The general principles of treatment in SLE encompass the concept of comprehensive management of a very complex disease. They highlight the role of the rheumatologist as the leader of the multidisciplinary care team and the importance of regular patient assessment. They emphasise the need for an end goal of treatment (remission or low disease activity) and relapse prevention as the primary means to reduce progression and long-term damage. They consider the importance of non-pharmacological measures, as well as the selection of drugs based on their increased efficacy, safety, and availability. They also stress that the patient should always be involved in therapeutic decisions.3–6 (Tables 1 and 2)

Treatment of SLE includes a combination, often sequential, of antimalarials, glucocorticoids (GCs), non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying drugs, immunosuppressants, and biological therapy. The choice of drugs, as well as the dose and duration of administration, should be individualised according to the type and severity of clinical manifestations, disease activity, organs and systems involved, as well as associated comorbidities.

Antimalarials are considered mainstays in the treatment of SLE; they have photoprotective, lipid-lowering, anti-angiogenic, antithrombotic, and hypoglycaemic effects and, through their interaction with Toll-like receptors (TLRs), they also inhibit the function of B-cell activating factor (BAFF) and phospholipase A2 (PLA2). This pleiotropic effect makes them drugs of choice to treat cutaneous manifestations, mild to moderately active SLE, to concomitantly treat major organ involvement, and to prevent long-term relapse.20–22

GCs are the cornerstone of the immediate treatment of the disease. Their anti-inflammatory and immunomodulatory effect allows rapid control of many manifestations of lupus. The dose and time of administration of this group of drugs is determined by the severity of the condition and, by international consensus, the doses of prednisone (or its equivalent) have been defined as low dose (<7.5 mg), moderate dose (>7.5 mg and <30 mg), high dose (>30 mg and <100 mg), and very high dose (>100 mg).23 Despite their undoubted efficacy, because of their short- and long-term adverse effects, GCs should always be administered concomitantly with other disease-modifying or immunosuppressive drugs so as to reduce the dose and even discontinue them as quickly as possible.24

NSAIDs are often used for symptomatic treatment of pain and inflammation in SLE patients. Generally, NSAIDs are used at the full recommended dose for as short a time as possible in acute conditions, and at the minimum dose necessary to maintain clinical response in chronic conditions. The choice of individual NSAID will depend on the variability of response and the patient's risk factors for gastrointestinal, cardiovascular, renal, and hepatic toxicity, among others. It is necessary to periodically evaluate the indication for continued use and always assess the risk of interactions and adverse events when using other commonly used drugs in SLE patients (GCs, antihypertensives, hypoglycaemics, anticoagulants, etc.).25,26

Disease-modifying drugs such as methotrexate and leflunomide are useful when there are musculoskeletal manifestations.27 Immunosuppressants are used in various moderate and severe manifestations of the disease, but also in mild forms due to their GC-sparing effect. The most commonly used are azathioprine (AZA), mycophenolate mofetil (MMF), cyclophosphamide (CPM), and calcineurin inhibitors (cyclosporine, tacrolimus, and voclosporin). In some circumstances, a remission induction schedule followed by a lower dose as maintenance therapy is used to consolidate remission and prevent relapse. The choice of immunosuppressant will depend on the type of manifestation, its severity, and the individual toxicity profile. Multiple therapy is increasingly indicated as a way to achieve better short- and long-term outcomes with less toxicity.28–35

Biological therapy has been used for a decade in SLE, specifically monoclonal antibodies directed against B cells, T cells and, more recently, type I interferon. These mechanisms of action have been shown to be effective, and they work in conjunction with standard therapy to control various manifestations of the disease and to reduce the frequency and severity of relapses, as well as delay cumulative damage. Although results appear better in antinuclear antibody-positive patients, their use should not be limited to this subset of patients. Belimumab has recently been licensed for use as concomitant therapy in patients with lupus nephritis.36–41

Clinical trials of Janus tyrosine kinase inhibitors in SLE patients are currently underway with promising results for manifestations in various organs, including the kidney. CAR-T cells (chimeric molecules capable of redirecting T-cell specificity against target antigens) are a novel area of research in patients with severe and refractory SLE, with encouraging results.42–44

Tables 3–5 describe the treatment recommendations for SLE with the different drug groups.

