National guidelines for the management of lupus nephritis in Saudi Arabia

Hanan M Al Rayes; Huda Alfaris; Mohammad Alkhowaiter; Khawla K Alghanim; Roaa Aljohani; Abdulaziz Alkhalaf; Sultana Abdulaziz; Tariq E Aljohani; Abdulkareem Alsuwaida

doi:10.4103/ara.ara_12_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 2 | Issue : 2 | Page : 35-44

National guidelines for the management of lupus nephritis in Saudi Arabia

Hanan M Al Rayes¹, Huda Alfaris¹, Mohammad Alkhowaiter², Khawla K Alghanim³, Roaa Aljohani⁴, Abdulaziz Alkhalaf², Sultana Abdulaziz⁵, Tariq E Aljohani⁶, Abdulkareem Alsuwaida²
¹ Department of Medicine, Rheumatology Unit, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
² Department of Internal Medicine, College of Medicine, and King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
³ Department of Medicine, Rheumatology Unit, King Fahad Military Medical Complex, Dhahran, Saudi Arabia
⁴ Department of Medicine, College of Medicine, Taibah University, Madinah, Saudi Arabia
⁵ Department of Medicine, Unit of Rheumatology, King Fahd Hospital, Jeddah, Saudi Arabia
⁶ Department of Pathology and Laboratory Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission	16-Jul-2022
Date of Decision	22-Aug-2022
Date of Acceptance	08-Sep-2022
Date of Web Publication	25-Jan-2023

Correspondence Address:
Dr. Huda Alfaris
Department of Medicine, Rheumatology Unit, Prince Sultan Military Medical City, Riyadh
Saudi Arabia

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ara.ara_12_22

Abstract

Context: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can affect all organs and cause considerable morbidity and mortality. The estimated prevalence of SLE in the central region of Saudi Arabia is 19.28/100,000 individuals. Approximately half of those will eventually develop clinically significant renal disease. Therefore, screening for renal involvement is essential for early diagnosis and optimal disease management. Aims: This study aims to develop a pathway that can facilitate the early diagnosis and management of lupus glomerulonephritis in the Kingdom of Saudi Arabia. Methodology: The Saudi Society of Rheumatology in collaboration with the Saudi Society of Nephrology and Transplantation and under the supervision of the Saudi Commission for Health Specialties formed a committee involving rheumatologists, nephrologists, and a renal pathologist. Multiple workshops were conducted to adapt the 2019 Update of the Joint European League against Rheumatism and European Renal Association–European Dialysis and Transplant Association recommendations for the management of SLE, as well as The Kidney Disease: Improving Global Outcome 2020 using the ADAPTE process. Results: This document includes recommendations related to screening for renal involvement, renal pathology and classification, initial and subsequent therapy for lupus nephritis (LN), the treatment of refractory and relapsing LN, and the management of advanced renal disease. Recommendations concerning pregnancy and postpartum care are also included. Conclusion: We developed a guideline for the management of adults with LN based on recommendations developed elsewhere. This guideline was adapted to the local context of our health-care system.

Keywords: Lupus nephritis, management, Saudi Arabia, systemic lupus erythematosus

How to cite this article:
Al Rayes HM, Alfaris H, Alkhowaiter M, Alghanim KK, Aljohani R, Alkhalaf A, Abdulaziz S, Aljohani TE, Alsuwaida A. National guidelines for the management of lupus nephritis in Saudi Arabia. Ann Rheumatol Autoimmun 2022;2:35-44

How to cite this URL:
Al Rayes HM, Alfaris H, Alkhowaiter M, Alghanim KK, Aljohani R, Alkhalaf A, Abdulaziz S, Aljohani TE, Alsuwaida A. National guidelines for the management of lupus nephritis in Saudi Arabia. Ann Rheumatol Autoimmun [serial online] 2022 [cited 2023 Feb 4];2:35-44. Available from: http://www.ara.ssr.com/text.asp?2022/2/2/35/367434

