Clinical practice guidelines for systemic lupus

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onsensus statement

linical practice guidelines for systemic lupus erythematosus:ecommendations for general clinical management�

aría M. Trujillo-Martína,b, Inigo Rúa-Figueroa Fernández de Larrinoac,∗, Guillermo Ruíz-Irastorzad,osé María Pego-Reigosae,f, José Mario Sabio Sánchezg, Pedro Serrano-Aguilarb,h, on behalf of theevelopment group of the CPG-SLE♦

Fundación Canaria de Investigación Sanitaria (FUNCANIS), La laguna, Santa Cruz de Tenerife, SpainRed de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Madrid, SpainServicio de Reumatología, Hospital Universitario de Gran Canarias Dr. Negrín, Las Palmas de Gran Canaria, SpainUnidad de Investigación de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario Cruces, Barakaldo, Vizcaya, SpainServicio de Reumatología, Hospital Meixoeiro, Vigo, SpainIRIDIS (Investigation in Rheumatology and Immuno-Mediated Diseases) Group, Instituto de Investigación Biomédica (IBI) de Vigo, Pontevedra and Ourense, SpainServicio de Medicina Interna, Hospital Virgen de Las Nieves, Granada, SpainServicio de Evaluación y Planificación (SESCS), Servicio Canario de la Salud, Santa Cruz de Tenerife, Spain

r t i c l e i n f o

rticle history:eceived 19 November 2015ccepted 21 January 2016vailable online xxx

eywords:ystemic lupus erythematosuslinical practice guidelinesonsensus

a b s t r a c t

Systemic lupus erythematosus (SLE) is a complex rheumatic multisystemic disease of autoimmune originwith significant potential morbidity and mortality. It is one of the most common autoimmune dis-eases with an estimated prevalence of 20–150 cases per 100,000 inhabitants. The clinical spectrum of SLEis wide and variable both in clinical manifestations and severity. This prompted the Spanish Ministry ofHealth, Social Services and Equality to promote and fund the development of a clinical practice guideline(CPG) for the clinical care of SLE patients within the Programme of CPG in the National Health Systemwhich coordinates GuiaSalud. This CPG is intended as the reference tool in the Spanish National HealthSystem in order to support the comprehensive clinical management of people with SLE by all healthprofessionals involved, regardless of specialty and level of care, helping to standardize and improvethe quality of clinical decisions in our context in order to improve the health outcomes of the peopleaffected. The purpose of this document is to present and discuss the rationale of the recommendationson the general management of SLE, specifically, clinical follow-up, general therapeutic approach, healthylifestyles, photoprotection, and training programs for patients. These recommendations are based on thebest available scientific evidence, on discussion and the consensus of expert groups.

© 2016 Elsevier Espana, S.L.U. All rights reserved.

Guía de práctica clínica para el lupus eritematoso sistémico: recomendacionespara el abordaje clínico general

r e s u m e n

alabras clave:upus eritematoso sistémicouía de práctica clínicaonsenso

El lupus eritematoso sistémico (LES) es una compleja enfermedad reumática multisistémica de ori-gen autoinmune con una morbimortalidad importantes. Es una de las enfermedades autoinmunes máscomunes, con una prevalencia estimada de 20-150/100.000 habitantes. El espectro clínico del LES esamplio y variable tanto en manifestaciones clínicas como en gravedad. Esto ha hecho que el Ministe-rio de Sanidad, Servicios Sociales e Igualdad haya promovido y financiado el desarrollo de una guíade práctica clínica (GPC) sobre el LES dentro del Programa de GPC en el Sistema Nacional de Salud

� Please cite this article as: Trujillo-Martín MM, Rúa-Figueroa Fernández de Larrinoa I, Ruíz-Irastorza G, Pego-Reigosa JM, Sabio Sánchez JM, Serrano-Aguilar P, et al. Guía deráctica clínica para el lupus eritematoso sistémico: recomendaciones para el abordaje clínico general. Med Clin (Barc). 2016. http://dx.doi.org/10.1016/j.medcli.2016.01.013∗ Corresponding author.

E-mail address: [email protected] (I. Rúa-Figueroa Fernández de Larrinoa).♦ The remaining members of the development group of the CPG-SLE are listed in Annex.

387-0206/© 2016 Elsevier Espana, S.L.U. All rights reserved.

MEDCLE-3518; No. of Pages 14

www.elsevier.es/medicinaclinica

http://dx.doi.org/10.1016/j.medcli.2016.01.013

mailto:[email protected]

2 M.M. Trujillo-Martín et al. / Med Clin (Barc). 2016;xxx(xx):xxx–xxx

que coordina GuiaSalud. Esta GPC pretende ser el instrumento de referencia en el Sistema Nacional deSalud para dar soporte a la gestión clínica integral de las personas con LES por parte de todos los profesio-nales sanitarios implicados, independientemente de la especialidad y el nivel asistencial, contribuyendoa homogeneizar y mejorar la calidad de las decisiones clínicas en nuestro entorno con el objetivo demejorar los resultados de salud de las personas afectadas. En el presente artículo se presentan y discutenlas recomendaciones formuladas en relación con el manejo general de la enfermedad, en concreto, elseguimiento clínico, el abordaje terapéutico general, los estilos de vida saludables, la fotoprotección y laformación para los pacientes. Recomendaciones basadas en la mejor evidencia científica disponible y enla discusión y consenso de grupos de expertos.

© 2016 Elsevier Espana, S.L.U. Todos los derechos reservados.

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ntroduction

Systemic lupus erythematosus (SLE) is a complex, multisys-emic, chronic and autoimmune disease and affects about half

million people in Europe. The prevalence in Spain has beenstimated at around 9/10,000 inhabitants.1 Although the progno-is has improved in recent years, the quality of life of patientsith SLE is lower than the general population2 and the risk

f death is 2–3 times higher,3 with a significant socioeconomicmpact.4

The systemic nature of SLE requires a cooperative approach fromarious medical specialties.5 To this end, to help reduce differ-nces in clinical practice and potential unwanted effects of careragmentation and also improve the clinical management of peo-le affected by SLE, the European League Against RheumatismEULAR) prepared in 2008 a set of 12 recommendations based onhe scientific evidence available for the purpose of guiding thelinical decisions.6 Other 2 recommendation documents on SLEanagement were published in 20117 and 20138 respectively in

pain and Chile, with a limited degree of interdisciplinary partici-ation and methodological transparency.

The Institute of Medicine of the USA described in 2011 a clinicalractice guideline (CPG) as a set of recommendations to supportlinical decisions and improve patient care. This CPG is based onhe best scientific evidence from systematic reviews of the litera-ure, where the benefits and risks of several alternatives have beenonsidered.9 GuiaSalud is the agency of the Spanish National Healthystem (NHS) responsible for promoting the development, dissem-nation and use of CPGs and other tools and products based oncientific evidence [www.guiasalud.es].

The complexity involved in the clinical management of SLElong with the requirement of multidisciplinary approach, theecent development of new drugs with high economic impact,imited range of clinical questions previously addressed by theULAR recommendations and the added need to update the scien-ific basis supporting these recommendations,6 justify the decisionf the Ministry of Health to fund the development of a CPG on SLECPG-SLE). This activity was entrusted to the Assessment Service ofhe Canary Islands Health Service as part of the Spanish Networkf Agencies for Health Technology Assessment and NHS assistanceBOE order SSI/1833/2013, 2 October].