The constitutional manifestations of lupus, as is common in many chronic systemic conditions, are a multifactorial phenomenon that significantly impacts patients' quality of life. In the event of fever, infectious processes must be ruled out before attributing fever to disease activity alone.

Treatment of fatigue should be symptomatic and holistic, including regular assessments, exercise programmes, and psychoeducational interventions, always considering other related causes such as injury or comorbidities and taking the influence of psychological, societal, and lifestyle factors into account. The evidence found in the literature allows the following recommendations to be made for this group of manifestations of the disease.56,57 (Table 6)

Mucocutaneous involvement in SLE is very common and can occur in the context of patients with or without systemic involvement; it is usually classified into specific and non-specific manifestations.73 The choice of optimal treatment is difficult because most efficacy evaluations group the outcome as ‘cutaneous manifestations’ without any further distinction as to the type of manifestation.

Nevertheless, current information on this particular topic is useful for issuing a number of recommendations including management using increasingly fewer GCs, the addition of topical therapy, the use of antimalarials as a cornerstone and, if necessary, immunosuppressants and biological therapy.73–78 (Table 7)

Joint manifestations are common in SLE patients, occurring in up to 85% of cases in the course of the disease. Most patients present with arthralgias with inflammatory features, but a low percentage develop persistent and/or erosive arthritis. Myalgias and, in rare cases, myositis with weakness and elevated muscle enzymes may also occur, almost always with a self-limiting course. Treatment of this group of manifestations depends on their severity and includes the use of NSAIDs, GCs, disease-modifying drugs and, in some cases, biological therapy.26,81–84 (Table 8)

Haematological involvement in SLE is very common and occurs in more than 90% of patients.89 It affects all cell lines and is characterised by mild manifestations such as chronic leukolymphopenia, and severe and acute life-threatening conditions requiring prompt specific treatment, such as haemolytic anaemia, autoimmune thrombocytopenia, thrombotic thrombocytopenic purpura, and haemophagocytic syndrome. In addition, multifactorial disorders occur such as anaemia of chronic disease and cytopenias associated with chronic organ damage (liver or kidney), infectious events, and/or drugs.90

Under the heading of recommendations for the treatment of haematological manifestations, guidelines on the evaluation and treatment of antiphospholipid syndrome (APS) have been included in this update. Up to 30% of patients with SLE have APS or positive antibodies, and the impact of this association on patient morbidity and prognosis is well known.91–93 (Table 9)

Renal involvement in lupus is one of the most frequent manifestations and has the greatest impact on patient prognosis. There are populations, such as the Mexican population, in which lupus nephritis presents at a younger age and is usually more severe.166,167

The optimal treatment of lupus nephritis is defined by both histological findings and clinical behaviour. In proliferative nephritis, a period of remission induction followed by prolonged maintenance therapy is still recommended, although multiple therapy may be initiated early on (e.g., MMF or CPM plus a calcineurin inhibitor), especially in patients with poor prognostic data. Recent evidence shows that this regimen may be superior to monotherapy in terms of long-term outcomes.168–170 The use of anti-Blys/BAFF biological therapy (specifically belimumab) is also suggested as an adjuvant to standard management, as this has been shown to result in longer renal survival and fewer relapses.50,171,172

Current recommendations emphasise the detection of associated poor prognostic data (e.g., antiphospholipid antibodies) and concomitant management of risk factors for progression of renal damage as an indispensable measure to improve long-term prognosis.173,174 (Table 10)