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs and cause significant morbidity and mortality. It is more prevalent in females of childbearing age.^[1] The estimated prevalence of SLE in the central region of Saudi Arabia is 19.28/100,000 individuals.^[2] Approximately half of those develop clinically significant renal disease^[3] and up to 10% will eventually develop end-stage renal disease (ESRD).^[4] Screening for lupus nephritis (LN) is recommended on SLE diagnosis as, in most cases, LN is present early in the disease course.^[5]

Risk factors for the development of LN include young age at SLE diagnosis, male sex, and non-European descent.^[5] A study performed in a tertiary center in Riyadh demonstrated that older age at onset (>50 years; P = 0.037), hypertension (P = 0.009), renal impairment (P = 0.000), and proliferative LN (classes III and IV; P = 0.013 and 0.039, respectively) are associated with a higher risk for progression to ESRD.^[6] In a similar study conducted in a tertiary hospital in Riyadh using the International Society of Nephrology/Renal Pathology Society classification system,^[7] class IV was the most common (43.18% of biopsied cases), followed by class III (27.28%), and classes II and V (6.81% each).

The provision of high-quality, evidence-based medical care is essential. However, international guidelines often fail to provide a sufficiently substantial basis for medical decision-making. Therefore, we aim to improve awareness, acceptance, and adherence among physicians by customizing preexisting guidelines (i.e., European League against Rheumatism-European Renal Association-European Dialysis and Transplant Association [EULAR/ERA-EDTA], 2019^[8] and Kidney Disease: Improving Global Outcome [KDIGO], 2020^[9]). This effort takes into consideration region-specific circumstances and limitations.

When making clinical decisions, physicians are expected to take these recommendations into account, along with the specific preferences and needs of patients.

Methodology

This adaptation of the EULAR/ERA-EDTA and KDIGO recommendations was performed using the Grading of Recommendations, Assessment, Development and Evaluations methodology. This five-step appraisal system was selected due to its simplicity and practicability.

The following recommendations were formulated through collaboration between the Saudi Society of Rheumatology (represented by six rheumatologists) and the Saudi Society of Nephrology and Transplantation (represented by two nephrologists). The histopathologic classification was performed by a renal pathologist. Multiple workshops were conducted in 2021 under the supervision of the Saudi Commission for Health Specialties. The five-step adaptation process was selected due to its simplicity and practicability. The final document was peer-reviewed and amended accordingly.

Screening

All patients with lupus should undergo regular screening as clinical manifestations do not always correlate with the extent or severity of kidney involvement. Therefore, all patients with SLE should be evaluated for kidney pathology:

At initial diagnosis
Every 3–6 months
When there is clinical evidence of a lupus flare-up.

Initial investigations include [Figure 1]:

Figure 1: Screening for LN. GFR: Glomerular filtration rate, LN: Lupus nephritis, SLE: Systemic lupus erythematosus

Click here to view

Urine analysis with microscopy
Urine protein-to-creatinine ratio (UPCR)
Serum creatinine levels with estimated glomerular filtration rate (GFR).

Proteinuria is quantified through a 24-h urine collection if:

Urine analysis shows proteinuria of ≥1 on two occasions
UPCR >0.3.

Kidney biopsy:

A kidney biopsy helps to confirm the diagnosis, assess the severity and chronicity of LN, and potentially predict prognosis. Similarly, a kidney biopsy is important to define the nature of the renal involvement (i.e., immune-complex-mediated or another mechanism, such as thrombotic microangiopathy or lupus podocytopathy). However, in case of suspected LN, the initiation of induction therapy should not be delayed in anticipation of the biopsy procedure/results.

Indications for kidney biopsies include:

Proteinuria >500 mg/24 h or UPCR >0.5 g protein per g creatinine
Persisting proteinuria >300 mg/24 h with active urine sediments
Renal impairment that cannot be attributed to other causes.

Classification and pathology

The following histopathologic classification was developed by the International Society of Nephrology/Renal Pathology Society in 2004^[10] and revised in 2018.^[11]

Class I: Minimal mesangial lupus nephritis

Normal glomeruli are visualized by light microscopy, and mesangial immune complexes are visualized by immunofluorescence or electron microscopy.

