wide association studies (GWAS) and candidate gene approaches has led to the identification of > 40 robust genetic associations with SLE (12-15). These are genes which induce the transcription of proteins involved in key pathogenic pathways, including apoptosis and clearance of apoptotic material or immune complexes, innate and adaptive immunity functions, and the production of cytokines, chemokines, or adhesion molecules (16).

Both HLA and several non-HLA genes have been found to influence SLE susceptibility (see Chapters 16-18). Highly penetrant mutations such as complete complement fraction (C) 1q, C2, C4A, C4B, and FcyR (Fc fragment of IgG, low affinity receptor) type IIIB deficiency, or mutations in DNA exonuclease named TREX1 (three prime repair exonuclease) account for no more than 1–2% of cases (17). SLE genetic susceptibility is mainly provided by the interplay of fairly common genetic variants, any of which may only slightly increase the disease risk (17). Notably, a remarkable diversity in the genetic background among SLE patients has been observed although the nature of the genes identified so far suggests that patients with SLE have an immune system predisposed to aberrant responsiveness.

Most single-nucleotide polymorphisms (SNPs) associated with SLE fall within noncoding DNA regions of immune response-related genes (18). Some genes have been associated with several autoimmune diseases (e.g., STAT4 and PTPN22 with rheumatoid arthritis and diabetes); others appear to specifically increase the risk of SLE. Certain SNPs linked to SLE have been identified for genes whose products may contribute to abnormal T cell function in SLE (CD3-ς, and PP2Ac) (18, 19). A recent large-scale replication study confirmed some of these associations and identified TNIP1, PRDM1, JAZF1, UHRF1BP1, and IL10 as risk loci for SLE (20). Although these findings are promising, the loci identified so far only account for about 15% of the heritability of SLE (21). In addition, an altered copy number of certain genes, such as C4, FCGR3B, and TLR7, have been linked to disease expression (22-24).

Epigenetics represents a new aspect in the pathogenesis of SLE and refers to changes in gene expression that do not involve changes in the DNA sequence. Epigenetic mechanisms are sensitive to external stimuli, and thus, environmental effects on immune responses can be mediated by changes in epigenetic regulation, leading to stable – but reversible and cell specific – heritable changes in gene expression (25, 26). These modifications in gene expression could explain, at least partly, why no full concordance for SLE is found among homozygotic twins, although it is greater than that found among dizygotic twins or siblings (24–57% vs. 2–5%) (16). The major mechanisms of epigenetics are DNA methylation, histone modifications, and microRNA (miRNA) interference (27), which interact with each other in modulating chromatin architecture and allowing gene transcription or lead to gene silencing. In SLE, abnormalities in both DNA methylation and histone modifications have been reported (26-28) and clues are emerging on the function of miRNA in SLE.

B and T signalling abnormalities

Aberrant immune activation in SLE is crucial, and although failure in tolerance checkpoints is required for the shedding of autoreactive lymphocytes (Figure 1) (29, 30), intrinsic abnormalities in cel signaling are also paramount. Under normal conditions, antigenic stimulation causes clustering of antigen-specific receptors at the cellular membrane (alternatively BCR or TCR) together with their co-receptors and adaptor molecules, and the subsequent recruitment of Src-family kinases that bring about phosphorylation of the ITAM (immune receptor tyrosine-based activation motifs) domains in the cytoplasm (31). Subsequently, kinases of the Syk/ZAP70 family recognize the phosphorylated tyrosine residues of ITAMs and initiate an activator cascade resulting in lymphocyte priming and differentiation. Both T and B cells of SLE patients display multiple signalling abnormalities which may be at least partially due to genetically or epigenetically determined defects (32) and lead to intrinsic hyperactivity and hyper-responsiveness of T and B cells (Figure 2).

Figure 1

Mechanisms for the induction and amplification of lupus autoimmunity. A Although normal T cells exposed to self-antigen in the periphery become tolerized, lupus-prone T cells are sensitive to lower thresholds of activation by agonist or weak-agonist peptides. (more...)

Figure 2

Immunopathogenesis of SLE. The disease is the result of interaction between hereditary and environmental factors over time. Immune abnormalities characterizing the disease are represented in frames to display susceptibility (or protection) genes and possible (more...)

