Question 1:

Is your patient showing ongoing lupus disease activity in an organ, despite applying the recommended treatment approach for the severity of disease?

Periods of increased disease activity can increase the risk of organ damage in patients with SLE [11]; this highlights the importance of regular treatment reviews to identify patients in need of therapy adjustments to work toward these treatment goals and improve patient outcomes. The European Alliance of Associations for Rheumatology (EULAR) recommendations highlight the importance of formally assessing lupus disease activity at each patient visit, using validated measures such as variations of the SLE Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG), to determine the potential need for therapy alteration [12]. While these recommendations do not cover every manifestation of SLE, they provide treatment guidance across multiple SLE organ manifestations (skin, hematological, neuropsychiatric, and kidney) and recommend a multidisciplinary approach to SLE care [12]. In addition to these manifestations, physicians should be vigilant for any signs of disease activity in other organs, including rare manifestations such as myocarditis and lupus enteritis [13, 14]. Owing to the phenotypic heterogeneity and variable severity of organ involvement and response to therapy across patients with SLE, EULAR emphasizes the need for an individualized approach to disease management [12]. In patients with inadequate response to standard care, defined as residual disease activity that does not allow tapering of GCs and/or frequent relapses [15], EULAR and the Asia Pacific League of Associations for Rheumatology (APLAR) recommendations suggest considering the addition of traditional immunosuppressive agents, or belimumab [12, 16] or anifrolumab [12] where available. In patients with organ- or life-threatening disease, intravenously administered cyclophosphamide should be considered, or rituximab in refractory cases [12].

Question 2:

Has your patient been showing notable changes in or persistently abnormal laboratory values (hematology, renal, and serology) over the past 6 months?

Findings from previous studies have shown that changes in certain laboratory values, such as anti-double-stranded (ds)DNA and serum complement levels, may precede disease exacerbations in SLE [17]. In a study of the Milan SLE Consortium (SMiLE) cohort, patients with low complement and increased dsDNA binding at pre-flare evaluation had a higher 10-year risk of flare compared with patients with a fully negative serology [3], highlighting the importance of regularly monitoring serological markers in patients with SLE. Furthermore, EULAR recommendations emphasize the importance of increased awareness for new-onset kidney involvement owing to the profound prognostic repercussions associated with delayed lupus nephritis diagnosis [12]. Other laboratory values that should be monitored include hematological parameters. Changes in or persistently abnormal hematological values may indicate autoimmune hemolytic anemia or thrombocytopenia, both of which may be associated with increased disease activity [18,19,20] and, therefore, warrant a treatment review.

Conversely, improvements in laboratory values may indicate that the patient is a suitable candidate for treatment tapering; the EULAR recommendations recommend that in patients who have achieved sustained remission, gradual tapering of treatments should be considered, starting with GC withdrawal [12]. In a survey of 130 clinicians across 30 countries, 96.7% of clinicians preferred to reduce or withdraw GCs in patients who were serologically quiescent after 5 years of remission [21]. In patients with stable, serologically inactive disease, 92.4% of clinicians planned to reduce GCs and 17.8% planned to completely withdraw GCs at 1 year after a previous flare [21].

Question 3:

Has your patient sought urgent care (e.g., hospitalization or visit to the ED) owing to a flare/increased lupus activity since your last consultation?

Moderate flares may precede severe flares in the same organ or domain, which can result in irreversible organ damage and have detrimental consequences in patients with SLE [17]; this suggests that patients who are hospitalized or require urgent care as a result of a flare may carry a worse prognosis. Increased flare frequency is associated with worse patient outcomes, including increased hospitalizations, work productivity loss, and activity impairment; timely response with access to treatment options and implementation of preventive strategies may help to reduce the burden of disease [22]. EULAR recommendations from 2019 suggest that in patients with SLE flares, treatment should be reviewed and adapted according to the severity of organ(s) involvement by adjusting ongoing therapies (GCs, immunomodulating agents) to higher dosages, switching, or adding new therapies [15]. A flare can occur even in patients who have achieved a treatment target of remission or LLDAS [17]; therefore, it is important to closely monitor all patients and assess their risk of flare.

