key: cord-0835568-uonndf6f
authors: Ruiz-Irastorza, Guillermo; Bertsias, George
title: Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs
date: 2020-12-05
journal: Rheumatology (Oxford)
DOI: 10.1093/rheumatology/keaa403
sha: b9ca99885baf6b65d4d2b8f3d6bf766643f0762e
doc_id: 835568
cord_uid: uonndf6f

Besides treating acute flares, the management of SLE should aim at preventing organ damage accrual and drug-associated harms, improving health-related quality of life and prolonging survival. At present, therapy is based on combinations of antimalarials (mainly HCQ), considered the backbone of SLE treatment, glucocorticoids and immunosuppressive drugs. However, these regimens are not universally effective and a substantial degree of damage can be caused by exposure to glucocorticoids. In this review we provide a critical appraisal of the efficacy and safety of available treatments as well as a brief discussion of potentially novel compounds in patients with SLE. We emphasize the use of methylprednisolone pulses for moderate–severe flares, followed by low–moderate doses of oral prednisone with quick tapering to maintenance doses of ≤5 mg/day, as well as the prompt institution of immunosuppressive drugs in the setting of severe disease but also as steroid-sparing agents. Indications for the use of biologic agents, namely belimumab and rituximab, in refractory or organ-threatening disease are also presented. We conclude by proposing evidence- and experience-based treatment strategies tailored to the clinical scenario and prevailing organ involvement that can aid clinicians in managing this complex disease.

SLE represents the prototype systemic autoimmune disease featuring remarkable clinical heterogeneity due to synchronous and non-synchronous involvement of several organs with variable severity. As a result, treatment of SLE poses significant challenges and is often based on clinical acumen. Nevertheless, in recent times a number of controlled trials and well-conducted observational studies have focused on novel treatments and also on the more efficient use of old, conventional drugs. In this review we summarize the existing evidence on traditional and more recently introduced therapeutic agents, including biologics, in patients with SLE, followed by our proposal for disease treatment according to the clinical scenario and severity of manifestations.

Antimalarials are among the oldest drugs for treating SLE [1] . Following empirical use for years, the Canadian Hydroxychloroquine Study demonstrated in 1991 the efficacy of HCQ in preventing lupus flares [2] . However, for many years the use of antimalarials was limited to

Rheumatology key messages . Hydroxychloroquine is the cornerstone of lupus therapy. . Methylprednisolone pulses followed by low-medium doses of prednisone rapidly control most moderatesevere flares. . Immunosuppressive drugs are indicated in the setting of severe disease and also as steroid-sparing agents.

patients with cutaneous and/or articular involvement, thus playing a marginal role in core lupus therapy [3] . This scenario has changed substantially during the last 10 years.

Two observational cohort studies published in 2006 [4] and 2007 [5] showed for the first time that antimalarials can reduce mortality in SLE patients by >50% (Table 1) . Both studies used propensity score-adjusted analysis, thus overcoming the confounding by indication bias. Indeed, subsequent studies have widely confirmed these results in various ethnic groups, including Latin American [6] and Chinese [7] populations.

Apart from the well-known effects of antimalarials on disease activity, improvement in long-term prognosis is mediated by a reduction in the risks of thrombosis, vascular disease and damage accrual [8] . A recent study from the Toronto Lupus Cohort showed that treatment with antimalarials for >60% of the time during the first 5 years of disease may reduce the number of flares, damage accrual and cumulative dose of glucocorticoids (GCs) [9] . In addition, protection against infections has been observed in several cohort studies [10] [11] [12] [13] . A reduced risk of cancer was already suggested in 2007 by an early study of the Lupus-Cruces cohort [14] . A 2017 British population-based study of patients with connective tissue diseases exposed and not exposed to HCQ did not find a reduced risk of developing cancer, however, the risk of metastases and death were significantly lower in the former group [15] . More recently, a large nested case-control study including >14 000 Chinese lupus patients has confirmed a protective, dose-dependent effect of HCQ against neoplastic diseases [16] .