Dysregulated apoptosis and defective clearance of cellular debris

Increased exposure of autoantigens due to disturbed apoptosis as well as to defective clearance of cellular debris has been reported (33). This abnormal antigenic availability is thought to play an important role in autoantibody induction since a wide variety of epitopes become accessible for aberrant presentation to the immune system.

Neutrophils and NETosis

Neutrophil extracellular traps (NETs) are web-like structures that are released by neutrophils and optimize microorganism entrapment and killing. They are composed of chromatin, histones, and proteins derived from granules including myeloperoxidases, elastases, matrix metalloproteinases 9, pentraxin 3, and antimicrobial molecules such as cathelcidins (34). NETs are mainly released by activated neutrophils that undergo a novel cell-death mechanism, named NETosis although release from intact cells has also been described (34, 35). Physiologically, NETs represent a means of defence against pathogens that can also control inflammation and damage to the surrounding tissues (36); nevertheless, NETs may become a harmful source of autoantigens and promote autoimmunity if not promptly degraded as has been shown to occur in SLE (36). In fact, NETs expose a large amount of dsDNA together with immunostimulatory molecules (37) and can therefore aid autoantibody production.

Antibody formation and perpetuation

To date more than 100 different autoantibodies have been described in SLE (38) with a widely varying frequency, ranging from some antibodies reported only in a few patients to others that are almost always present in SLE. Autoantibodies target a multitude of antigens, mainly nuclear components and other cellular constituents such as phospholipid-associated proteins, cytoplasmatic molecules, endothelial membrane antigens, complement fragments, IFNs, etc. (39).

In SLE, the breakdown of tolerance is often triggered by an infection, mostly due to molecular mimicry, epitope spreading, or bystander activation of immune cells (40), and, conceivably, to NET deposition (34). Of the different pathogens, the Epstein Barr virus (EBV) plays a major role due to its protein repertoire, which includes EBNA-1 (Epstein Barr nuclear antigen 1) and other molecules that may mimic or modify self-antigens, therebyrendering them more immunogenic (41) (See chapter 19). Other reported environmental triggers can also induce an autoimmune response (e.g., drug-induced SLE), mostly by acting at the epigenetic level (42).

Autoantibodies and organ damage

Of SLE autoantibodies, only anti-dsDNA have been shown to correlate with disease activity and specific organ damage (43). Anti-dsDNA antibodies are also included in the American College of Rheumatology (ACR) criteria for the classification of SLE together with anti-Sm, antiphospholipid (anti-PL) antibodies, and ANA. ANA may be found in sera of SLE patients many years before overt SLE occurs (44). Prediction based on genetic and serological biomarkers is an encouraging challenge (45). Noteworthy, the presence of an autoantibody by itself does not constitute a diagnosis of SLE. In addition, not all autoantibodies are pathogenic (i.e., with high affinity and specificity, activating the complement). Both pathogenic and non-pathogenic antibodies are known to exist in SLE as well as in other autoimmune conditions. In this respect, ANA may be classified as pathological (i.e., they only occur in people affected with an autoimmune or pre-autoimmune condition, especially SLE) or non-pathological (i.e. ANA do not predict the development of any autoimmune disorder and may also occur in healthy people, e.g. following infection) (46). As a corollary, SLE without ANA is unlikely, whereas ANA without SLE may occur. Moreover, pathological ANA may either be pathogenic, i.e., they trigger disease manifestations by any mechanism (e.g. nephritogenic, interferogenic or even neuropathogenic antibodies) or protective, i.e., they prevent disease by somehow counteracting pathogenic antibodies (e.g., by preventing immune complex formation) or, intriguingly, by hindering antigen antigenicity, meaning they can bind and mask some immunogenic epitopes and thereby carry out a kind of epitope selection which, in turn, prevents the immune cells from being tantalized. The mechanisms by which autoantibodies may harm cells are diverse and not mutually exclusive. They may vary depending on the nature and localization of the target antigens and on the effectiveness of the autoantibody itself, including direct cellular lysis, cell opsonization, immune complex deposition, complement fixation, and subsequent inflammation (43). Table 1 summarizes the most widespread autoantibodies in SLE and their links to the disease course.

Table 1

Antibodies in SLE and clinical associations.