The CPG-SLE addressed the assistance provided from primaryare and specialized care to adults affected by SLE exclud-ng the disease involving only the skin (cutaneous lupus) andatients with advanced renal failure. Sixty clinical questions wereesponded in 5 major sections: diagnosis, general management,anagement of specific clinical manifestations (renal, hemato-

ogic, mucocutaneous, neuropsychiatric and joint manifestationsnd antiphospholipid syndrome), sexual and reproductive healthnd, finally, comorbidity. This large number of questions havead to be split to enable their dissemination in general scientific

journals in Spain. In this paper the report and discuss the recom-mendations suggested in response to clinical questions consideredin the CPG on the general management of SLE patients.

The recommendations are based on scientific evidence avail-able when drafting the guide or, if no evidence available, on thediscussion and consensus of expert groups. These recommenda-tions should be reviewed in the coming years when new relevantscientific knowledge is available.

Methods

This CPG was performed following the Methodology Manual onthe Development of CPGs at the NHS10 and following the qualitycriteria provided in the AGREE II11 instrument. The methodology isdetailed in the full document of the guideline.12

The guideline development group (GDG) consisted of special-ists in rheumatology, internal medicine, nephrology, hematology,dermatology, immunology, family and community medicine andclinical pharmacy, along with a nurse assigned to a hospitalrheumatology department, a representative of patients, and CPGmethodologists.

To ensure that this CPG gave answers to the most importanthealth requirements perceived by SLE patients, from the initialdesign phase, 2 additional activities were conducted; a systematicreview of the international literature and, subsequently, a surveyto SLE patients in Spain.13

Once the scope and objectives of the CPG-SLE has been defined,to specify its contents, there was a process of identifying andprioritizing the clinical questions to be included, which wouldbe answered with the available scientific evidence, and the rec-ommendations would be based on that. Table 1 shows the17 questions for the general management of SLE patients finallyincluded.

The literature searches were run until December 2013 in the fol-lowing electronic databases: Medline and PREMEDLINE via OvidSP,Embase via Elsevier and Science Citation Index Expanded (SCI-EXPANDED) and the Social Science Citation Index (SSCI) via Web ofKnowledge. To identify potential relevant clinical trials publishedsubsequently, the entire working group was consulted until April2014, deadline for the first draft of the guideline.

The studies considered were systematic reviews, meta-analyses,experimental, quasi-experimental studies and observational stud-ies in adults (≤18 years) with SLE, published in English and Spanish.The clinical trials focusing on cutaneous lupus or in patients withadvanced renal failure on dialysis, or kidney transplant recipients,were excluded. If the study intervention was addressed to a hetero-geneous group of patients, the study was included if the results for
target patients of CPG-SLE were reported separately or if they repre-sented more than 80% of the target population. Qualitative studies,studies with fewer than 5 participants, conference proceedings andprotocols were also excluded.
http://www.guiasalud.es/

M.M. Trujillo-Martín et al. / Med Clin (Barc). 2016;xxx(xx):xxx–xxx 3

Table 1Clinical questions of the PGC-SLE on the general clinical management.

Follow-upWhat clinical follow-up protocol is most recommended for SLE patients?What additional tests should be performed and how often, to SLE patients,

in monitoring and control visits? What are the most effective andcost-effective disease activity biomarkers for monitoring the SLE? Shouldthe levels of 25-OH vitamin D be monitored as an activity marker of SLE?

How effective are the available standardized tools to assess disease inclinical practice? Should they be used in routine clinical practice?

What are the biological or predictive laboratory markers of disease outbreakor what factors have been associated with increased SLE activity?

General therapeutic approachWhat are the therapeutic purposes in SLE patients?What nonbiological immunosuppressive therapies are effective in

extrarenal lupus?Is the use of antimalarials indicated in all people with SLE? How effective,

cost-effective and safe are these drugs in preventing outbreaks? Do theyhave any other additional beneficial effects to justify their widespreaduse?

What is the recommended glucocorticoid dose to keep the disease undercontrol with an acceptable risk of adverse effects?

What biological therapies are effective and safe in SLE patients?How effective and safe are immunoglobulins in the treatment of SLE?What are the complications and adverse effects of the most frequent SLE

immunosuppressive and biological therapies? What are the mostdesirable monitoring guidelines?

How effective and safe is the therapeutic apheresis in SLE treatment?What measures are effective in preventing the reactivation of SLE?What are the effective treatment options to help people with SLE-associated

asthenia?

Lifestyle measuresWhat measures on lifestyle should be recommended to SLE patients?

PhotoprotectionIs the use of photoprotection indicated in all SLE patients? What are the

effective measures of photoprotection?

Training patientsAre the educational programs structured from he nursing department

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Table 2Levels of evidence and degrees of recommendation (SIGN).

Level of evidence Type of study

1++ High quality MA, SR of RCT, or very well-performedRCT with very low risk of bias

1+ Well-performed MA, SR of RCT, or well-performedRCT with low risk of bias

1− MA, SR of RCT, or RCT with high risk of bias2++ High quality SR of cohort or case–control studies.

Cohort or case–control studies with very low risk ofconfusion, bias or randomness and high probabilityof causal relation

2+ Well-performed cohort or case–control studies withlow risk of bias and moderate probability of causalrelation

2− Cohort or case–control studies with high risk ofconfusion, bias or randomness and significantprobability of no causal relation

3 No analytical studies (case reports and case series)4 Expert reviews

Degree ofrecommendation

Level of evidence

A At least one MA, SR or RCT rated as 1++ and directlyapplicable to the target population of the guideline;or evidence consisting of studies rated as 1+, directlyapplicable to the target population of the guidelineand showing overall consistency of results

B Evidence consisting of studies rated as 2++ directlyapplicable to the target population of the guidelineand showing overall consistency of results; orevidence extrapolated from studies rated as 1++ or 1+

C A volume of scientific evidence consisting of studiesrated as 2+, directly applicable to the targetpopulation of the guideline and showing overallconsistency of results; or scientific evidenceextrapolated from studies rated as 2++

D Scientific evidence of level 3 or 4; or scientificevidence extrapolated from studies rated as 2+

and aimed at people with SLE effective?

PG-SLE, clinical practice guideline on SLE; SLE, systemic lupus erythematosus.

Levels of evidence and degrees of recommendations werestablished in accordance with the classification proposed by thecottish Intercollegiate Guidelines Network (SIGN) (Table 2).14 Toetermine the strength of the recommendations, not only the levelf evidence available was considered but also the balance betweenhe desirable and undesirable consequences of carrying out theecommendation. When the GDG found important practical aspectsonsidered necessary to emphasize but with no available scien-ific evidence, recommendations were formulated for good clinicalractice (identified as

√), agreed by consensus of a group of experts

ollowing a modified standard Delphi methodology.13

In order to improve the quality of the guideline, after the GDGrdered an advanced draft, it was externally reviewed by a multi-isciplinary group of experts in various clinical areas, methodologyxperts and a representative of the patients.