Collectively, there is wide consensus in considering HCQ an essential drug for lupus. Recent consensus guidelines agree in recommending indefinite therapy with HCQ (unless contraindicated) for all SLE patients [17, 18] , including patients with LN [19, 20] and during pregnancy [21] . However, there is some controversy regarding the optimal dose, mostly due to concerns about retinal toxicity. Antimalarial toxicity HCQ can be considered a safe drug without serious toxicity risks in the majority of patients [8] . Minor side effects include gastric intolerance; rash; hyperpigmentation of the skin, nails and gums and aquagenic pruritus [8] . Cardiotoxicity, usually presenting as congestive heart failure and/or syncope, can rarely occur after prolonged therapy [22] . The potential prolongation of the QT interval by HCQ has recently gained attention in the context of antimalarial therapy of coronavirus disease 2019 pneumonia [23] . However, the actual risk is likely influenced by the age of the patient, concomitant therapy and the use of much higher doses than those administered in SLE. Moreover, studies focusing on lupus patients have not found a significant occurrence of QT prolongation [24] .

Maculopathy continues to be the most feared side effect of antimalarials. Definite retinal damage with some degree of visual loss is estimated to occur in $0.1% of SLE patients treated with antimalarials for >10 years [8] . Nevertheless, to detect early asymptomatic-but reversible-toxicity, the 2016 updated recommendations of the American College of Ophthalmology have advocated for the use of new monitoring techniques, such as automated visual fields and spectral-domain optical coherence tomography [25] . Although use !5 years and a cumulative dose of HCQ >1000 g were initially identified as the main risk factors for eye toxicity, new data point to a daily dose of HCQ >5 mg/kg (real body weight) as the principal predictor of maculopathy [26] . Renal insufficiency and concomitant therapy with tamoxifen further increase the risk for retinal damage [26] . A recent longitudinal study of 110 patients at 5 years of follow-up has revealed no new cases of eye toxicity or clinically relevant retinal thinning. Of note, 99% of patients received HCQ at a dose 5 mg/kg/day [27] .

Regarding the relationship between dose and efficacy, low blood levels of HCQ were identified in the early 2000s as a predictor of SLE flares [28] , although adapting the daily dose to measured blood levels did not result in better control of lupus activity [29] . On the other hand, measuring drug concentrations can be useful to monitor treatment adherence [30] , although the determination of blood levels of HCQ is not yet widely available. Despite the lack of comparative efficacy studies of doses ranging from 200 to 400 mg/day, it is worth noting that in the studies of the The role of mepacrine Mepacrine (also known as quinacrine) was the first antimalarial drug used in cutaneous lupus and later replaced by HCQ [31] . In case HCQ has to be stopped due to retinal damage, mepacrine is a good substitute. Besides replacing one for the other in the setting of toxicity, combining mepacrine with HCQ has shown a synergistic clinical effect in patients with refractory skin and/or articular disease [31] . Yellowish skin discolouration is the most prevalent side effect of mepacrine [31] . SLE. A number of serious complications such as osteonecrosis, osteoporosis, cardiovascular disease, infections and, in general, damage accrual and increased mortality have been consistently linked to GC exposure [32] . However, it has also become clear that GC-related toxicity is dose related, due to their biological effects.

GCs act by two distinct ways. The genomic way consists of two different processes, namely transrepression and transactivation [33] , and it is known that GC-related toxicity increases in parallel with anti-inflammatory potency as the genomic way becomes more activated [33] . GCs can also act by non-genomic mechanisms, which produce a rapid and potent anti-inflammatory action [34] .