Class II: Mesangial proliferative lupus nephritis

Pure mesangial hypercellularity with mesangial immune deposits; mesangial matrix expansion observed by light microscopy. Mesangial hypercellularity is defined as the presence of ≥4 nuclei surrounded by matrix in the mesangial area.

Class III: Focal lupus nephritis

Focal disease involving <50% of all glomeruli with predominantly mesangial and subendothelial immune deposits.

Class IV: Diffuse lupus nephritis

Diffuse disease involving ≥50% of all glomeruli with predominantly mesangial and subendothelial immune deposits.

For both classes III and IV, the lesions are:

Active Lesions

Glomerular endocapillary hypercellularity
Glomerular fibrinoid necrosis
Glomerular karyorrhexis
Glomerular subendothelial deposits-wire loop lesions
Glomerular cellular or fibrocellular crescents
Interstitial inflammation.

Chronic Lesions

Glomerular sclerosis
Glomerular fibrous crescents
Tubular atrophy
Interstitial fibrosis.

Class V: Lupus membranous nephropathy

Membranous glomerulonephritis, diffuse thickening of capillary walls, subepithelial and mesangial immune deposits ("spike and dome" pattern with silver stain). Of note, this class may present in combination with class III or IV.

Class VI: Advanced sclerosing lupus nephritis

Advanced sclerosing glomerulonephritis; ≥90% glomerular obsolescence and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and few immune deposits.

Poor prognostic factors include the presence of higher chronicity and activity indices.^[12]

Immunofluorescence

Typically, immunofluorescence analysis reveals the characteristic "full house" pattern classically observed in LN; however, it is not required for diagnosis. This immunofluorescence pattern refers to the presence of all immunoreactants, including immunoglobulin G (IgG), IgA, IgM, C1q, and C3. In addition, C1q is fairly specific for LN.

Initial lupus nephritis therapy

Goals of therapy

The therapeutic goals in LN are proteinuria reduction and the prevention of glomerular damage and chronic kidney disease progression. Currently, there is no consensus across guidelines regarding the definition of the clinical response in LN. Nevertheless, proteinuria is the most important clinical variable used to assess response. Treatment response in LN is clinically characterized as complete, partial, or no response.

European league against rheumatism definition of lupus nephritis remission

Partial clinical response: ≥50% reduction in proteinuria to subnephrotic levels and GFR within 10% of baseline by 6–12 months
Complete clinical response: proteinuria <500 mg/24 h and GFR within 10% of baseline by 12 months
No response: Failure to achieve a complete or partial remission.

Relapse of proliferative LN is defined as recurrent inflammation confirmed by active urine sediment, increase in urine protein excretion, and impaired GFR after an initial response to treatment.^{[13],[14],[15]}

General measures

All patients with LN should receive hydroxychloroquine (HCQ) unless contraindicated or they develop side effects^[16]
Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are recommended for all patients with UPCR >500 mg/g or arterial hypertension, aiming for blood pressure (BP) <130/80 mmHg^[17]
Statin therapy should be considered based on lipid levels and other cardiovascular risk factors.

Class I lupus nephritis

Immunosuppressive therapy is generally not required. However, controlling extrarenal activity and managing comorbidities (e.g. high BP) is important.

Class II lupus nephritis

Immunosuppressive therapy, in addition to treatment with a glucocorticoid, is required if proteinuria exceeds 1 g/day.^[8]

Induction therapy for proliferative lupus nephritis (class III/IV or mixed class III/IV + V)

Mycophenolate mofetil/mycophenolate acid (MMF/ MPA) or a cyclophosphamide-based regimen with corticosteroids are recommended as first-line options for the initial (induction) treatment of proliferative LN [Figure 2]^[18],[19]
Treatment with MMF/MPA or cyclophosphamide is associated with lower relapse rates and improved long-term kidney survival compared with glucocorticoid treatment alone. Furthermore, combined immunosuppressive and glucocorticoid regimens enable steroid minimization, which reduces the occurrence of adverse effects.^[18]