The selection of members of the GDG, panel of experts to reach aonsensus on the recommendations of best practices, and externaleviewers of the guideline, was carried out with the cooperationf the relevant scientific societies. All of them filled out and signedform of potential conflicts of interest. No conflicts were reported

imiting the participation of any of these people in the developmentf the CPG-SLE.

esults

Below, we report the 49 recommendations of the CPG-SLE onhe overall management of SLE patients, briefly discussing someundamentals. The recommendations are organized under five

RCT, randomized clinical trial; MA, meta-analysis; SR, systematic review; SIGN,Scottish Intercollegiate Guidelines Network.

different headings: clinical follow-up (Table 3); general therapeu-tic approach (Table 4), measures on lifestyle, photoprotection andtraining for patients (Table 5). The order of the recommendationsdoes not respond to their significance or consistency but conformsto the logical sequence in a clinical and procedural hierarchy. TheGDG selected 20 key recommendations, because of their most sig-nificant clinical relevance and special priority in implementation,which are identified in the relevant tables on gray background.

Recommendations and analysis of evidence

Clinical follow-upClinical follow-up protocol and additional tests.

1. A comprehensive assessment is suggested (clinical and labora-tory assessment) in confirming the diagnosis of SLE (recommendation√

).No studies are available evaluating clinical follow-up protocols

in SLE patients. Therefore, this is a recommendation of good clinicalpractice based on the recommendation of international profes-sional organizations,15–17 GDG clinical experience and consensusof the expert group.

2. The activity of SLE, organ damage, comorbidities (includingvascular risk factors) and the possible toxicity of drug treatmentshould be monitored through: clinical interview, physical examination,
blood pressure measurements and basic testing (blood count, renalbiochemistry profile and urinalysis, complement and anti-dsDNA)(recommendation
√).

4 M.M. Trujillo-Martín et al. / Med Clin

Table 3Recommendations for follow-up.

Degree

Clinical follow-up protocol and laboratory tests1. A comprehensive assessment is suggested (clinical

and laboratory assessment) in confirming thediagnosis of SLE

√

2. The activity of SLE, organ damage, comorbidities(including vascular risk factors) and the possibletoxicity of drug treatment should be monitoredthrough: clinical interview, physical examination,blood pressure measurements and basic testing(blood count, renal biochemistry profile andurinalysis, complement and anti-dsDNA)

√

3. In people with active SLE, monitoring interval isvariable and must be adjusted to the clinical severity

√

4. In the clinical and laboratory remission, monitoring issuggested every 6–12 months, depending on the timeof course of disease and treatment intensity

√

5. In patients clinically quiescent with maintainedlaboratory activity criteria, closer monitoring issuggested, every 3–4 months during the first years

C

6. Periodic determination of C3, C4 and anti-dsDNA isrecommended as markers of active disease and riskof lupus nephritis

B

7. Levels of 25-OH vitamin D should be periodicallymeasured when there are risk factors for osteoporoticfracture

D

Assessing the state of health of SLE patients8. The use of validated instruments is recommended to

quantify the degree of activity, cumulative damageand quality of life

√

Predictors of outbreak or increased disease activity9. Routine use of anti-C1q and antinucleosoma

antibodies is not recommended as markers of lupusnephritis.

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The lack of scientific evidence on monitoring SLE patientsequires that this evidence be based on the opinion and consen-us among experts, who recommend assessing at least once a yearhe standard factors of cardiovascular risk, the presence of vascu-ar events and physical activity.18,19 Among the additional tests,here is a consensus among experts to request a blood count duringollow-up, a biochemical test with glucose, lipids, renal profile andrinalysis, along with another set of biomarkers of lupus activityiscussed below.15

3. In people with active SLE, monitoring interval is variable andust be adjusted to the clinical condition (recommendation

√).

This recommendation, unsubstantiated evidence, was based onlinical experience of experts and the recommendations of the ACRnd EULAR and seeks to emphasize that, given the enormous vari-bility of the clinical condition of SLE throughout the course of theisease, follow-up intervals should be individualized.20,21

4. In the clinical and laboratory remission, monitoring is suggestedvery 6–12 months, depending on the time of course of disease andreatment intensity (recommendation

√).

This recommendation was agreed by the expert group fromhe ACR and EULAR recommendations, which place the frequencyf reviews in stable patients from 3 to 12 months. The intervaletween follow-ups (clinical and laboratory) to detect new silentnalytical changes in people with mild or inactive SLE might be–4 months approximately, according to a study on the cohort oforonto.22

5. In patients clinically quiescent with maintained activity labora-ory criteria, closer monitoring is suggested, every 3–4 months during
he first years (evidence 2+, recommendation C).
This recommendation is supported by the evidence that patientslinically quiescent and serologically active have around 50% riskf clinical outbreak in the following months.23,24

(Barc). 2016;xxx(xx):xxx–xxx

6. Periodic determination of C3, C4 and anti-dsDNA is recom-mended as markers of active disease and risk of lupus nephritis(evidence 2++, recommendation B).

In 6–13% SLE patients, disease is clinically quiescent but serolog-ically active. In about a year, 43–59% of these cases develop someoutbreak.23,24 This limited correlation between symptomatologyand laboratory explains the need to monitor both clinical and sero-logical aspects in people with SLE.25 The decline in the levels ofC3 and C4 and/or increased titers of anti-dsDNA have been associ-ated with increased lupus activity generally. There is acceptableevidence about their ability to predict SLE outbreak.26–29 How-ever, its usefulness in the individual patient is less clear, giventhe inconstant association with active disease. On the other hand,these markers of activity have also been shown associated with thepresence of active lupus nephritis.30–33

7. Levels of 25-OH vitamin D should be periodically measured whenthere are risk factors for osteoporotic fracture (evidence 3, recom-mendation D).

This is the major indication for periodic determination of serum25-OH vitamin D, since its relation with SLE activity is clinically notvery relevant.34–36 However, as indicated below, asthenia can alsobe associated with vitamin D deficiency.

Assessment of state of health.

8. The use of validated instruments is suggested to quantify thedegree of activity, cumulative damage and quality of life (recommen-dation

√).

Despite widespread agreement on the appropriateness of usingmeasurement scales validated to quantify and monitor the SLE clin-ical activity, currently there is no agreement on the activity scale(index),37 regardless their sensitivity to changing.38 Updated ver-sions of SLEDAI (SLEDAI-2K or SELENA-SLEDAI), a numerical globalindices, short and easy to apply even for non-experts, might be theinstrument of choice. Other numerical global indices such as ECLAMor SLAM-R are also appropriate.15,39 The SLICC/ACR DI is a vali-dated instrument to measure cumulative damage in SLE patientswith proven relation with long-term survival.40,41 Patient BILD andLDIQ questionnaires might be a useful and reliable alternative toSLICC/ACR DI but confirming studies are not available.42–44

9. Routine use of anti-C1q and antinucleosoma antibodies is notrecommended as markers of lupus nephritis (evidence 2++, recom-mendation C).

Studies reporting that antinucleosoma or anti-C1q antibodiesappear to predict SLE outbreaks better than levels of anti-dsDNAantibodies have no sufficient scientific validity,45 placing theseprognostic determinations as merely promising.

Overall therapeutic approachTherapeutic purposes.

10. The recommendation as a major therapeutic purpose is to mon-itor the perceived or verifiable clinical activity, preventing irreversibledamage due to SLE or its therapies, trying to reduce the impact onquality of life and increase survival of patients (evidence 2++/2+, rec-ommendation B).