Activation of both the genomic and non-genomic ways mostly depends on the dose of GCs received, independent of the patient's weight [35] . Doses 7.5 mg/ day of prednisone (low doses) saturate GC receptors by <50%. GC receptor saturation increases progressively with increasing doses: at 7.5-30 mg/day (medium doses), it is >50%. Almost complete saturation occurs at doses between 30 and 100 mg/day (high doses). No significant activation of the non-genomic way occurs up to this point. GC receptors are completely saturated at doses >100 mg/day (very high doses) and, in addition, meaningful activation of the non-genomic way starts at this point, reaching a maximum at 250-500 mg/day (pulse doses) [35] .

In clinical terms, low doses would have both low antiinflammatory potency and a low rate of adverse effects. At a prednisone dose >30 mg/day, genomic-dependent anti-inflammatory effects and toxicity would be close to maximum. When doses between 125 and 500 mg/day are given during a short period of time (pulse therapy), a rapid and very potent immunomodulatory action is obtained, with the potential for avoiding transrepression-/ transactivation-mediated toxicity [35] and the additional advantage of priming the mononuclear cells for the genomic effects of subsequent doses [34] . Of note, methylprednisolone has higher potency than prednisone with a more selective activation of the non-genomic way [36] .

Large observational studies support that GC-mediated toxicity is largely dependent on the dose and the time of exposure [7, [37] [38] [39] (Table 1 ). The limit for a 'safe' dose has not been firmly established and doses 7.5 mg/day (prednisone equivalent) are often recommended [18, 19] . However, it seems more prudent to use 5 mg/day in the long term [37, 38] , since GC-associated damage accrual can occur even at doses of 5-7.5 mg/day [38] . On the other hand, the use of doses in the range of full genomic activation, i.e. !30-40 mg/day, has been linked with the occurrence of osteonecrosis, infections and even death [32] . In terms of toxicity, pulses of methylprednisolone at doses 500 mg/day for 3 days seem virtually free of serious side effects, including infections and damage accrual [37, 39] .

Clinical trials and observational studies support that SLE, including severe forms such as LN, can be successfully treated with regimens including lower doses of oral prednisone, with maximum doses 30 mg/day followed by a rapid reduction over a few weeks to 2.5-5 mg/day [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] . Pulses of methylprednisolone combined with the early initiation of immunosuppressive drugs, not limited to patients with severe disease, and the universal use of HCQ may contribute to rapid and prolonged control of lupus activity [48, 49] accompanied by a reduction of not only GC-related damage, but also of cardiovascular and global damage [48] . In this context, the repeated use of pulses of methylprednisolone promote the achievement of complete remission in LN [44] and spares oral GCs [49] in observational studies. Doses of 5 mg/day seem a reasonably safe limit for long-term maintenance therapy [37, 38, 48, 49 ].

Despite limited randomized evidence, immunosuppressive agents such as MTX, AZA, mycophenolate and CYC are considered in SLE patients who respond inadequately to antimalarials and GCs (defined as any of persistent disease activity, relapses, inability to lower GC to <5 mg/day prednisone equivalent) and/or who develop organ-threatening disease (Table 2 ) [17, 18] . MTX is generally efficacious in controlling musculoskeletal, skin and serosal disease [50, 51], whereas AZA has been used to treat a wider spectrum of manifestations, including constitutional, vasculitis, haematological and neurological lupus [52, 53] . An open-label controlled study in active SLE patients showed that mycophenolate was superior to AZA, both administered in combination with moderate doses of oral GCs, in inducing remission and preventing flares, including new-onset kidney disease [54] . The two drugs differ in their safety profile (leucopenia being more common with AZA and gastrointestinal complaints being more common with MMF), and AZA is compatible with pregnancy. In addition, mycophenolate (mofetil or sodium) has been successfully used in the treatment of refractory or severe manifestations such as subacute cutaneous lupus, haemolytic anaemia, thrombocytopenia, vasculitis and neuropsychiatric and musculoskeletal diseases [55] . Due to safety concerns, especially increased risk for gonadal toxicity [56] and infections [57] , the use of high-dose CYC (i.v. pulses of 0.75-1 g/m 2 ) has been restricted to cases of major neuropsychiatric [58, 59] or life-threatening disease. In such cases, maintenance of the response can be achieved with either mycophenolate or AZA in combination with antimalarials and gradually tapered GCs. Finally, calcineurin inhibitors such as ciclosporin and tacrolimus, although infrequently used in non-renal SLE, can be useful in selected cases of refractory thrombocytopenia or during pregnancy [60, 61] .