Question 4:

Has your patient been in persistent need of GC administration of more than 5 mg/day (prednisone equivalent) over the past 6 months?

There is a wealth of data demonstrating the adverse effects associated with long-term GC use, particularly at dosages > 5 mg/day (prednisone equivalent), including organ damage accrual, increased risk of infection, and death [12, 23, 24]. Owing to these detrimental effects, the EULAR and Pan-American League of Associations for Rheumatology (PANLAR) recommendations advise that, if clinically needed, GCs should be prescribed at the lowest possible dosage and for the shortest period of time [12, 25]. EULAR recommends that complete withdrawal of GCs should be the optimal target in SLE management [12], although this is often difficult to attain. In a multinational cohort study with 1850 patients with modified serologically active clinically quiescent SLE, tapering GCs by 1 mg/day was not associated with an increased risk of either overall or severe flare. Furthermore, tapering GCs in patients who were treated with > 5 mg/day was found to be protective against damage accrual [26]. In patients demonstrating an inadequate response to hydroxychloroquine (HCQ, either alone or combined with GCs) or those unable to reduce GCs below the acceptable chronic maintenance dosage (≤ 5 mg/day), treatment should be adjusted to include immunomodulating/immunosuppressive agents, such as methotrexate, azathioprine, or mycophenolate, and/or biologics [12]. While not all these treatment options may be available to everyone, owing to accessibility and cost issues, there may still be sufficient options to support the reduction of GC dosage across the globe. Guidance from EULAR and APLAR recommends that early administration/initiation of immunosuppressive or biological agents should be considered to control the disease and allow for lower GC dosages to be used [12, 16]. HCQ is recommended for all patients with SLE, unless contraindicated; patients withdrawing from GC use should continue HCQ therapy as a protective factor against disease relapse [12].

Question 5:

Is your patient experiencing difficulty with their current treatment regimen?

Q5A) Is your patient showing signs of concern around their therapy?

Q5B) Is your patient having difficulty tolerating the medication?

Q5C) Have your patient’s circumstances/preferences changed?

Given the heterogeneous and chronic nature of SLE, it is important to take an individualized and long-term approach to management and encourage shared decision-making, taking patient preferences into consideration when making treatment decisions [12]. This is highlighted in the recent EULAR recommendations, where it is suggested that treatment should be individualized to consider patient preferences, individual and societal costs, and patient education [12]. Significant discordance has been identified between patient and physician health concerns in SLE; patients’ greatest concerns focus mainly on HRQOL aspects, whereas physicians’ concerns focus primarily on organ manifestations [27]. In a survey of 4347 patients with SLE, 28.2% of patients felt their disease had not been under control in the previous 3 months, and 49.7% highlighted either a medium, high, or very high impact of disease on their work, family, and daily life [28]. Absence of clinical disease manifestations for ≥ 3 consecutive years may have a positive impact on the physical components of QOL and on minor depressive symptoms in patients with SLE [29]. However, even well-controlled disease is negatively associated with mental health, social functioning, fatigue, and perception of disease burden in patients with SLE [29]. This highlights the importance of incorporating the patient voice in treatment decisions to optimize QOL.

EULAR recommendations underline that adherence to treatment is essential to prevent flares and organ damage, improve prognosis, and enhance QOL [12]; this notwithstanding, poor treatment adherence is far from uncommon in SLE [8, 9]. Some patients with SLE feel that physicians consider laboratory test results more important than patient HRQOL, which can negatively affect mutual trust and result in subsequent non-adherence to medications [9]. EULAR recommendations state that a trusting relationship between physicians and patients forms the basis for the minimization of the risk of non-adherence [12]; addressing patients’ concerns about side effects and encouraging shared decision-making may improve the relationship between healthcare professionals and patients, thereby improving adherence [9]. In patients where cost is a barrier to adherence, recommendations advise that generic compounds are acceptable alternatives and may improve adherence [16]. It is also important to consider patient preferences and changes in circumstances when determining treatment options; for example, patients wishing to start a family will need to have their therapies reviewed owing to the fact that several therapies are contraindicated during pregnancy [30].