The risk of death in people with SLE is 3 times higher thanthe general population due to cardiovascular, infectious or kid-ney causes.46 The irreversible organ damage is the major predictorof mortality,40,47,48 especially if it happens in kidney or neuropsy-chiatric level.49 The lupus outbreaks,50,51 kidney and neurologicalcondition,50 hypertension,52 antiphospholipid antibodies48 andantiphospholipid syndrome53 are associated with development
of damage. Moreover, therapy with cyclophosphamide and aza-thioprine and especially with glucocorticoids50,54–56 increases therisk of damage. Serologically active patients in prolonged clini-cal remission report a favorable evolution and require no active

M.M. Trujillo-Martín et al. / Med Clin (Barc). 2016;xxx(xx):xxx–xxx 5

Table 4Recommendations for general therapeutic approach.

Degree

Therapeutic purposes10. The recommendation as a major therapeutic purpose is to monitor the perceived or verifiable clinical activity, preventing irreversible damage due

to SLE or its therapies, trying to reduce the impact on quality of life and increase survival of patientsB

Indications for treatmentAntimalarials

11. The use of antimalarials is recommended indefinitely (preferably hydroxychloroquine [HCQ] for best safety) as the baseline treatment of all SLEpatients without contraindications for use

B

12. Combined mepacrine and HCQ is suggested in patients with refractory lupus activity, especially cutaneous, due to its potential synergistic effects D13. In patients with antimalarial-induced retinal toxicity replacing HCQ or chloroquine with mepacrine is suggested D14. Monitoring the retinal toxicity is suggested in patients treated with HCQ or chloroquine D

Glucocorticoids15. Prednisone dose should not exceed 30 mg/day in patients with lupus nephritis. The dose should be individualized B16. Prednisone dose should not exceed 30 mg/day in the remaining SLE manifestations. However, the dosage should be assessed individually for each

patient

√

17. In severe outbreaks, adjuvant therapy is recommended with pulses of methyl prednisolone B18. Quick reduction of glucocorticoids (prednisone) to 5 mg/day is recommended within 6 months, with full withdrawal as soon as possible C19. If maintenance therapy is required, doses of prednisone should not exceed 5 mg/day B20. The use of pulses of methylprednisolone below 1000 mg has been suggested. However, a specific dose cannot be recommended

√

Nonbiological immunosuppressive therapies21. Intravenous cyclophosphamide is recommended as the first immunosuppressant drug in the treatment of severe non-renal manifestations B22. Methotrexate is recommended as the first immunosuppressant drug in the treatment of non-renal SLE with moderate activity, particularly on skin

and joint manifestationsA

23. The use of immunosuppressants such as azathioprine, cyclosporine A, leflunomide or mycophenolate is recommended as alternatives to thetreatment of non-renal SLE

√

Biological therapies24. Belimumab is recommended in subjects with active SLE not caused by renal or neurological condition, not responding to standard treatment A25. Candidates for treatment with belimumab are subjects with active SLE and lack of response after at least 3 months of treatment, including

anti-malarial and prednisone therapy and at least one immunosuppressant at suitable dose. Or, when requiring prednisone at 7.5 mg/day or higherto maintain remission despite the use of antimalarials and, at least, one immunosuppressant. Or with the contraindication of immunosuppressants

B

26. Rituximab is recommended in patients with renal, neurological or severe hematologic condition not responding to first-line immunosuppressivetherapy

C

27. Today, there is no approved indication for the use of any other biological agents in SLE. However, when they have failed or the routine therapeuticmeasures cannot be used (including belimumab and rituximab), the following could be considered: infliximab (in refractory arthritis and nephritis),etanercept (arthritis and serositis), abatacept (especially in arthritis) and tocilizumab (deficient control of clinical activity)

√

Immunoglobulins28. The use of intravenous immunoglobulins is justified in severe immune thrombocytopenia with life threatening risk for active bleeding or when

surgery or bleeding-risk procedure is requiredD

29. The risk of toxicity associated with immunoglobulin should be reduced, considering in each case the balance between risks and benefits, and alsocontrolling the rate of infusion, avoiding compounds with high sucrose content and previously discarding immunoglobulin A deficiency. Ensuringhydration and considering thromboprophylaxis with heparin is recommended, to prevent the risk of thrombosis. In patients at risk of renal failureassociated, monitoring of renal function is suggested in the days following the infusion

D

30. The intravenous immunoglobulins may be used in people with high organ activity and involvement, highest in the presence of or suspected seriousinfection substantially limiting or contraindicating immunosuppressive therapy at 0.4 g/kg/day doses for 5 consecutive days. Lower doses (e.g.0.5 g/kg one day) can also be effective, except with thrombocytopenia

√

31. Intravenous immunoglobulins are not recommended in maintenance treatment of any of the SLE manifestations since more effective and lower costalternative therapies are available

√

Monitoring guidelines for the immunosuppressive and biological therapies32. For monitoring hematological and liver toxicity of immunosuppressants, blood count and liver biochemistry is recommended at one to three month

intervalsB

33. In patients treated with cyclophosphamide, active monitoring of bladder cancer is recommended by urinalysis to detect microscopic hematuria. Thismonitoring should not be discontinued after treatment discontinuation

B

34. Thiopurine methyltransferase enzyme activity or its polymorphisms should be determined before treatment with azathioprine D

Indication of therapeutic apheresis35. Apheresis is not recommended as first or second line therapy in general SLE or lupus nephritis A36. In severe cases refractory to other treatments, using plasmapheresis individually should be considered C

Prevention of disease reactivation37. Prolonged antimalarial therapy is recommended, even during pregnancy, to prevent SLE reactivation A38. Due to the unfavorable balance between the beneficial effect reported and the potential toxicity associated with excess glucocorticoid therapy,

preventive administration of prednisone is not recommended for patients with serological activity without associated clinical manifestationsA

39. Patients with serologically active and clinically quiescent lupus are not recommended to undergo immunosuppressive therapy to prevent outbreaksbeyond their baseline treatment or remission maintenance therapy of lupus nephritis

B

40. Although vitamin D supplementation is not recommended with the sole aim of preventing activity outbreaks, the vitamin D deficiency should becorrected due to its adverse effects on bone mass and asthenia (only to normalize levels), not discarding a beneficial effect in controlling lupus activity

C

41. In addition to its harmful impact on overall health, smoking is not recommended for its potential effect on lupus activity, particularly at skin level C

Treatment of associated astheniaRecommendation 40

42. Despite the effectiveness data arising from RCTs, the administration of belimumab is not recommended for the sole purpose of improving asthenia√

43. People with stable SLE should follow gradual home sessions of supervised aerobic exercise, due to its overall improvement effect on perceived healthstatus by patients

B

44. Psychoeducational support is recommended to improve knowledge and understanding of the disease, restructure beliefs, and improve coping skills,self-management and social support

B

RCT: randomized clinical trial; SLE: systemic lupus erythematosus.With gray background, key recommendation.

6 M.M. Trujillo-Martín et al. / Med Clin

Table 5Recommendations for lifestyle, photoprotection and training of patients.