Both the EULAR/ERA-EDTA [19] and the ACR [20] recommend either low-dose i.v. CYC (boluses of 500 mg, biweekly for a total six times) or mycophenolate (target dose 2-3 g/day of mofetil for 6 months) as first-line induction treatment of active proliferative LN. Both regimens have shown equivalent efficacy and more favourable toxicity profiles as compared with high-dose i.v. CYC [62] . Notably, the low-dose CYC regimen has minimal impact on ovarian reserve as assessed by the anti-Mü llerian hormone levels [63] . With regards to pure membranous (class V) LN, randomized evidence is limited [64] , but extrapolation from the proliferative nephritis trials supports the use of the same treatments. The aforementioned agents are recommended in combination with GCs, usually including pulses of i.v. methylprednisolone followed by oral prednisone at 20-30 mg/ day, depending on the severity of renal and extrarenal disease [19, 40, 41, 43, 44] .

Recently calcineurin inhibitors, especially tacrolimus and voclosporin, have gained attention as part of multitarget regimens in LN [45, 65] . Whether calcineurinbased regimens should become first-line treatment of active LN remains uncertain, as scepticism remains regarding their long-term efficacy and safety. Of note, the higher the starting level of proteinuria, the longer it may take to remit [66] .

Patients who manifest a sustained reduction in proteinuria with stabilization or improvement of their glomerular filtration rate can be switched to maintenance with either mycophenolate (especially if the same drug was used for induction or in more severe forms of LN) or AZA [17, 19, 20] . There is limited published evidence regarding the use of multitarget regimens [67] , whereas monotherapy with calcineurin inhibitors can be considered during pregnancy or when other options are unavailable or cannot be tolerated [68, 69] . The duration of treatment is individualized but generally lasts at least 3-5 years.

Belimumab Since 2011, belimumab, a monoclonal antibody targeting B cell activating factor (BAFF) has been approved as add-on therapy for active SLE not responding to conventional treatment. The effectiveness of belimumab over the standard of care has been demonstrated in four randomized controlled trials including patients of various ethnic backgrounds [70] [71] [72] . Clinical response rates [defined according to the 4-point Systemic Lupus Erythematosus Responder Index (SRI-4) composite index] were 50.6% in belimumab-treated vs 38.6% in placebo-treated patients, and the respective frequencies of a low disease activity state were 13.4% vs 6.8% [73] . Importantly, the addition of belimumab led to a significant reduction of severe flares, lower cumulative exposure to GCs [74] , lower accrual of irreversible organ damage [75, 76] and improved health-related quality of life [77] , which are all important aspects in the treatingto-target context [78] . These effects are maintained or even enhanced during prolonged use of the drug, although disease exacerbations can occur [79, 80] .

Post-hoc analysis of trial data has suggested that the therapeutic benefit of belimumab may be greater within subgroups of patients with high disease activity, abnormal serology (hypocomplementemia and/or high anti-dsDNA titres) or those receiving GCs [81, 82] . Nonetheless, the drug is effective also in serologically quiescent patients [83, 84] . On the other hand, smoking and existing organ damage have been associated with lower response rates [85, 86] . Better improvement is seen in musculoskeletal (except for severe arthritis) and mucocutaneous (especially acute and subacute cutaneous lupus) manifestations and serositis [84, 87] . Although belimumab has not been extensively evaluated in severe, organ-threatening disease, still it can be used to maintain the response induced by other agents, to prevent relapses and expedite GC tapering. Importantly, clinical practice and the long-term extension of randomized trials support a favourable safety profile of the drug with a relatively low incidence of serious and opportunistic infections, although monitoring serum immunoglobulin levels is advised [88] .