Female hormones and sex

Hormones contribute, through unknown mechanisms, to the increased prevalence of SLE in women (47). The X chromosome may contribute apart from hormones as in castrated female and male mice genetically manipulated to express XX, XO (female), XY, or XXY (male) combinations. the presence of two X chromosomes increases the severity of SLE (48). Among the genes known to contribute to the pathogenesis of SLE is CD40, which is located on chromosome X. Pregnancy may aggravate SLE and, although it is not clear whether rising levels of estradiol or progesterone play a role, a link between pregnancy outcome and the status of the disease at conception has been reported (49); in fact, the levels of these hormones are lower during the second and third trimesters in patients with SLE than in healthy pregnant women (50). Treatment with dehydroepiandrosterone has shown some clinical benefit (51). Pregnancy in patients with SLE presents a clinical challenge that requires the involvement of the relevant specialists.

Constitutional symptoms

Fatigue, fever, and weight loss are typically present at some time during the course of the disease, occurring in 50 to 100 percent of patients. Fatigue is the most common complaint and, occasionally, the most debilitating. It occurs in 80 to 100 percent of patients, and its presence is not clearly correlated with other measures of disease activity (55). Fatigue is strongly associated with diminished exercise tolerance (56). However, fatigue may not be due to active SLE but to one or more of the following: increased work load, depression, unhealthy habits (smoking, fad diets, sedentary living, drug abuse), stress, anaemia, hypothyroidism, some medications (including prednisone and beta-blockers), any inflammatory and/or infectious disease, coexistent fibromyalgia, sleep disturbances, deconditioning, or a perception of poor social support. Fatigue due to SLE may respond to glucocorticoids or antimalarials and, in some studies, to exercise and psychosocial interventions (57, 58).

Weight loss often occurs prior to the diagnosis of SLE. Unintentional weight loss may be due to decreased appetite, the side effects of medications (particularly diuretics or antimalarials), and gastrointestinal disease (e.g., gastroesophageal reflux, abdominal pain, peptic ulcer disease, or pancreatitis).

Fever attributed to active disease is seen in over 50% of patients with SLE (52). Fever may also be caused by infections or drug reactions. The medical history may be helpful in determining the cause of fever. As an example, fever developing while on moderate or high doses of glucocorticoids should lead to a strong suspicion of new infection, particularly if other signs of active lupus have begun to remit. The pattern of fever may be helpful diagnostically. Episodic fever is suggestive of active SLE or infection; in contrast, sustained fever may reflect CNS involvement or an adverse drug effect (59).

Joint involvement

Joint symptoms occur in > 90% of patients at some time during the disease course and are often the earliest manifestation (59). Arthralgia is more often encountered than arthritis. Arthritis occurs in around 70% of patients and tends to be migratory and symmetrical. Only a few joints are usually affected, especially those of the hands. The arthritis is moderately painful and is rarely deforming. When this occurs (i.e., Jaccoud’s arthropathy), rheumatoid factor may be present and renal involvement is rarely observed (11).

Mucocutaneous

The skin and/or mucous membranes are involved at some point in > 80% of patients with SLE (60, 61). There is great variability and diversity in the type of involvement, ranging from the classic butterfly rash to fixed lesions that may be associated with scarring and atrophy (also referred to as discoid lupus erythematosus). In addition, cutaneous bullae, oral and nasopharyngeal ulcers, scarring and non-scarring alopecia, and skin changes resulting from vasculitis may occur in patients with SLE. Photosensitivity is a common theme for lesions characterized by an interface dermatitis and for the tumid lesions characterized by dermal mucin and lymphohistiocytic perivascular and peri-appendageal infiltrate. This includes discoid LE lesions and lesions of subacute cutaneous lupus erythematosus, acute cutaneous LE, and tumid LE. In some chronic forms, the rash can be disfiguring and may require aggressive therapy to minimize scarring and dyspigmentation (62).

Inflammatory periorbital edema is uncommon in patients with SLE, which is useful as a distinguishing feature from dermatomyositis. Patients with localized discoid LE, hypertrophic LE, LE panniculitis, and lupus tumidus tend to have skin disease only; however, progression to systemic disease is possible (63). Table 2 summarizes the main skin lesions in SLE.

Table 2

Skin lesions associated with systemic lupus erythematosus.

Raynaud phenomenon

Cold- or emotion-induced color changes in the digits of the hands and/or feet (Raynaud phenomenon) are frequent problems and may antedate other features of SLE. Self-reported skin color changes consistent with Raynaud phenomenon occurred in 16 to 40 percent of patients in two large series (51).

