Systemic lupus erythematosus (SLE) is an autoimmune disease that behaves very heterogeneously, and is characterised by remissions and exacerbations. Its incidence and prevalence adjusted by age is 5.5 per 100,000 persons (95% CI: 5.0–6.1) and 72.8 (95% CI: 70.8–74.8).1 There is no national registry of cases in Mexico but it is known that there are substantial differences in the load of the disease in different populations and countries.2 For example, the black American population have an incidence and prevalence more than twice that of the Caucasian population.1 Even among “Hispanic” populations – as Latin Americans are often grouped in clinical studies – there are significant differences in the presentation of the disease.3

There are several national and international clinical practice guidelines (CPG) for the treatment of SLE.4–7 However, the majority of those available are not designed for the Mexican population or only seek to manage specific manifestations, such as lupus nephritis, or physiological conditions, such as pregnancy. National guidelines facilitate the inclusion of certain disease in national health plans. There is no proposal as yet in this country for managing this disease that encompasses representatives of the principal health systems in a global and standardised way.

The disease has distinct features in the different ethnic groups, as reported in cohorts such as LUMINA and GLADEL.8,9 Mixed race people suffer severe forms, with a higher frequency of glomerulonephritis, higher mortality and accumulated damage. Similarly, some manifestations, such as demyelinating neuropathies and transverse myelitis, are more frequent in Latin American populations, although they usually respond better to treatment than Caucasian populations.10,11 Some studies have been published on Mexican patients, that assess biochemical variants that might be related to therapeutic response,12 and specific lupus nephritis induction treatments13 or specific response to biological drugs.14 However, these studies have the weakness that they were performed on captive populations, with a limited number of participants, and therefore general peculiarities of Mexican patients or generalised recommendations cannot be established based on this local evidence.

These facts justify the drawing up of national guidelines in a country where most of the population is of mixed race and requires access to public health systems for medical advice and treatment.

Based on the above, the Mexican College of Rheumatology (MCR) set out to draw up a CPG that would combine the majority of the disease's manifestations, and which would also include guidelines for controversial situations such as vaccination and the perioperative period. Although the recommendations provided in this CPG are based on scientific evidence, all guidelines have limitations in terms of individual decision-making, since each patient has unique features, and therefore this document, as its name states, is only intended as a guide and in no way attempts to substitute or limit the clinical judgement of the physician. Publishing this CPG marks the start of process of continuous updating which the MCR will undertake every 2 years or when appropriate in light of new evidence. The report on the evidence to support the recommendations is being drawn up to complement this guideline, and will be published later.

In preparing this guideline, we endeavoured to cover a wide range of patients. To make the recommendations we took into account publications on patients with SLE, and all organ and systemic involvement, with possible comorbidities. The only two cases that we did not consider were the paediatric population and lupus during pregnancy since the MCR already has a guideline to cover these groups.5 Because response to treatment and the presentation of the disease can differ in different ethnic groups, the recommendations were made with the Mexican population in mind. The country's socioeconomic context was taken into consideration, because the cost of some drugs can be very high for patients who are not insured or who are not right holders, and for the health institutions themselves. The recommendations included in this guideline, therefore, apply to adult, non-pregnant, Mexican patients with SLE.

This document was undertaken to provide the most complete guideline possible to serve as support particularly for non-rheumatologist doctors who have to treat patients with SLE and lack the training of rheumatology specialists. It is common for primary care doctors and those of other specialties to have to manage patients with SLE due to the lack of rheumatologists in the health institutions. It is important to stress that patients with SLE should always be treated by rheumatologists, but, where this option does not exist, this guideline can provide useful evidence-based information and serve as support in decision-making in the treatment of these patients. This guideline presents recommendations on the management of general, articular, renal, cardiovascular, pulmonary, neurological, haematological and gastrointestinal manifestations.

The rheumatologists who formed the panel of experts drawing up this CPG were chosen by the governing board of the MCR based on their expertise in the treatment of lupus. Senior rheumatologists from various states of the Mexican Republic were included, and young rheumatologists who had shown great interest in participating in the academic activities of the MCR were invited to form part of the teams.

The panel of experts met for the first time in Mexico City in December 2016 to draft this document. The working groups were formed during this meeting, and the methodology outlined for the preparation of this document. After this meeting, there were 2 face-to-face meetings to check that the proposed methodology was being followed, and the findings from the literature were presented by each of the teams. In addition, there was constant electronic communication. The teams, after presenting their results to the other panellists, prepared their recommendations and sent them to the methodologist coordinating the work, who in turn drafted a document with all the recommendations. This document was submitted electronically to all the panellists for their consideration, and the final recommendations were chosen by consensus: there was no disagreement between the team members.

The author responsible for publication submitted the subjects that the guideline needed to cover to the Research Committee, and together they made the final decision to produce recommendations per type of manifestation, and include recommendations on general management.