Driven by experimental evidence underscoring the role of BAFF in the formation of intrarenal germinal centre-like lymphoid structures [89] , as well as post-hoc analysis of the BLISS-52/76 trials suggesting possible anti-proteinuric effects of belimumab [90] , the compound has also been tested in patients with active LN. According to a press release [91] , belimumab plus standard therapy (CYC or mycophenolate, followed by AZA or mycophenolate, respectively) was superior to standard therapy alone in meeting the primary efficacy endpoint. The publication of these results will help define the indications for using belimumab in lupus kidney disease.

Two randomized controlled studies [92, 93] failed to demonstrate the superiority of rituximab (RTX; monoclonal anti-CD20 antibody causing the depletion of B cells) over the standard of care in the treatment of SLE and LN, possibly as a result of high background therapy and underpowered study design [94] . Nevertheless, observational studies support the drug's effectiveness in difficult-to-treat lupus, including severe joint, haematological, cutaneous, renal and neuropsychiatric disease [95] [96] [97] [98] . Approximately 65-80% of patients will respond at 3-9 months, with particularly high remission rates (61%) in immune cytopenias [99] . Relapses are not uncommon (25-40%) but can be successfully re-treated in 80% of patients. To this end, there is no definitive answer as to whether RTX should be administered repeatedly or 'on demand', although the former approach should be considered in recalcitrant cases [100] . Of note, concomitant use of immunosuppressives has been associated with a lower risk for secondary non-depletion non-response to RTX [97] . Finally, monitoring peripheral blood B cells is predictive of both treatment response and the risk for clinical relapse [97] . Other fully humanized anti-CD20 antibodies such as ofatumumab [101] and obinutuzumab have shown encouraging results and are currently being tested in SLE.

Potential indications and safety issues of belimumab and RTX in SLE are shown on Table 3 .

In a phase 3 randomized study, anifrolumab, a monoclonal antibody directed against type I IFN receptor, was shown to induce higher response rates (assessed by the BILAG-based combined lupus assessment index) as compared with the standard of care (47.8% vs 31.5%) in patients with SLE (excluding active renal and neurological disease) [102] . The drug was particularly effective in controlling cutaneous-but not joint-disease, prevented flares and allowed a reduction in the dose of GCs. In line with the pivotal role of type I IFN in antiviral immunity, zoster infections were increased in anifrolumab-vs placebo-treated patients (7.2% vs 1.1%) [102] . Notably, the effect size (active drug À placebo) was comparable to that observed in belimumab trials, although different response definitions were used. Additional real-world data will be needed to reconcile differences in the efficacy of these two biologics.

Janus kinase (JAK) inhibitors represent another promising class of agents in SLE, considering their capacity to suppress signalling from multiple cytokines, including type I IFN. Anecdotal experience suggests the efficacy of JAK inhibition in improving lupus rashes and nonscarring alopecia [103, 104] , and a randomized, placebo-controlled, phase 2 trial suggested a possible . Need to screen for latent infections . Haematological (neutropenia) and infectious adverse events (need to monitor serum immunoglobulins) a Belimumab is currently not licensed for the treatment of active renal or neuropsychiatric lupus.

Guillermo Ruiz-Irastorza and George Bertsias v74 benefit of baricitinib (JAK1/JAK2 inhibitor) in SLE [105] . Other agents currently being evaluated include proteasome inhibitors [106] , low-dose IL-2 [107] and inhibitors of the mammalian target of rapamycin [108] .