Renal

Lupus nephritis (LN) is common in SLE. An abnormal urinalysis with or without elevated plasma creatinine levels is present in a large proportion of patients at the diagnosis of LN, and may eventually develop in up to 75 percent of patients with a diagnosis of SLE. The most frequently observed abnormality in patients with LN is proteinuria (58). There are several types of renal disease in SLE, mostly immune complex-mediated glomerular disease, which are usually differentiated by renal biopsy. In addition, renal diseases unrelated to lupus may be seen (64). The pattern of glomerular injury seen in SLE (and in other immune complex-mediated glomerular diseases) is primarily related to the site of formation of the immune deposits, which are mainly due to anti-double stranded DNA antibodies (anti-dsDNA, or anti-DNA) directed against nucleosomes (i.e., double stranded DNA wound around a histone octamer) (Figure 3) (65). The higher incidence of LN in patients with SLE in the United States as compared with Europe may in part reflect racial and ethnic differences. The incidence of LN is higher in blacks (34 to 51 percent), Hispanics (31 to 43 percent), and Asians (33 to 55 percent) than in whites (14 to 23 percent). Blacks and Hispanics also tend to present with more-severe underlying histopathology, higher serum creatinine levels, and more proteinuria than whites (66, 67). In addition, Blacks, Hispanics, and those living in poverty have a worse prognosis than whites and people with a higher socioeconomic status.

Figure 3

Pathology of lupus nephritis. There is an imbalance between cytokine homeostasis and immune complex (IC) deposition. In predisposing susceptible individuals who develop SLE, there is an acquired poor clearance of apoptotic bodies and a diminished phagocytic (more...)

Patients with SLE should undergo testing for renal involvement at regular intervals, including a urinalysis with examination of the urinary sediment, an estimate of urine protein excretion (usually a spot urine protein-to-creatinine ratio), and a serum creatinine and estimated glomerular filtration rate (67). Elevated anti-DNA titers and low complement (C3 and C4) levels often indicate active lupus, particularly LN. The frequency of testing depends upon whether or not the patient has a previous history of renal involvement.

A kidney biopsy should be done on all patients with SLE who develop evidence of renal involvement in order to establish the diagnosis and the class of LN. Determining the class of LN is important for the following reasons: 1) treatment is guided by the histological subtype (i.e., the International Society of Nephrology/Renal Pathology Society or World Health Organization class, the degree of activity and chronicity) and by complicating lesions such as interstitial nephritis and thrombotic microangiopathy, and 2) the clinical presentation may not accurately reflect the severity of the histological findings. For example, proliferative lupus may be present even if the patient has minimal proteinuria and normal serum creatinine.

Most patients with LN have an immune complex-mediated glomerular disease. Over the last two decades, there have been several attempts by different societies, particularly the World Health Organization (WHO), to classify the different glomerulopathies associated with SLE. Based upon clinical and pathologic correlations, an LN classification system was developed by a group of renal pathologists, nephrologists, and rheumatologists in 2004 (the International Society of Nephrology, or ISN, classification) (68) (Table 3).

Table 3

International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis.

Some patients with renal disease have a histological pattern of injury that is indistinguishable from LN, but have no extra-renal symptoms, signs, or laboratory abnormalities suggestive of SLE (69).

Gastrointestinal tract

The gastrointestinal tract is often involved, mostly from medication side effects than from active SLE. Examples of the former include gastritis and even peptic ulcers secondary to the use of nonsteroidal antiinflammatory drugs (NSAIDs) alone or in combination with glucocorticoids. On the other hand, SLE vasculitis can lead to pancreatitis, peritonitis, and colitis. Symptoms of esophageal irritation or reflux may occur. Nonspecific abdominal pain is frequent. Liver involvement in lupus is rare, and a presentation with liver abnormalities and a positive ANA test is more consistent with chronic active hepatitis, as part of polyautoimmunity (i.e., “lupoid hepatitis”) (70).

Pulmonary

Pleurisy, pleural effusion, pneumonitis, interstitial lung disease, pulmonary hypertension, and alveolar hemorrhage can all occur in SLE. The risk of thromboembolic involvement is increased in patients with antiphospholipid antibodies or lupus anticoagulant. The presence of dyspnea, episodic pleuritic chest pain, and a progressive decrease in lung volume in the absence of interstitial fibrosis or significant pleural disease suggests shrinking lung syndrome. Pulmonary function tests are often significantly abnormal with restrictive abnormalities, prior to complaints of dyspnea (71).