Lifestyle Degree

Recommendation 41Recommendation 43

45. Overweight and physical inactivity is detrimentalin all SLE patients

C

46. Diet should be poor in saturated fat and richin omega-3 fatty acids in SLE patients

C

Photoprotection

47. Regular use of broad spectrum sunscreens with highsun protection factor is recommended, applieduniformly in all areas exposed in quantity of2 mg/cm2, 15–30 min before sun exposure andreapplied every 2 h and/or after immersion orsweating

A

48. SLE patients, particularly those with cutaneous lupusor reporting a history of photosensitivity, should besystematically informed and trained onphotoprotection measures, and the importance of usefor best control of their disease and for preventingemergence of other symptoms

√

Training patients

49. Educational programs should be structured andconducted from the department of nursing, aimedat SLE patients

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rug treatment aimed at improving the analytical parameters.57

or these reasons, expert groups have also pointed out similarbjectives in managing SLE.58 Other intermediate objectives arehe complete clinical response, disease stabilization and discontin-ation of immunosuppressive and steroidal therapy.39

ndications for treatment. Use of antimalarials11. The use of antimalarials indefinitely (preferably hydroxychloro-

uine [HCQ] for best safety) is recommended as the baseline treatmentf all SLE patients without contraindications for use (evidence 2++,ecommendation B).

Antimalarial treatment increases survival in SLE patients.59,60

pecifically, their use reduces the risk of outbreaks,59 irreversiblergan damage,59 severe infections,60 arterial and venoushrombosis59,61,62 and metabolic syndrome in SLE patients.63,64

hey also have a low frequency and severity of adverse effects.59

hloroquine toxicity is higher compared to HCQ, particularly inetina.59

12. Combined mepacrine and HCQ is suggested in patients withefractory lupus activity, especially cutaneous, due to the synergisticffects caused (evidence 3, recommendation D).

It has been reported that the addition of mepacrine to base-ine therapy (including HCQ) in subjects with active SLE despitetandard therapy reduces disease activity and prednisone dose.65,66

13. In patients with antimalarial-induced retinal toxicity, replacingCQ or chloroquine with mepacrine is suggested (evidence 3, recom-endation D).The risk of HCQ-induced retinal toxicity appears to increase rel-

vantly from cumulative dose of 1000 g.67 For mepacrine, however,etinal toxicity has not been reported.68 This drug has not been mar-eted in Spain but it can be obtained through hospital pharmaciess a foreign medication.

14. Monitoring retinal toxicity is suggested in patients treated withCQ or chloroquine. A baseline eye examination is recommended at

east during the first year of treatment and annually after 5 years of
reatment, although control should be started earlier in patients withacular disease from any other source or with additional risk factors
evidence 2++/2−/4, recommendation D).


Because of the risk of retinal toxicity associated with prolongeduse of HCQ and, mainly, with chloroquine,59 periodical monitoringof the potential retinal involvement is recommended. The rec-ommendation regarding the frequency of eye examinations arisefrom the most recent recommendations of the American Collegeof Ophthalmology.69 Among these recommendations, the follow-ing techniques of screening should be included: at least a sensitivetechnique such as spectral domain optical coherence tomography,retinal autofluorescence or multifocal electroretinography with anautomated visual field 10-2.69

Use of glucocorticoids15. Prednisone dose should not exceed 30 mg/day in patients with

lupus nephritis. The dose should be individualized (evidence 1−/2+,recommendation B).

Treatment with average doses of prednisone (≤30 mg/day)obtain a similar response rate to high-dose treatment in patientswith lupus nephritis,70–72 reducing the risk of adverse events. Long-term renal prognosis appears to be best in patients with lupusnephritis treated with average doses of prednisone (≤30 mg/day),pulses of methylprednisolone, HCQ and cyclophosphamide com-pared to patients treated with high doses of prednisone andcyclophosphamide.71 However the evidence supporting this state-ment is still low.

16. Prednisone dose should not exceed 30 mg/day in the remainingSLE manifestations. However, the dosage should be assessed individu-ally for each patient (recommendation

√).

This recommendation was carried out by consensus, from theevidence showing that glucocorticoid therapy increases the risk ofinfections regardless of the dosage70,73 and it is associated withirreversible damage,25,54–56 with no comparative data to supportthe higher effectiveness of high-dose compared to low-mid dosage.

17. In severe outbreaks, adjuvant therapy with methylprednisolonepulses is recommended (evidence 1+/1−, recommendation B).

The pulses of methylprednisolone improve short-term responsein patients with lupus activity.74,75 Pulses of methylprednisolonecombined with cyclophosphamide in induction therapy for lupusnephritis improves effectiveness of both drugs separately.76

18. Quick reduction of glucocorticoids (prednisone) to 5 mg/dayis recommended within 6 months, with full withdrawal as soon aspossible (evidence 2+/2++, recommendation C).

Glucocorticoid therapy is associated with irreversibledamage25,54–56 and it increases the risk of infections depending onthe dosage.70,73

19. If maintenance treatment is required, doses of prednisoneshould not exceed 5 mg/day (evidence 2+/2++, recommendation B).

There are data supporting that prednisone doses below5–6 mg/day do not cause an increased risk of clinically relevantirreversible damage,54,56 although the purpose is full suspension.

20. The use of pulses of methylprednisolone below 1000 mg hasbeen suggested. However, a specific dose cannot be recommended(recommendation

√).

Pulses of methylprednisolone do not cause serious adverseeffects and irreversible damage when used at doses below1000 mg/day.54,56 At higher doses they are associated withincreased risk of serious infection.74,77 With this evidence, assessedas low (1−/2−), it was only possible to formulate a recommenda-tion of good practice.

Using nonbiological immunosuppressants21. Intravenous cyclophosphamide is recommended as the first

immunosuppressant drug in the treatment of severe non-renal mani-festations (evidence 1+/1−, recommendation B).

prednisolone is better than glucocorticoids alone in the short- andlong-term neuropsychiatric SLE treatment and in reducing theirrelapses.78,79 Cyclophosphamide also improves functional class of

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he New York Heart Association scale and reduces systolic pul-onary artery pressure in patients with SLA-associated pulmonary

rterial hypertension.80 This recommendation is also supported bysystematic review of the evidence.81

22. Methotrexate is recommended as the first immunosuppressantrug in the treatment of non-renal SLE with moderate activity, particu-

arly in skin and joint manifestations (evidence 1++, recommendation).

In subjects with extrarenal lupus activity, despite standardreatment, the combination with methotrexate (7.5–20 mg/week)educes the overall, joint and skin activity of the disease in thehort/medium term (6/12 months) with a glucocorticoid sparingffect.82,83

23. The use of immunosuppressants such as azathioprine,yclosporine A, leflunomide or mycophenolate is recommended aslternatives to the treatment of non-renal SLE (recommendation

√).

The association of azathioprine with prednisone might reducehe relapse rate in people with serious SLE.84 In patients withenal and/or non-renal activity refractory to glucocorticoids or inlucocorticoid-dependent patients, the addition of cyclosporin Aay reduce the activity and induce remission of the disease in the

hort term. Treatment with cyclosporine A is no less effective thanzathioprine and both drugs have a similar glucocorticoid sparingffect in the medium term.84 The addition of cyclosporin A has alsohown a glucocorticoid sparing effect in the long term.85 In patientsith mild to moderate activity despite prednisone, leflunomide isore effective than placebo in reducing disease activity in the short

erm.86

se of biological treatments24. Belimumab is recommended in subjects with active SLE with no

enal or neurological involvement not responding to standard treat-ent (evidence 1++/1+, recommendation).