Treating lupus is not just treating lupus flares [17, 78] . Additional objectives are to prevent or minimize damage accrual and serious drug side effects, prolong survival and improve quality of life [17, 78] . Accordingly, every effort should be made to design therapeutic schemes that rapidly control lupus activity, prevent future flares, do not increase damage by themselves and prevent other short and long-term complications. To achieve these objectives, combinations of the previously discussed drugs can be used. Unfortunately, many choices are not guided by strong evidence and mostly depend on the experience and preferences of the treating physicians. While the role of HCQ or different immunosuppressive regimes in LN have been extensively studied, the indication for individual agents in other disease manifestations is supported by weaker evidence (see previous sections). An example of the variability in real-world clinical practice has been recently shown by a study revealing the great differences in GC use among the different SLICC participating centres [109] .

A number of preliminary steps should be considered. Photoprotection is universally recommended, particularly in patients with photosensitivity and/or skin disease. All patients should receive HCQ as background therapy unless contraindicated, in which cases mepacrine can be considered.

In inducing a rapid remission of active lupus, GCs are still the main weapon. Data suggest that pulses of methylprednisolone can help control moderate-severe disease activity and allow the use of lower starting doses of prednisone (much less than the dogma of 1 mg/kg/ day), with quick tapering [49] . In the long-term prevention of flares, GCs should be considered on a case-bycase basis according to disease activity, with the final goal of discontinuation, if possible. If not, prednisone doses should not exceed 5 mg/day for chronic treatments [38, 48] .

As recommended by the EULAR, immunosuppressive drugs should be added early in severe disease and also to minimize the adverse effects of long-term GC treatment whenever prednisone cannot be rapidly reduced due to recurrent activity [17, 49] . It is also recommended [17] that all patients on long-term GC therapy should be supplemented with calcium and vitamin D with monitoring of 25-hydroxyvitamin D levels.

Specific regimes are available, based on the different clinical scenarios (Table 4) [18, [110] [111] [112] . Specifically, we propose that mild flares can be initially managed with minor increases in the dose of prednisone up to 7.5 mg/day, with tapering to 5 mg/day in no more than 2 weeks. If there is no rapid response or if a relapse occurs upon withdrawal, then therapy for a moderate flare should be started.

Moderate flares can be managed with three consecutive pulses of methylprednisolone of 125-250 mg/day, followed by prednisone of 5-20 mg/day, again with rapid tapering to 5 mg/day. If the disease is not adequately controlled, methylprednisolone pulses can be repeated in 2-4 weeks and then an additional drug should be added, depending on the clinical scenario. To this end, our selection based on evidence and personal experience includes the following agents:

. Joint or skin manifestations:

. Mepacrine 50-100 mg/day (in combination with HCQ) . MTX at a starting dose of 5-15 mg/week . Gradual increase in dose until disease activity is under control . Doses >25 mg/week not recommended.

. Thrombocytopenia or haemolytic anaemia:

. AZA 1.5-2 mg/kg/day.

. Serositis:

. MTX at a starting dose of 5-15 mg/week . Mepacrine 50-100 mg/day (in combination with HCQ).

In addition, mycophenolate and tacrolimus can be used in any of these settings as second-line agents.

Severe flares, i.e. those involving vital organs, severe haemolytic anaemia or thrombocytopenia, or moderate flares not responding to the abovementioned scheme, should be managed more aggressively. By extrapolation from the acute treatment of LN, initial therapy consists of pulse methylprednisolone, 250-500 mg/day for 3 days (dexamethasone 40 mg/day, oral or i.v., for 4 consecutive days is our preferred option for severe thrombocytopenia or haemolytic anaemia) followed by prednisone at a maximum starting dose of 20-30 mg/day, reduced every 2 weeks (20-15-10-7.5 mg/day) to 5 mg/day. Towards the goal of minimizing exposure to GCs, the prednisone dose should be tapered independent of the clinical course of the patient, therefore options to keep patients off of high doses of prednisone must be accomplished, in order to decrease the risk of infections or other serious side effects such as diabetes, osteonecrosis, severe skin changes or weight gain [37, 39, 48, 49] .