Cardiovascular

There are a variety of cardiovascular manifestations in SLE. Pericarditis is relatively common. Verrucous (Libman-Sacks) endocarditis is usually clinically silent, but may lead to valvular insufficiency and may be a source of emboli. Myocarditis is uncommon but may be severe. Patients with SLE have an increased risk of coronary artery disease (72) (see Chapter 38). Accelerated atherosclerosis with coronary heart disease (CHD) is a significant cause of morbidity and premature death in SLE patients. The greatest increase in relative risk (55-fold greater) is among young women, who otherwise have a low risk of CHD (73).

Neurologic

Neurologic and psychiatric symptoms are reported to occur in 10 to 80 % of patients either prior to the diagnosis of SLE or during the disease course (74, 75). The wide range in reported prevalence reflects, in part, the use of different criteria for neuropsychiatric disease. The American College of Rheumatology (ACR) has formulated case definitions, reporting standards, and diagnostic testing recommendations for 19 neuropsychiatric SLE syndromes. Neurological complications include cognitive defects, organic brain syndromes, delirium, psychosis, seizures, headache, and/or peripheral neuropathies. Other, less common problems are movement disorders, cranial neuropathies, myelitis, and meningitis. Psychosis, which may be due to SLE or to glucocorticoid treatment, is one of several psychiatric manifestations of SLE. Others include depression, anxiety, and mania. Thromboembolic events, often in association with antiphospholipid antibodies or with lupus anticoagulant, may occur in around 20 percent of patients with SLE (76). Arterial thromboemboli may cause focal neurological problems, such as stroke or seizures, and/or more diffuse cognitive defects.

The term lupus cerebritis refers to the neuropsychiatric manifestations of lupus that appear to have an organic basis, rather than a specific pathophysiological mechanism. Assaying for specific autoantibodies can help to make the distinction between organic and functional causes of some neuropsychiatric symptoms. Some investigators believe that a strong association exists between the occurrence of neuropsychiatric symptoms and the presence of antineuronal and other antibodies (77). Anti-ribosomal P antibodies have been associated with lupus psychosis and depression by some authors (77), but other authors have not confirmed this association. Some data suggest that cognitive defects may be associated with the presence of elevated levels of antineuronal antibodies, antiphospholipid antibodies, or antibodies to N-methyl-D-aspartate (NMDA) receptors (78).

Ophthalmologic

The eye is frequently involved in SLE, with the most common manifestation being keratoconjunctivitis sicca. Note that, not all patients with Sicca symptoms have Sjögren’s syndrome (see Chapter 28). Uncommon or rare ophthalmologic manifestations of SLE include: cotton wool exudates due to retinal vasculitis, episcleritis or scleritis, and anterior uveitis (iritis, iridocyclitis).

Hematologic

Cytopenias and thrombophilia, an increased propensity to develop thromboembolic disease, may be features of SLE. Patients with SLE frequently develop abnormalities in one or more of the three blood cell lines. Leukopenia is common. While diagnostically useful, it is usually not symptomatic unless severe (i.e., <2000/mm3). White blood counts of <4500/mm3 have been noted in 43 to 66 percent of patients. Many patients have mild anemia, which is most often due to the anemia of chronic disease. Hemolytic anemia is rare but can be very severe. Other patients may have hemolytic anemia, which is more severe and requires immediate therapy. Thrombocytopenia is also frequently seen. However, bleeding usually occurs only with platelet counts < 25,000/mm3. Acute thrombocytopenia is usually associated with active disease. However, some patients have chronic thrombocytopenia, which does not require therapy unless there is evidence of bleeding.

Pancytopenia may result either from peripheral destruction of red cells, leukocytes, and platelets together or from bone marrow failure. Thus, in patients with pancytopenia, bone marrow examination is the most important diagnostic test. There are a number of potential causes to consider such as drugs, other diseases, and bone marrow abnormalities.

An uncommon cause is macrophage activation syndrome. Lymphadenopathy occurs in approximately 50 % of patients with SLE most frequently at disease onset or in association with an exacerbation. Splenomegaly may also be present, particularly during active disease. A lymph node biopsy may be warranted when the degree of lymphadenopathy is out of proportion to lupus activity. Other causes include infection or a lymphoproliferative disorder such as non-Hodgkin lymphoma or angioimmunoblastic T cell lymphoma.