This recommendation is based on evidence from randomizedlinical trials (RCTs) that prove that belimumab is effective in indi-iduals with active SLE not responding to standard treatment.87,88

elimumab has shown particular effectiveness in treating SLE mus-uloskeletal and cutaneous manifestations.89

25. Candidates for treatment with belimumab are subjects withctive SLE and lack of response after at least 3 months of treat-ent, including anti-malarial and prednisone therapy and at least

ne immunosuppressant at suitable dose. Or, when requiring pred-isone at 7.5 mg/day of higher to maintain remission despite the usef antimalarial and, at least, an immunosuppressant. Or with theontraindication of immunosuppressants (evidence 2++, B recom-endation).There is sufficient evidence to recommend, as candidates for

reatment with belimumab, SLE patients not responding to a com-rehensive therapy with antimalarials, prednisone and, at least,n immunosuppressant at suitable dose. However, the data areore limited over the time that must elapse to consider that the

tandard treatment has failed. The GDG recommends at least 3onths. Candidates can also be patients requiring prednisone (or

quivalent glucocorticoid dose) at 7.5 mg/day doses or higher toaintain remission (given the risk of damage associated with dosesaintained above this limit), despite being concomitantly receiving

ntimalarials and at least one immunosuppressant. Finally, can-idates may also be SLE patients with a contraindication to use

mmunosuppressants.90

26. Rituximab is recommended in patients with renal, neurologicalr severe hematologic disorders not responding to first-line immuno-uppressive therapy (evidence 2+, recommendation C).

91–94
Based on observational studies, rituximab appears to beffective in people with active SLE refractory to standard immuno-uppressive therapy, including severe renal and neurologicalisorders, although in the 2 RCTs conducted to date (in active SLE
(Barc). 2016;xxx(xx):xxx–xxx 7

without renal or CNS disorders and in lupus nephritis) the primarypurposes have not been reached.95–97

27. Today, there is no approved indication for the use of other bio-logical agents in SLE. However, when they have failed or the usualtherapeutic measures cannot be used (including belimumab and rit-uximab), the following could be considered: infliximab (in refractoryarthritis and nephritis), etanercept (arthritis and serositis), abatacept(especially in arthritis) and tocilizumab (deficient control of clinicalactivity) (recommendation

√).

Infliximab has been shown to have some effectiveness in lupuspatients with refractory nephritis and arthritis, but with a nar-row margin of safety.98 Etanercept was effective in patients withrefractory arthritis and serositis without serious adverse effects inthe short-term without worsening of renal activity.99 Abataceptmight be effective in lupus arthritis.95 Tocilizumab has shown somebenefits in the control of SLE clinical activity.100 All these studiesevaluating these drugs individually, present a very high risk of bias(evidence 1−/2−/3). Therefore, the GDG decided that this recom-mendation should be for good practice. This recommendation ofgood practice is in line with the proposals in the Consensus of theSpanish Society of Rheumatology on the use of biologic therapy inSLE.39

Use of immunoglobulins28. The use of intravenous immunoglobulins is justified in severe

immune thrombocytopenia with life threatening risk for active bleed-ing or when surgery or a bleeding-risk procedure is required (evidence3, recommendation D).

Intravenous immunoglobulins can be effective in patients withSLE-associated severe thrombocytopenia, being potentially use-ful in situations of active bleeding by their rapid onset of action,although their effects are transient in most cases.101

29. The risk of toxicity associated with immunoglobulin should bereduced, considering in each case the balance between risks and ben-efits, and also controlling the rate of infusion, avoiding compoundswith high sucrose content and previously discarding immunoglobulinA deficiency. Ensuring hydration and considering thromboprophylaxiswith heparin is recommended, to prevent the risk of thrombosis. Inpatients at risk of renal failure associated, monitoring of renal functionis suggested in the days following the infusion (evidence 4, recom-mendation D).

The risks inherent to the indication and administration ofintravenous immunoglobulin can be reduced if the risk factorsassociated with potential adverse effects are considered and if pre-ventive measures are used to improve the safety of intravenousadministration.102

30. The intravenous immunoglobulins may be used in people withhigh organ activity and involvement, highest in the presence of orsuspected serious infection substantially limiting or contraindicatingimmunosuppressive therapy at 0.4 g/kg/day doses for 5 consecutivedays. Lower doses (e.g. 0.5 g/kg one day) can also be effective, exceptwith thrombocytopenia (recommendation

√).

The use of intravenous immunoglobulins is not associatedwith an increased risk of acute infection103,104 having shown anacceptable safety profile when used in patients with active SLE orblood disorders103–105 and they can be effective as maintenancetreatment in lupus nephritis.106,107 This evidence, however, wasassessed as high risk of bias (1−/2−) which justified the recom-mendation was on good practice.

31. No intravenous immunoglobulin is recommended in themaintenance therapy of any of the SLE manifestations sincemore effective and lower cost alternative therapies are available√
(recommendation ).
Despite the evidence on the potential effectiveness of intra-venous immunoglobulin in the maintenance therapy in lupusnephritis and because of its acceptable level of safety, the panel

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f experts stresses they should not be used in the maintenance ofny SLE manifestations, since best cost-effective ratio alternativesre available.106,107

dverse effects and monitoring guidelines of biological and immuno-uppressive therapies. 32. For monitoring hematological and liveroxicity of immunosuppressants, blood count and liver biochemistrys recommended at one to three month intervals (evidence 1++, rec-mmendation B).

This recommendation is based on a systematic review of recom-endations for monitoring the drugs commonly used in SLE81 that,

ccording to its authors, is based on the opinion of expert groups.33. In patients treated with cyclophosphamide, active monitoring

f bladder cancer is recommended by urinalysis to detect microscopicematuria. This monitoring should not cease after treatment discon-inuation (evidence 1+, recommendation B).

A systematic review concluded that cyclophosphamide isssociated with cumulative damage, development of cervi-al intraepithelial neoplasia, urothelial neoplasms and ovarianailure.108 In the treatment of lupus nephritis, mycophenolate

ofetil has a better safety profile compared to oral or intravenousyclophosphamide. In the absence of data, the GDG has not beenositioned on specific screening recommendations for cervical can-er in women undergoing immunosuppressive therapy, other thanhose recommended in the general population.17,109

34. Determining the thiopurine methyltransferase enzyme activityr its polymorphisms is recommended before treatment with azathio-rine (evidence 2+, recommendation D).

There is poor evidence that reducing the thiopurine methyl-ransferase enzyme activity is associated with an increased riskf serious adverse effects in homozygous patients treated withzathioprine.110

ndication of the therapeutic apheresis.

35. Apheresis as first or second line therapy is not recommendedither in people with general SLE or with lupus nephritis (evidence++ to 2+, recommendation A).

Although treatment with extracorporeal immunoadsorption is aorm of safe and effective apheresis for reducing proteinuria,111 C3,4 levels112 and the circulating immune complexes,113 the avail-ble studies do not show that the addition of other plasmapheresisrocedures to traditional therapies improve the course of mildLE or lupus nephritis.112,114,115 In addition, other studies reporthigher frequency of life-threatening infections in SLE patients

reated with plasmapheresis (in addition to treatment with pred-isone plus cyclophosphamide).116 However, these data are notonsistent in the literature.117

36. In severe cases refractory to other treatments, using plasma-heresis individually should be considered (evidence 1+ to 2+,ecommendation C).