Figure 2: Induction therapy for proliferative LN. LN: Lupus nephritis, MMF: Mycophenolate mofetil, MPA: Mycophenolate acid, NIH: National Institutes of Health

Click here to view

Glucocorticoid dosage

Glucocorticoids continue to be a crucial part of the early therapy for classes III and IV LN due to their anti-inflammatory and immunosuppressive properties. The dose used during induction therapy is determined by the severity of the disease. Specifically, this therapy involves either intravenous methylprednisolone 250–500 mg daily for 3 days or oral prednisolone 1 mg/kg daily for 2 weeks depending on disease severity and the presence of poor prognostic factors (i.e., pathologic findings or reduction in GFR), followed by oral prednisone (0.3–0.5 mg/kg/day) tapered to ≤7.5 mg/day by 3–6 months.^[20],[21]

Mycophenolate mofetil/mycophenolate acid-based regimen

This option is preferred by patients with concerns regarding fertility. For patients with gastrointestinal intolerance, a trial treatment with enteric-coated MPA at an equivalent dose is recommended.^[19]

Cyclophosphamide-based regimen

This option is preferred for patients who are not compliant with oral therapy. A low-dose cyclophosphamide regimen (Euro-Lupus protocol) is preferred as the initial induction therapy.^[22] We may consider a high-dose cyclophosphamide regimen (National Institute of Health protocol) in severe LN if crescent formation is detected in >50% of glomeruli.

If one regimen fails, treatment should be switched to the alternative regimen
If both of these regimens fail, the condition should be treated as refractory LN.

Voclosporin and belimumab

These agents can be considered first-line therapies if the previous two regimens are unavailable or contraindicated.

Initial therapy for pure membranous class V lupus nephritis

Immunosuppressive medications are indicated as the initial therapy in patients with class V LN and nephrotic-range proteinuria, as well as those with worsening kidney function [Figure 3]. Moreover, most experts recommend initiating immunosuppressive therapy in patients with persistent proteinuria >1 g/day despite treatment with angiotensin receptor blockers and BP control, unless extensive chronic damage is observed on kidney biopsy.^[23]

Figure 3: Initial therapy for pure class V (membranous LN). BID: Twice daily, BP: Blood pressure, CNI: Calcineurin inhibitor, LN: Lupus nephritis, MMF: Mycophenolate mofetil, MPA: Mycophenolate acid

Click here to view

For patients with pure class V lupus nephritis

MMF can be used in combination with oral prednisolone 0.5 mg/kg, tapered to ≤5 mg/day by 3–6 months.^[24] Cyclophosphamide or calcineurin inhibitors (CNIs) in combination with glucocorticoids are alternative options, especially for patients who are allergic to or cannot tolerate MMF.^[25] Multitarget therapy (MMF and CNI) is also an alternative.

Maintenance therapy for proliferative lupus nephritis (class III/IV)

Maintenance therapy follows the induction therapy to maintain remission, prevent renal relapses, and decrease the risk of developing end-stage kidney disease.

When to start subsequent therapy for proliferative lupus nephritis (class III/IV)

This depends on the initial therapy regimen used:

In patients who received IV cyclophosphamide as initial therapy, subsequent therapy is initiated 24 weeks after the last dose of cyclophosphamide when the following criteria are met: white blood cell count >4000 cells/μL and absolute neutrophil count >1500 cells/μL.
In patients who received MMF as their initial therapy, the dose of MMF is gradually reduced from 6 months after treatment initiation.

Cytotoxic agents frequently used for maintenance therapy in the treatment of proliferative lupus nephritis (class III/IV)

We recommend MMF (1–2 g/day) or MPA at an equivalent dose for maintenance based on high-level evidence of data [Figure 4].

Figure 4: Maintenance therapy for proliferative LN. AZA: Azathioprine, LN: Lupus nephritis, MMF: Mycophenolate mofetil, MPA: Mycophenolate [email protected]

Click here to view

Azathioprine (AZA) is an acceptable alternative to MMF or MPA after completing the induction therapy in patients who cannot tolerate or do not have access to treatment and those who are considering pregnancy
In patients receiving allopurinol (gout), AZA should be prescribed at 25% of the recommended dose, and the patient's blood count should be monitored frequently to avoid fatal blood dyscrasias
HCQ should be continued lifelong unless contraindicated.

