Comment on: Fanouriakis A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78:736-45.
Commented by: Nathalie Costedoat-Chalumeau, Internal Medicine Department, Cochin Hospital, Referral center for rare autoimmune and systemic diseases, Paris, France.
The 2008 EULAR recommendations for the management of systemic lupus erythematosus (SLE) have been updated in 2019 , using a classical methodology (systematic literature review, followed by modified Delphi method to form questions, elicit expert opinions and reach consensus).
Here we summarize and discuss the main points.
In the overarching principles, the authors remind us that the diagnosis of SLE is clinical and should not focus exclusively on evidence of serological autoimmunity (antinuclear and more specific autoantibodies). They encourage the use of validated disease activity and chronicity indices, including physician global assessment (PGA) and the multidisciplinary management especially when multiple organs are involved. The importance of preventing SLE flares and of achieving remission or, if not feasible, low disease activity (see comment of article by Laurent Arnaud) is emphasized. More specifically, they also recommend assessing renal response via the reduction of proteinuria (that should be less than 0.8 g/day at 1 year) but not via residual haematuria.
Regarding the treatment, the difference compare to the 2008 recommendations could be summarized as “more Hydroxychloroquine (HCQ) and less steroids”.
Indeed, the authors first state that HCQ is recommended in all patients with lupus. They also wrote that the dose should not exceed 5 mg/kg/day. Interestingly, 3 out of the 4 published correspondence following these recommendations [2-4] focused on this specific statement (the other discussing the definition of remission ).
- Figueroa-Parra et al. emphasized that chloroquine (CQ) should also have been mentioned as a major treatment in SLE . Indeed, even though HCQ may have fewer side effects and has replaced CQ in many countries, CQ remains an alternative when HCQ is not available (or not affordable).
- Michaud et al discussed the multiple benefits of antimalarial therapy and concluded that HCQ is still in 2019, the cornerstone of the treatment of SLE .
- While we could not agree more on the fact that HCQ should be used in all SLE patients, with David Isenberg and Michelle Petri , we wrote that we disagree on the recommended daily dose of 5 mg/kg that is based on what we believe to be a misinterpretation of an ophthalmological study by Melles and Marmor . Briefly, this study of 2500 patients was based on pharmacy refill information meaning that their estimates represent actual HCQ intake (by the patient) rather than prescribed dose (by the physician). Because 100% adherent patients are rare, the gap between both doses may be very important [7, 8]. It is thus difficult to recommend a maximum dose of 5 mg/kg without specifying that it refers to the true intake and in reality, means that we just need to prescribe the same dose as the one we have been using for decades. By the way, the revised recommendations on screening for HCQ retinopathy published in 2016 clearly state that because of varying adherence, 5.0 mg of HCQ/kg used corresponds with present medical prescription practices  meaning that we do not need to lower the dose of HCQ we prescribe.
- Due to irreversible damage they may cause, oral steroids should be avoided or if needed, used at a daily dose ≤7.5 mg/day prednisone equivalent. In this setting, the interest of rapid non- genomic effects of pulses of intravenous methylprednisolone (MP) is emphasized .
- Immunosuppressive (IS) drugs are another means to avoid or decrease steroids, especially methotrexate, azathioprine and mycophenolate mofetil. When cyclophosphamide is used (preferably low-dose CYC -Euro-Lupus regimen, for renal manifestation), concomitant use of GnRH analogues is recommended in premenopausal patients. This means that it should be offered not only in those who may wish to become pregnant in the future but in all patents not yet menopaused since avoiding premature ovarian insufficiency has other advantages (bones etc). Information about the possibility of ovarian cryopreservation should be offered when appropriate.
- Finally, belimumab should be considered in extrarenal disease with inadequate control to first-line treatments (typically including combination of HCQ and prednisone with or without IS agents), and inability to taper steroids daily dose below 7.5 mg/day, especially in case of serological activity (low C3/C4, high antidsDNA titres).
In our experience, such cases are very rare once we make sure patients are adherent to the treatment. In this setting, it is stated that HCQ blood levels can be used to assess adherence, but that data are currently insufficient to recommend routine monitoring of drug levels. Of note, such monitoring is considered essential in French recommendations on SLE management  since it is often very difficult to diagnose severe non adherence without it . Finally, rituximab should be considered in patients with thrombocytopenia or autoimmune haemolytic anaemia with no response to steroids or relapses.
- The importance of attributing neuropsychiatric manifestations to SLE as opposed to non-SLE-related neuropsychiatric manifestations, is emphasized. Of note, this is especially true for antiphospholipid syndrome manifestations that require a completely different treatment than SLE.
- The importance of repeat biopsy in case of incomplete renal response (persistent proteinuria >0.8–1 g/24 hours after at least 1 year) to distinguish chronic from active kidney lesions is also emphasized.
Finally, the authors remind us that optimal management also includes:
- UV protection,
- cessation of smoking,
- proteinuria monitoring (at least every 3 months in patients at high risk of developing renal involvement: males, juvenile lupus onset, serologically active including positivity for anti-C1q antibodies),
- low-dose aspirin in patients with antiphospholipid antibodies (aPL), at least in those carrying a high risk aPL profile (ie, triple aPL positivity, lupus anticoagulant or high titres of anticardiolipin antibodies)
- prevention of infections with immunizations at least against seasonal influenza and pneumococcal infection (both PCV13 and PPSV23)
- Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78:736-45.
- Figueroa-Parra G, Gamboa-Alonso CM, De-Leon-Ibarra AL, Galarza-Delgado DA. 2019 update of the EULAR recommendations for the management of SLE: don’t forget chloroquine. Ann Rheum Dis 2019.
- Michaud M, Catros F, Ancellin S, Gaches F. Treatment of systemic lupus erythematosus: don’t forget hydroxychloroquine. Ann Rheum Dis 2019.
- Costedoat-Chalumeau N, Isenberg D, Petri M. Letter in response to the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis et al. Ann Rheum Dis 2019.
- Rua Figueroa I, Erausquin C. Concerns about the operational definition of remission in 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019.
- Melles RB, Marmor MF. The Risk of Toxic Retinopathy in Patients on Long-term Hydroxychloroquine Therapy. JAMA Ophthalmol 2014;132:1453-60.
- Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, Le Guern V, Leroux G, Marra D, et al. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol 2013;27:329-40
- Feldman CH, Collins J, Zhang Z, Subramanian SV, Solomon DH, Kawachi I, et al. Dynamic patterns and predictors of hydroxychloroquine nonadherence among Medicaid beneficiaries with systemic lupus erythematosus. Semin Arthritis Rheum 2018;48:205-13.
- Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology 2016;123:1386-94.
- Ruiz-Irastorza G, Ugarte A, Saint-Pastou Terrier C, Lazaro E, Iza A, Couzi L, et al. Repeated pulses of methyl-prednisolone with reduced doses of prednisone improve the outcome of class III, IV and V lupus nephritis: An observational comparative study of the Lupus-Cruces and lupus-Bordeaux cohorts. Autoimmun Rev 2017;16:826-32.
- Protocole National de Diagnostic et de Soins (PNDS) Lupus systémique, 2017. https://www.has-sante.fr/upload/docs/application/pdf/2017-03/dir1/pnds_-%20_lupus_systemique.pdf.
- Costedoat-Chalumeau N, Houssiau F, Izmirly P, Guern VL, Navarra S, Jolly M, et al. A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self-Administered Questionnaires. Clin Pharmacol Ther 2018