For severe flares, we recommend that GCs should always be combined with immunosuppressive drugs, the drug of choice depending on the clinical scenario. In general, CYC is preferred for life-threatening disease, like pneumonitis, alveolar haemorrhage, psychosis, cerebral vasculitis or acute myelitis. Although high doses have been recommended, we also advocate for the Euro-Lupus regime, i.e. 500 mg i.v. every 2 weeks for a total of 3 g. Intravenous immunoglobulin (2 g/kg total dose, distributed within 2-5 days) can be used in patients with severe immune haemolytic anaemia or thrombocytopenia or whenever a concomitant infection is suspected, although these are off-label indications.

AZA, MTX, mycophenolate and sometimes tacrolimus [61] can be used as maintenance therapy, depending on the target organ. Recommendations for LN have been recently updated [19] .

To date, the role of biologic drugs is mostly limited to disease refractory to conventional therapy. Despite being an off-label drug for SLE, RTX is usually chosen in acute settings, including immune cytopenias or severe lung disease [110] . Belimumab is licenced for patients with persistent non-life-threatening activity despite combination therapy with HCQ, low-dose prednisone and/or immunosuppressive drugs [110] . Future indications of these drugs may include earlier use of belimumab [76] and sequential therapy of RTX-belimumab [113] . The role of newer agents will hopefully be clarified in the near future.

In summary, SLE can be successfully managed today in the vast majority of patients, taking as cornerstone principles the universal prescription of HCQ, the initial administration of methylprednisolone pulses to treat moderate-severe flares, the use of low-medium initial doses of prednisone with very rapid tapering to maintenance doses 5 mg/day and the utilization of immunosuppressive drugs not only in the setting of severe disease, but also as steroid-sparing agents. Current and future biologic drugs may provide additional solutions in the minority of patients not responding to the standard of care.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. This paper was published as part of a supplement supported by an educational grant from GSK. 

with systemic lupus erythematosus

Antimalarials may influence the risk of malignancy in systemic lupus erythematosus

Effects of chronic exposure of hydroxychloroquine/chloroquine on the risk of cancer, metastasis, and death: a population-based cohort study on patients with connective tissue diseases

Cumulative immunosuppressant exposure is associated with diversified cancer risk among 14832 patients with systemic lupus erythematosus: a nested casecontrol study

2019 update of the EULAR recommendations for the management of systemic lupus erythematosus

The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults

Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis

American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome

Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus

Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision)

The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy

Evolution of retinal changes measured by optical coherence tomography in the assessment of hydroxychloroquine ocular safety in patients with systemic lupus erythematosus

Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus

Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study)

A prospective international study on adherence to treatment in 305 patients with flaring SLE: assessment by drug levels and self-administered questionnaires

Combined mepacrinehydroxychloroquine treatment in patients with systemic lupus erythematosus and refractory cutaneous and articular activity

Glucocorticoids and antimalarials in systemic lupus erythematosus: an update and future directions

Genomic and nongenomic effects of glucocorticoids

Unraveling the functions of the membrane-bound glucocorticoid receptors: first clues on origin and functional activity

Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action

Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology

Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus

Independent association of glucocorticoids with damage accrual in SLE

Damage in systemic lupus erythematosus and its association with corticosteroids

Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis

Renal outcome in patients with lupus nephritis using a steroid-free regimen of monthly intravenous cyclophosphamide: a prospective observational study

Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids

Prednisone in lupus nephritis: how much is enough?