Therapeutic apheresis may be an additional option in the treat-ent of severe SLE. The choice of treatment with plasmapheresis

hould be individualized depending on the patient’s conditions,he experience of the center and financial aspects.118,119 Synchro-izing therapy with plasmapheresis might be useful in inducingemission in patients with proliferative lupus nephritis,111,120 andn decreasing SLE clinical activity.121–124

revention of disease reactivation.

37. Prolonged antimalarial treatment is recommended, even duringregnancy, to prevent SLE reactivation (evidence 1++ to 2++, recom-
endation A).Antimalarials reduce the risk of no serious outbreaks and, possi-
ly, the risk of serious outbreaks in SLE patients, including pregnantomen.59,125,126 Low blood levels of HCQ are associated with a


higher likelihood of having a lupus outbreak.127 In the GDG’s opin-ion, this recommendation, despite being strong, should be subjectto a process of shared decision making between the professionaland the pregnant woman.

38. Due to the unfavorable balance between the beneficial effectobserved and the potential toxicity associated with excess gluco-corticoid therapy, preventive administration of prednisone is notrecommended for patients with serologic activity without associatedclinical manifestations (evidence 1++ to 2++, recommendation A).

Therapy with medium-dose prednisone prevents short-term outbreaks associated with significant increased anti-dsDNA antibodies, with a significant difference even in seriousoutbreaks.128,129 However, GDG does not recommend preventiveuse since it causes increased cumulative dose of prednisone withan unfavorable benefit/risk ratio.128,129

39. Patients with lupus and serologically active clinically quies-cent are not recommended to undergo immunosuppressive therapyto prevent outbreaks beyond their baseline treatment or remissionmaintenance therapy of lupus nephritis (evidence 2++, B recommen-dation).

The clinical course of clinically quiescent and serologically activepatients is usually benign. Therefore, preventive treatment withimmunosuppressants is not recommended.57

40. Although vitamin D supplementation is not recommended withthe sole aim of preventing activity outbreaks, vitamin D deficiencyshould be corrected due to its adverse effects on bone mass and asthe-nia (only to normalize levels), not discarding a beneficial effect incontrolling lupus activity (evidence 2+, recommendation C).

While the levels of 25-OH vitamin D and lupus activity appearto be related,36,130 it has not been shown that supplementationwith vitamin D3 in deficient patients results in a clinically relevantSLE activity reduction.36,131 Although some clinical observationssuggest it, there is no consistent evidence on the effectiveness ofvitamin D to improve asthenia.131,132

41. In addition to its harmful impact on overall health, smoking isnot recommended for its potential effect on lupus activity, particularlyat skin level (evidence 2+ to 2−, recommendation C).

While relation between smoking and SLE systemic activity isnot well defined,133,134 scientific evidence shows an associationbetween smoking and increased activity and severity of lupus skinlesions.135 Moreover, tobacco use interferes with the therapeuticeffect of antimalarials on cutaneous lupus.135,136

Treatment of systemic lupus erythematosus-associated asthenia. Inthis section, in addition to recommendation 40 on supplemen-tation with vitamin D mentioned in the previous section to preventreactivation of the disease, the following recommendations areadded:

42. Despite the effectiveness data arising from RCTs, the admin-istration of belimumab is not recommended for the sole purpose ofimproving asthenia (recommendation

√).

The evidence available on using belimumab with standardtreatment at 1 and 10 mg/kg doses versus placebo with standardtreatment suggests that belimumab marginally reduces astheniabut with a high cost.88

43. People with stable SLE should follow gradual home sessions ofsupervised aerobic exercise, due to its overall improvement effect onperceived health status by patients (evidence 1+ to 2++, recommen-dation B).

Supervised aerobic exercise in people with stable SLE does not
worsen disease activity and appears to improve health, vitality andphysical capacity.137 To improve physical capacity in SLE patients,some degree of professional supervision is required in the designand implementation of physical exercise programs.138

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44. Psychoeducational support is recommended to improve knowl-dge and understanding of the disease, restructure beliefs, and improveoping skills, self-management and social support (evidence 2++, Becommendation).

Psychoeducational interventions based on cognitive, personalr telephone treatment, can reduce asthenia and improve socialupport among patients receiving family support, also improv-ng self-effectiveness in managing the disease. Interventions tomprove SLE knowledge and understanding, beliefs, coping skillsnd social support as well as stress management programs andctivities of expressive writing resulted in favorable health andppeared to reduce the asthenia levels in the short-mediumerm.139

ifestyleThis section, in addition to the 41st recommendation (on

hether or not to quit smoking) and 43rd recommendation (forromoting supervised aerobic exercise) already included in a pre-ious section, the following are added:

45. Overweight and physical inactivity is detrimental in all SLEatients (evidence 1+ to 3, recommendation C).

Low physical activity and sedentary lifestyle in people withLE are associated with increased subclinical atherosclerosis andnflammatory and cardiovascular risk markers.140,141 The evidencen the effect of exercise on anxiety, depression and pain is contra-ictory. No detrimental effect has been reported in these areas.

46. Diet should be poor in saturated fat and rich in omega-3 fattycids in SLE patients (evidence 1+ to 3, recommendation C).

Consumption of omega-3 EPA and DHA has a positive effect onisease activity in the short term.142–145 Currently, the effects onardiovascular disease in SLE patients are unknown.

hotoprotection47. Regular use of broad spectrum sunscreens with high sun pro-

ection factor is recommended, applied uniformly in all areas exposedn quantity of 2 mg/cm2, 15–30 min before sun exposure and reap-lied every 2 h and/or after immersion or sweating (evidence 1++ torecommendation A).

Most people with SLE have some degree ofhotosensitivity.146–148 Regular use of topical sunscreen is asso-iated with reduced renal impairment, lower thrombocytopenia,ewer hospitalizations and fewer treatments with cyclophos-hamide. Therefore, the use of sunscreen improves SLE prognosis,educing the risk of kidney damage and the need for immunosup-ressive therapy.149 In addition to photosensitivity, after a brieferiod of exposure to sunlight, certain clinical manifestations suchs fatigue, arthralgias, fever, etc. may occur.148 Broad-spectrumunscreens show high effectivenesss in preventing skin lesions inLE patients.150

48. SLE patients, particularly those with cutaneous lupus or repor-ing a history of photosensitivity, should be systematically informednd trained on photoprotection measures, and the importance of useor best control of their disease and for preventing emergence of otherymptoms (recommendation

√).

Despite the lack of available scientific evidence on the effec-iveness of specific educational programs on photoprotection, thisecommendation of good practice was adopted by consensus inhe group of experts, from the evidence on the deleterious effect ofxacerbation of SLE symptoms after exposure to both sunlight anduorescent light, particularly in those patients showing photosen-itivity and/or SLE skin manifestations.151

raining for patients49. Educational programs should be structured and conducted from

he department of nursing, aimed at SLE patients (evidence 1+/1−/2−,ecommendation C).