Some patients with SLE, particularly those with antiphospholipid antibodies or with severe nephrotic syndrome, have an increased risk of thromboembolic disease which, in nephrotic syndrome, may manifest as renal vein thrombosis, venous thromboembolism, or arterial disease.

Laboratory testing

Laboratory tests that may provide diagnostically useful information when SLE is suspected include: complete blood count and differential, comprehensive metabolic profile, creatine kinase, erythrocyte sedimentation rate and/or C reactive protein, urinalysis, and 24-hour urine collection for calculation of creatinine clearance and for quantification of proteinuria or protein/creatinine ratios.

Autoantibody testing is also indicated. Autoantibodies routinely assayed are: ANA, antibodies to double stranded DNA (dsDNA), anti extractable nuclear antigen antibodies (ENAs, i.e., anti-RNP, anti-Sm, anti-Ro and anti-La antibodies), and antiphospholipid antibodies (i.e., lupus antiacoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies).

Measurement of serum complement levels C3 and C4 may also be helpful, since hypocomplementemia is a frequent finding in active SLE and it is associated with activity of disease.

Most clinicians rely upon the diagnostic criteria for lupus that were developed by the ACR (79) (Table 4). These criteria were developed for the classification of SLE patients when SLE was compared with other rheumatic diseases for study purposes.

Table 4

American College of Rheumatology criteria for the diagnosis of systemic lupus erythematosus.

In an effort to address these weaknesses, a consensus group of experts on SLE, the Systemic Lupus International Collaborating Clinics (SLICC), has proposed revised criteria for SLE (80), which require either that a patient satisfy at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria, or that the patient has biopsy-proven nephritis compatible with SLE in the presence of ANA or anti-dsDNA antibodies. These criteria were developed as classification criteria, which are most applicable to use for clinical and epidemiologic research, and the SLICC group has proposed that they could serve as alternative classification criteria for use in SLE clinical care and research. They have not been evaluated for use in diagnosis.

Disease activity and severity

An effective therapeutic regimen first requires confirmation of the diagnosis and accurate determination of both disease activity and severity. Disease activity usually refers to the degree of inflammation while the degree of severity depends on the level of organ dysfunction and the organ’s relative importance. The degree of irreversible organ dysfunction is known as the “damage index” (81).

A number of research protocols on disease activity or damage measures or indices, including the Systemic Lupus Erythematosus (SLE) Disease Activity Index (SLEDAI), the Safety of Estrogens in Lupus Erythematosus: National Assessment-SLEDAI (SELENA-SLEDAI), the Systemic Lupus Activity Measure (SLAM), the British Isles Lupus Assessment Group (BILAG), the European Consensus Lupus Activity Measurement (ECLAM), etc., have been designed in an attempt to better monitor disease activity and assess trial outcomes. They all use a combination of the history, examination, and laboratory data; these protocols may have general applicability to clinical practice if simplified. The particular outcome measure used in a trial, even for organ-specific disease such as LN, can influence apparent trial outcomes (82).

General considerations

Avoid exposure to direct or reflected sunlight and other sources of ultraviolet (UV) light (e.g., fluorescent and halogen lights). Use sunscreens, preferably those that block both UV-A and UV-B, with a high skin protection factor (SPF). A sunscreen with a SPF of 55 or greater is suggested. Limited data exist concerning the effect of dietary modification in SLE. Patients with hyperlipidemia should be encouraged to eat a low-fat diet. Inactivity produced by acute illness causes a rapid loss of muscle mass, bone demineralization, and loss of stamina resulting in a sense of fatigue. This can usually be treated with isometric and graded exercise. Cigarette smoking may increase the risk of developing SLE (83) and smokers in general have more active disease (84). Patients should be counselled not to smoke or to quit smoking and should be provided with help to do so. Hidroxychloroquine is less effective in smokers (85).

Organ involvement

A number of medications are commonly used in the treatment of SLE, including (NSAIDs), antimalarials (primarily hydroxychloroquine), glucocorticoids, and immunosuppressive agents (including cyclophosphamide, cyclosporine, tacrolimus, leflunomide, methotrexate, azathioprine, mycophenolate, and belimumab). Patient compliance with recommended treatment is, as expected, associated with better outcomes than noncompliance.