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

Characteristics of azathioprine use and cessation in a longitudinal lupus cohort

The BILAG multicentre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE

Enteric-coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus: a randomised clinical trial

Mycophenolate mofetil in nonrenal manifestations of systemic lupus erythematosus: an observational cohort study

Effect of corticosteroids and cyclophosphamide on sex hormone profiles in male patients with systemic lupus erythematosus or systemic sclerosis

Zoster after cyclophosphamide for systemic lupus erythematosus or vasculitis: incidence, risk factors, and effect of antiviral prophylaxis

EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs

Cyclophosphamide in combination with glucocorticoids for severe neuropsychiatric systemic lupus erythematosus: a retrospective, observational twocentre study

inhibitors in systemic lupus erythematosus

Tacrolimus in non-Asian patients with SLE: a real-life experience from three European centres

Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis

Brief report: the Euro-Lupus low-dose intravenous cyclophosphamide regimen does not impact the ovarian reserve, as measured by serum levels of anti-Mü llerian hormone

Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial

Time to recovery from proteinuria in patients with lupus nephritis receiving standard treatment

Multitarget therapy for maintenance treatment of lupus nephritis

Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up

Long-term data on tacrolimus treatment in lupus nephritis

Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials

Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, doubleblind, placebo-controlled study

A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China

Lupus low disease activity state (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus

Cumulative corticosteroid dose over fifty-two weeks in patients with systemic lupus erythematosus: pooled analyses from the phase III belimumab trials

Longterm organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care

Organ damage in patients treated with belimumab versus standard of care: a propensity score-matched comparative analysis

Long-term impact of belimumab on health-related quality of life and fatigue in patients with systemic lupus erythematosus: six years of treatment

Treatto-target in systemic lupus erythematosus: recommendations from an international task force

Long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus: a continuation of a seventy-sixweek phase III parent study in the United States

Longterm safety and limited organ damage in patients with Treating systemic lupus erythematosus in the 21st century

Efficacy and safety of subcutaneous belimumab in anti-doublestranded DNA-positive, hypocomplementemic patients with systemic lupus erythematosus

Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response

Effectiveness and safety of belimumab in patients with systemic lupus erythematosus in a real-world setting

Low disease activity-irrespective of serologic status at baseline-associated with reduction of corticosteroid dose and number of flares in patients with systemic lupus erythematosus treated with belimumab: a real-life observational study

Smoking reduces the efficacy of belimumab in mucocutaneous lupus

Predictors of low disease activity and clinical remission following belimumab treatment in systemic lupus erythematosus

Clinical predictors of response and discontinuation of belimumab in patients with systemic lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study

Safety and efficacy of belimumab plus standard therapy for up to thirteen years in patients with systemic lupus erythematosus

BAFF induces tertiary lymphoid structures and positions T cells within the glomeruli during lupus nephritis

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE

GlaxoSmithKline. GSK announces positive headline results in phase 3 study of Benlysta in patients with lupus nephritis

Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial

Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study

Rituximab in moderate to severe non-renal systemic lupus erythematosus: a reanalysis of the EXPLORER study

Efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus: a systematic review

Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: results from the

Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus

Assessment of response to B-cell depletion using rituximab in cutaneous lupus erythematosus

Efficacy and safety of rituximab for systemic lupus erythematosus-associated immune cytopenias: a multicenter retrospective cohort study of 71 adults

Rituximab as maintenance treatment for systemic lupus erythematosus: a multicenter observational study of 147 patients

Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab

Trial of anifrolumab in active systemic lupus erythematosus

JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus

Efficacy of JAK 1/2 inhibition in the treatment of diffuse non-scarring alopecia due to systemic lupus erythematosus

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial

The proteasome inhibitor bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus

Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebocontrolled trial

Inhibition of mTOR suppresses IFNa production and the STING pathway in monocytes from systemic lupus erythematosus patients

Glucocorticoid use and factors associated with variability in this use in the Systemic Lupus International Collaborating Clinics Inception Cohort

Changing paradigms in the treatment of systemic lupus erythematosus

Seventy years after Hench's Nobel prize: revisiting the use of glucocorticoids in systemic lupus erythematosus

Mobile app version 1.05

Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series