For the literature search, a series of research questions were generated for the general management of the disease, and for each of its manifestations. Each research question resulted in one or more than one search, depending on its complexity. The PICO methodology was used, for searches clearly identifying the population (P), intervention (I), comparator (C), and outcome (O). In sum, the target population were patients with SLE, the interventions and comparators were all the treatments presented in this document, and there were multiple outcomes. Not only were the most clinically relevant outcomes considered, such as prevention of renal damage or reducing progression of the disease, remission after induction, prevention of relapse, the control or reduction of the manifestations of the disease, but also those relevant to the patients, such as fatigue and pain reduction. The searches were performed from 2000 to 2016, they were limited to adults and, given the limited scientific literature, the search was not restricted to publications on Mexican populations, although the articles that did cover this population bore more weight when making the recommendations. Given the absence of direct evidence, most of the recommendations were made based on the results from other populations.

Each team received from the methodologist the PICO search mechanisms for the subject that they had been allocated. Each team reviewed the articles and, based on the review of related articles and the references cited in the publications of interest, completed their search. The team members checked that the articles that were to be used to make the recommendations answered the research questions, and met the selection criteria that had been determined beforehand by the governing board of the MCR. Any disagreements among the teams were resolved through discussion between team members. Once all the scientific literature had been reviewed, the recommendations were drafted. Unlike most Mexican CPG that use the levels of evidence of Shekelle et al.,15 the GRADE16 system was used to draw up the recommendations of this CPG, and rate the level of evidence and strength of the recommendations. This is the system currently recommended by the same authors who developed the levels of evidence used in previous years in the new guideline for drawing up CPG.17 The GRADE method has proved superior to other systems for evaluating CPG18 recommendations, and has now been adopted by the Cochrane Collaboration.

The evidence-based recommendations for each type of manifestation that form part of this CPG for the management of SLE are found in the tables of recommendations for each manifestation. In addition, the section below and Table 2 present some generalities regarding the drug groups most used in the treatment of SLE.

GC are the cornerstone of treatment for SLE. It is common for GC pulses to be administered that, for the purposes of this document and unless otherwise specified, will be defined as the intravenous administration of high doses of steroids. Generally 1g of methylprednisolone succinate is administered over a period of 2h; an average of 3 pulses is given, one per day, for 3 consecutive days. Although there is no consensus on standardised recommendations, comorbidities and risk factors for adverse advents should be assessed in patients treated with GC, and treated if appropriate. During treatment the patient's body weight, blood pressure, peripheral oedema, heart failure, serum lipids and glucose must be monitored, and they must undergo an ophthalmological assessment. If the patient has a dose >75mg/day of prednisone and requires treatment for more than 3 months, a calcium and vitamin D supplement should be started. The use of antiresorptive agents must be assessed based on the patient's risk factors.29 Considerations on their use in the remission induction and maintenance schemes are shown in Table 3.

Antimalarials have been used in the treatment of SLE since the nineteenth century and, although there are few studies that aim to demonstrate their efficacy, the current evidence suggests the use of hydroxychloroquine (HCQ) (at 20–400mg/day) or chloroquine (at 150–300mg/day). There is no evidence that higher doses are more effective than low doses, and the appropriate dose must be left to the judgement of the clinician. Antimalarials have photoprotective, lipid lowering, antiangiogenic, antithrombotic effects, and also inhibit the function of the B cell-activating factor and phospholipase A2-activating factor, which means that they are indicated in the treatment of skin lupus, of SLE with mild to moderate activity, as concomitant treatment to prevent relapses and damage to major organs.30 Provided there are no contradictions, antimalarials are recommended for all patients with SLE. HCQ is associated with longer damage-free survival than when it is not used (45.1% vs 26.5%; P<.001), and correlates negatively with accumulated damage measured by SLICC (r=−.22; P=.015),31 reducing the probability of accumulated renal damage (HR .68; 95% CI: .53–.93)32 (OR .38; 95% CI: .25–.58)33 in those who use them compared to those who do not. They are also useful in the prevention of morbidity due to atherosclerosis, and in the management of antiphospholipid antibody syndrome associated with SLE.34,35 Discontinuing HCQ has been reported to increase the relative risk of relapse by 2.5 (95% CI: 1.08–5.58) over a period of 6 months.36 A baseline and subsequent annual ophthalmological assessment should be performed to monitor adverse events.

Most rheumatologists agree on the use of immunomodulators for moderate to severe SLE during an intense period of immunosuppression known as induction therapy, followed by a longer period of maintenance therapy. The three main objectives of induction therapy are to halt damage, recover function, and control immunological activity. Maintenance therapy is used to consolidate remission and prevent relapse with a treatment programme with a low risk of complications and more convenient for the patient, under the current concept of “personalised treatment”. The drugs that are traditionally used with these aims are the following:

• –

  Mycophenolic acid (MMF): the dose varies widely depending on the organ involved and the severity of the manifestation; it can range from 1 to 3g. Adverse events that must be monitored are cytopenia, altered LFT, diarrhoea and teratogenicity.38–41