Structured educational programs aimed at SLE patients areeffective in reducing asthenia, depression and improving man-agement and self-efficacy skills in these patients.152,153 Thepsychological status of SLE patients, physical function and socialsupport might improve significantly through interventions of tele-phone counseling focused on patients.154,155 Psychoeducationalgroup intervention might improve mental health outcomes in SLEpatients.156

Discussion

The 49 recommendations for the overall management of SLEincluded in the CPG-SLE, promoted by the Ministry of Health, SocialServices and Equality through the Spanish Network of Agencies forHealth Technology Assessment and benefits of NHS and GuiaSalud,address the most relevant aspects for the overall management androutine clinical management of SLE patients, including recommen-dations to standardize and improve the quality of clinical careand monitoring and general therapeutic approach; accompaniedby educational recommendations to improve skills and trainingpatients about their lifestyles. These recommendations are framedin 3 general principles.

In accordance with the first, the CPG-SLE has been intended asa reference tool to support comprehensive clinical managementof SLE patients by all health professionals involved, regardless oftheir specialty and level of care in Spain, helping to standardizeand improve the quality of clinical decisions in our environmentwith the purpose of improving health outcomes for the patientsinvolved.

In accordance with the second general principle, the CPG-SLE isa tool that contributes to patient-focused care. For this reason, SLEpatients have been represented at all stages of its development. TheCPG-SLE promotes informed and shared decision-making betweenprofessionals and patients, particularly in recommendations sub-ject to greater uncertainty, where the balance between benefits andrisks is not clear enough, or when there are different alternativesof similar effectiveness and safety. To facilitate this process moreeffectively, the CPG-SLE includes a material for patients, summarydocument drafted in more general terms and simple language,available on the website of GuiaSalud (www.guiasalud.com). Itwill be distributed to all associations of SLE patients throughFELUPUS.

Finally, the CPG-SLE is based on the principles of Evidence BasedMedicine and on the expert consensus methodology. Based uponthis principle, the CPG-SLE includes recommendations both on“what should be done” as on “what should not be done. “Thus, 8recommendations, numbers 10, 28, 32, 36, 39, 40, 41 and 48 explic-itly describe the clinical practices that should not take place basedon the scientific knowledge available today. A significant number ofthe recommendations are based on a limited volume of moderate-quality studies published, reflecting the current knowledge on SLEand highlighting the need for more research and more scientificvalidity. Consequently, most recommendations are based on mod-erate levels of evidence, and a significant number of them weredeveloped from expert judgment. Despite these limitations, theCPG-SLE is based on the most ambitious, inclusive and updatedscientific knowledge instrument available internationally.6–8

While the development of the CPG-SLE has been focused oneffectiveness and safety criteria due to the limited availabilityof cost-benefit studies, economic issues have also been taken
into account. Some recommendations have been assessed glob-ally (proven benefits/potential risks/costs), taking into accountboth the needs of patients and the sustainability of the healthsystem.
http://www.guiasalud.com/

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10. Grupo de trabajo sobre GPC. Elaboración de Guías de Práctica Clínica en elSistema Nacional de Salud. Manual Metodológico. Madrid: Plan Nacional para

0 M.M. Trujillo-Martín et al. / Me

The concern of the GDG for all aspects related to safety or tox-city is collected in the 11 recommendations specifically focusedn this aspect, which emphasize on both the episodic use of cor-icosteroids, such as maximum doses of prednisone at or below0 mg/day (for nephritis or other SLE manifestations), and on theapid reductions and maintenance doses below 5 mg/day. Similarly,ecommendations for appropriate use of antimalarials, immuno-uppressants and immunoglobulins include contents to improveatient safety.

The GDG indicated 20 of the 49 recommendations as key orriority. The CPG-SLE recommends the use of antimalarials indef-

nitely (preferably HCQ for best safety) as baseline treatment ofll SLE patients (recommendation Nr. 15) and limits the recom-endation of biological therapies to therapy with belimumab or

ituximab, when no response to the standard strategy (recommen-ations 25–28).

The challenge CPG-SLE is facing now is implementation in theHS. To this purpose, it must develop effective and cost-effective

trategies for dissemination.157 This challenge is especially com-lex in the case of SLE because it is a multisystem disease thatequires the intervention of a large group of health profession-ls and medical specialties. Recognition of the changing role ofatients who take an increasingly active and participatory role

n their interaction with health professionals,158 allow the use ofew implementation strategies. However, the PCGs have difficul-ies in obtaining a satisfactory degree of implementation.159,160 Toontribute to the implementation of the CPG-SLE, part of GDG isorking on its transformation into a computerized tool to helpecision-making, included in the electronic medical records.

Finally, the CPG-SLE should be reviewed and updated continu-usly within approximately 2–3 years.

unding

This work has been conducted under the collaboration agree-ent signed by the Institute of Health Carlos III, an autonomous

gency of the Ministry of Economy and Competitiveness, and theanary Islands Health Service, under the development of activitiesf the Spanish Network of Agencies on Health Technology and NHSssessment, funded by the Ministry of Health, Social Services andquality.

onflict of interests

The authors declare no conflict of interest with the subject mat-er or materials discussed in this manuscript.

cknowledgements

We thank Leticia Cuellar Pompa, documentarian, for the litera-ure search and the 29 reviewers of the literature that collaboratedn the development of the PCG. We would also like to thankhe following experts who conducted a thorough review of allecommendations and formed, along with the clinicians of theCG, the panel consensus for the recommendations on goodlinical practice: Loreto Carmona Otels (Instituto de Salud Mus-uloesquelética, Madrid), María Paz Carrillo Badillo (Hospitalirgen de las Nieves, Granada), Ricard Cervera Segura (Hospitallinic, Barcelona), Antonio Fernández-Nebro (Hospital Carlos Haya,
álaga), María Galindo Izquierdo (Hospital 12 de Octubre, Madrid),
uan Jiménez Alonso (Hospital Virgen de las Nieves, Granada),rancisco Javier López Longo (Hospital Gregorio Maranón, Madrid)nd María Prieto Blanco (Basque Health Service, Vitoria-Gasteiz).


Annex. Remaining members of the development groupof the CPG-SLE

Jaime Calvo Alén Rheumatology Service, HospitalSierrallana, Cantabria, Spain

Isidro Jarque Ramos Service of Hematology, La FeUniversity and Polytechnic Hospital,Valencia, Spain

M. Teresa Martínez Ibánez Teaching Unit of Family andCommunity Medicine, Gran Canaria,Spain

Pritti M. Melwani Department of Dermatology, HospitalUniversitario Insular de Gran Canaria,Las Palmas, Spain

Noemí Martínez López de Castro Hospital Pharmacy Department,Hospital Meixoeiro, HospitalUniversitario de Vigo, Vigo, Spain

M. José Cuadrado Lozano Rheumatology Department, SaintThomas Hospital, London

Miguel Ángel Frutos Sanz Nephrology Department, HospitalCarlos Haya, Malaga, Spain

M. Adoración Martín Gómez Nephrology Department, Hospital delPoniente, Almería, Malaga, Spain

Silvia García Díaz Rheumatology Department, HospitalMoises Broggi, Barcelona, Spain

Inmaculada Alarcón Torres Department of Clinical Analysis,Section of Autoimmunity, UniversityHospital of Gran Canaria Dr. Negrin, LasPalmas, Spain

Pilar Pazos Casal Spanish Federation of Lupus(FELUPUS), Galicia, Spain

Tasmania M. del Pino-Sedeno Canary Foundation for theAdvancement on Biomedicine andBiotechnology (BIOAVANCE), CanaryIslands, Spain

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Documents

Clinical practice guidelines for systemic lupus