Topical therapies are often useful for cutaneous manifestations of lupus and reduce the risk of side effects associated with the systemic use of NSAIDs, glucocorticoids or immunosuppressants. NSAIDs are generally effective for musculoskeletal complaints, fever, headaches, and mild serositis. Naproxen may have greater relative cardiovascular safety than other NSAIDs. Celecoxib has been used in SLE patients (86). Antimalarials are most useful for skin manifestations and musculoskeletal complaints. In addition, in long-term studies, the use of antimalarials such as hydroxychloroquine prevented major damage to the kidneys and CNS (87). Their use may also reduce the risk of disease flares, though this is less clear for renal and CNS manifestations.

Systemic glucocorticoids (e.g., high doses of 1 to 2 mg/kg/day of prednisone or equivalent or intermittent intravenous pulses of methylprednisolone, 10–15 mg/Kg/d for three days) used alone or in combination with immunosuppressive agents are generally reserved for patients with significant organ involvement, particularly renal and CNS disease. There is a paucity of data to support the use of intravenous pulses versus daily oral glucocorticoids (88). Patients with organ-threatening disease (e.g., cardiopulmonary, hepatic, renal, hemolytic anaemia, immune thrombocytopenia) are usually given the above-mentioned oral doses, whereas non-organ-threatening disease (e.g., cutaneous, musculoskeletal, constitutional) patients usually respond to 5 to 15 mg of prednisone (or equivalent) daily until a glucocorticoid-sparing agent or antimalarial can take effect.

Immunosuppressive medications other than glucocorticoids (e.g., methotrexate, cyclophosphamide, azathioprine, mycophenolate, or rituximab) (89) are generally reserved for patients with significant organ involvement and/or for patients who respond inadequately to glucocorticoids.

Immunosuppressive agents such as mycophenolate, azathioprine, or cyclophosphamide are given with glucocorticoids to patients with more than mild LN, and cyclophosphamide is given to those with alveolar hemorrhage, systemic vasculitis, and to most patients with significant CNS involvement. Lower doses of glucocorticoids (e.g., ≤10 mg/day of prednisone) may be used for symptomatic relief of severe arthralgia, arthritis, or serositis while awaiting a therapeutic effect from other medications.

Belimumab is a fully-human monoclonal antibody that inhibits the biological activity of the soluble form of a B cell survival factor, B-lymphocyte stimulator or BLyS [also known as B-cell activating factor belonging to the tumor necrosis factor (TNF) family (BAFF)]. Belimumab is a new therapy for the treatment of patients with active SLE who are receiving standard therapy, such as NSAIDs, glucocorticoids, or antimalarials, and/or immunosuppressives (90). However, it has not been adequately studied in patients with severe active LN or with CNS lupus or in patients who have previously used rituximab or who have recently used intravenous cyclophosphamide (90).

Hematopoietic stem cell transplantation

The proposed mechanism of action of hematopoietic stem cell transplantation is that it provides a period free from memory T Cell influence during which maturation of new lymphocyte progenitors can occur without recruitment to anti-self activity (91). Autologous stem cell transplantation remains complex, costly and, despite improvements in treatment-related mortality, risky. Additional studies, including direct comparison with more conventional treatment approaches in randomized controlled trials, are needed before any recommendation can be made regarding the role of stem cell transplantation in the treatment of SLE. The use of allogenic stem cells is an interesting alternative for which there is insufficient data to assess efficacy or safety. (91).

Immunizations

Patients should be advised to receive appropriate immunizations prior to the initiation of immunosuppressive therapies. It had previously been thought that immunization could exacerbate SLE. However, the influenza and pneumococcal vaccines are safe, but the resulting antibody titers are somewhat lower in patients with SLE than in controls (91). The use of glucocorticoids such as prednisone, or other immunosuppressive agents may contribute to the blunted antibody response. In contrast, it is inadvisable to immunize potentially-immunosuppressed patients (including those treated with glucocorticoids alone at doses equivalent to ≥20 mg/day of prednisone for more than two weeks) with live vaccines (e.g., measles, mumps, rubella, polio, and varicella) (92). While the issue of efficacy of hepatitis B (HepB) vaccination has not been completely resolved, the risks posed by this vaccination in SLE patients can be regarded as minimal (93).