• –

  Cyclophosphamide (CYC): the dose can vary from 500 to 1000mg/m2 of body surface area. Adverse events that must be monitored are cytopenia, teratogenicity, infertility, myeloproliferative disorders, haemorrhagic cystitis, and bladder cancer.40

• –

  Azathioprine: the dose varies between 1 and 3mg/kg/day and the adverse events to be monitored are myelosuppression, hepatotoxicity, lymphoproliferative disorders and teratogenicity.41,42

• –

  Methotrexate: can be used in doses from 7.5 to 25mg, orally or parenterally, and the adverse events to be monitored are myelosuppression, hepatotoxicity, pneumonitis, alopecia, stomatitis, and teratogenicity.39–42

• –

  Cyclosporine: principally used in resistant nephropathy, and the main adverse events are gingival hyperplasia, high blood pressure, hirsutism, renal failure, and anaemia.43

Other drugs used in SLE are the biologics belimumab and rituximab. Belimumab is used in mild to moderate manifestations such as arthritis, serositis or if there is a skin infection (dsDNA+ or C3/C4 consumption). B-lymphocyte depletion is the most common adverse event with this biologic. Rituximab is also used when there is joint involvement resistant to conventional treatment, haematological involvement, involvement of the central nervous system or resistant nephritis, and the principal adverse events are allergy, serum sickness, and progressive multifocal leukoencephalopathy.44

The tables below show the recommendations resulting from the literature review and the work by consensus of the participants in the working group who are the signatories of this CPG. Table 4 presents the recommendations for managing the general manifestations of SLE, and Tables 5–10 present the recommendations for the treatment of the renal, cardiovascular, pulmonary, neurological, haematological, and gastrointestinal manifestations of the disease.

SLE, because it is a rare disease, is a less frequent subject of research than other diseases. Therefore, there is a significant need for evidence on effective treatments that also have a lower rate of adverse events. The working panel identified a series of knowledge gaps, and made recommendations so that clinicians, researchers and the pharmaceutical industry can focus their efforts on these research needs to provide increasingly better treatments for patients with this disease.

• 1)

  In general, the following need to be designed:

  • a)

    National multicentre prospective cohort studies.

  • b)

    Comparative studies with populations from other countries.

  • c)

    Controlled clinical trials on treatment of the neuropsychiatric manifestations of lupus.

• 2)

  There is a need for clinical trials for the treatment of the articular manifestations of SLE.

• 3)

  More evidence is required on the efficacy and safety of tacrolimus in severe SLE, calcium antagonists and immunosuppressant medication (MMF and CYC) in patients with pulmonary hypertension, of CYC, azathioprine, mycophenolate mofetil, danazol, antimalarials in the treatment of patients with SLE and thrombocytopenia or haemolytic anaemia, of CYC for haemophagocytic syndrome and thrombotic thrombocytopenic purpura, giving multiple vaccinations at one visit and tetanus vaccination, recombinant human papilloma virus quadrivalent vaccine, hepatitis B virus and zoster herpes in patients with moderate and severe disease activity.

• 4)

  Therapeutic evidence of the use of splenectomy will require more evidence from retrospective studies, since it is not very feasible to undertake a controlled clinical trial.

• 5)

  Studies are required on the optimal duration of treatment, and dose tapering schemes when remission of symptoms has been achieved.

• 6)

  Studies with greater statistical power are required on gastrointestinal involvement in lupus, since the current studies are case series.

• 7)

  Studies are required to determine the required dose of CYC for haemophagocytic syndrome, and thrombotic thrombocytopenic purpura.

Daniel Xibille-Friedman has received honoraria from GlaxoSmithKline for training activities and in clinical trials. Sandra Carrillo-Vázquez has received honoraria from Abbvie, Bristol Myers Squibb, Eli Lilly, Novartis, Pfizer, Roche, Takeda and Janssen. Lilia Andrade-Ortega has received honoraria from Bristol Myers Squibb, Novartis, Pfizer, Roche, Janssen. Miguel Ángel Saavedra has received honoraria from UCB and Pfizer. Leonardo Limón-Camacho has received honoraria from Bristol Myers Squibb, UCB, Pfizer, Janssen, Roche, Lilly and Amgen. Leonor Barile Fabris has received honoraria from Abbvie, Jansen, Roche, Bristol Myers Squibb, UCB, Novartis, Pfizer and GlaxoSmithKline.

Marcela Pérez-Rodríguez, Everardo Álvarez-Hernández, Francisco Javier Aceves, Mario C. Ocampo-Torres, Conrado García-García, José Luis García-Figueroa, Javier Merayo-Chalico, Ana Barrera-Vargas, Margarita Portela-Hernández, Sandra Sicsik, Víctor Manuel Rosales-Don Pablo, Aline Martínez, Pilar Prieto-Seyffert, Mario Pérez-Cristóbal, Zully Castro-Colín, Azucena Ramos, Gabriela Huerta-Sil, María Fernanda Hernández-Cabrera, Luis Javier Jara and Lizbet Tinajero-Nieto have no conflict of interests to declare.