Neuropsychiatric involvement in SLE is highly variable, with frequencies reported to range from 14% to 75%.188 This wide variation in frequency is due to the difficulty in attributing neuropsychiatric manifestations with certainty to the disease, after secondary causes such as metabolic and infectious, have been ruled out.189 The American College of Rheumatology published the nomenclature for neuropsychiatric lupus syndromes,190 which includes 18 manifestations; however, virtually any manifestation can occur in SLE, whether or not accompanied by activity in another organ or system. Neuropsychiatric involvement is a major cause of mortality and cumulative damage. (Table 11)

The spectrum of cardiopulmonary manifestations in SLE patients is very diverse, ranging from mild, often subclinical conditions such as pleuritis or pericarditis, chronic manifestations with significant impact on quality of life such as interstitial pneumonitis or pulmonary arterial hypertension (PAH), to acute and life-threatening events such as diffuse alveolar haemorrhage.207,208 Timely detection of these manifestations requires a high degree of clinical suspicion and, of course, treatment will depend on the type and severity of each manifestation, ranging from symptomatic management to the use of high doses of GCs, immunosuppressants, or even biological therapies. Specific treatment recommendations are also included, for example for PAH, and the need for joint management with cardiology and pulmonology is highlighted.209 (Table 12)

Gastrointestinal and hepatic manifestations are common in SLE patients. They are complex to assess and treat because they are often multifactorial. Gastrointestinal involvement varies from drug-associated dyspepsia to episodes of intestinal pseudo-obstruction and severe vasculitis.239 Hepatitis and pancreatitis especially, can be explained by disease activity, but may also be due to primary autoimmune conditions, metabolic events, infectious conditions, or drug toxicity.239–241 (Table 13)

Current evidence is clear that most vaccines are safe and effective in lupus patients. Despite initial controversies regarding the possibility of polyclonal activation in patients upon vaccination, or doubts regarding the level of seroprotection and seroconversion, the benefit of vaccination has been shown to outweigh the risk and it is now recommended that all lupus patients have a full vaccination schedule. Ideally, vaccinations should be given before the start of immunosuppressive treatment, but when not possible they should be scheduled for the most appropriate time. A special situation is the live attenuated virus vaccines, which can be administered in patients with inactive SLE who are not receiving immunosuppressive drugs.258–261 (Table 14)

Undertaking surgical procedures in patients with lupus requires special attention because these patients are often medically complex due to disease activity, potential organ damage, comorbidities, and immunosuppressive therapy. It has been shown that patients with lupus suffer more perioperative complications than the general population and therefore, whenever possible, surgery in these patients requires adequate planning, adjustment of treatment, and careful monitoring during and after the procedure, with a multidisciplinary approach. The following recommendations highlight the most important aspects regarding the adjustment of treatment with GCs, immunosuppressants, and biological therapies during the perioperative period.274,275 (Table 15)

The period of pregnancy and lactation requires special attention in patients with SLE associated or not with antiphospholipid antibody syndrome. Because disease relapses are more frequent during pregnancy and there is a higher risk of complications for both mother and infant, basic recommendations for pregnancy planning, appropriate contraception, surveillance, and treatment of women during this period are included in this document.285,286 (Table 16)

Table 17 summarises the current evidence on the safety of the main drugs used in this disease during pregnancy and lactation. For a more extensive description of the topic refer to the CPG on the management of pregnancy in women with rheumatological autoimmune diseases.287

Patients with SLE are known to have an increased cardiovascular and cerebrovascular risk, which may be more than double that of the general population and is one of the main determinants of long-term morbidity and mortality. This increased risk is explained by a multifactorial process of accelerated atherosclerosis involving endothelial dysfunction, autoantibody-induced damage, chronic inflammation, changes in lipid and lipoprotein profile, increases in traditional risk factors and even adverse effects of GC and NSAID therapy.325–327 Therefore, in this update of lupus treatment recommendations, it was considered essential to include guidelines on the best methods of assessment, prevention, and treatment of cerebrovascular and cardiovascular events. (Table 18)