Other available maintenance therapies for proliferative lupus nephritis (class III/IV) in case of a partial clinical response

CNIs, alone or combined with low-dose MMF, are reasonable options for maintenance therapy in patients who cannot receive MMF, MPA, or AZA. CNIs can also be used safely during pregnancy.

Tacrolimus (trough blood level target: 4–6 ng/ml)^[26],[27]
Cyclosporine A (trough blood level target: 80–120 ng/ml).^[28]

Duration of subsequent therapy for proliferative lupus nephritis (class III/IV)

Most renal flares occur within the first 5–6 years following treatment initiation. Gradual withdrawal of immunosuppressive drugs can be attempted after at least 3–5 years from achieving complete clinical response.

Monitoring lupus nephritis

An early proteinuria response and the normalization of serum creatinine levels within 12 months of induction therapy are predictive of a favorable long-term patient outcome. Therefore, treatment should aim for at least a 25% reduction in proteinuria at 3 months, 50% at 6 months, and complete renal response (<500–700 mg/day) at 12 months.

Refractory lupus nephritis

Currently, there is no consensus definition of "refractory LN;" however, the term implies an inadequate or lack of response to remission-inducing treatment.

The therapy is considered a failure if there is clear evidence of worsening at 3 months (50% or more increase in proteinuria or doubling of serum creatinine levels) or failure to achieve complete or partial remission.

Severe disease with no improvement or worsening despite treatment for 34 weeks warrants an early appraisal of potential causes for this nonresponsiveness and early intervention. Patients who respond to treatment can be closely observed and investigated when the level of improvement is suboptimal or below expectation.

Potential causes of persistent proteinuria and worsening kidney function include:

Thrombotic microangiopathy
Lupus podocytopathy
Antiphospholipid antibody-induced vascular lesion
Tubulointerstitial nephritis.

A repeat renal biopsy should be considered in the following situations:

Patients who have not met the clinical criteria for complete or partial remission to first-line induction immunosuppression within 6–12 months
In the absence of clear improvement at 6 months
If renal function worsens following standard therapy in the first 3 months.

Treatment of refractory lupus nephritis [Figure 5]

Figure 5: Management of refractory LN^[29]. *Long-term efficacy and safety data are lacking. CNI: Calcineurin inhibitor, LN: Lupus nephritis, MMF: Mycophenolate mofetil

Click here to view

Switching to an alternative agent is recommended for patients who fail to improve within 3–4 months, and those who do not achieve partial response after 6–12 months or complete response after 2 years of treatment. For patients not responding to MPA or cyclophosphamide, evidence from uncontrolled studies suggests that treatment may be switched from MPA to cyclophosphamide, from cyclophosphamide to MPA, or rituximab (anti-CD20 monoclonal antibody) may be given either as an add-on treatment or monotherapy. Additional options include CNIs (e.g., ciclosporin A and tacrolimus), intravenous immunoglobulin, and plasma exchange for rapidly progressive glomerulonephritis.

Lupus nephritis Relapse

Risk factors^[30],[31]

Severe disease at baseline
Delay in reaching a complete response
Attaining a partial but not complete response
Nephritic sediment (active urine sediment, increase in serum creatinine levels by at least 30% above baseline, worsening proteinuria).

Monitoring

Serial monitoring of urine sediment, UPCR, serum creatinine levels, and serologic factors (complement C3 and C4 levels and anti-double-stranded DNA titers) should be performed every 3–4 months in stable patients with proliferative LN to detect renal relapses.^[32],[33]

Management

After a complete or partial remission has been achieved, LN relapse should be treated with the same initial therapy used to achieve the original response or an alternative recommended first-line therapy. If this fails, other options should be used as in the management of refractory LN.

A repeat biopsy may be helpful since the disease in such patients may have progressed from proliferative LN to lupus membranous nephropathy or combined proliferative LN and lupus membranous nephropathy.^[34]

End-stage renal disease and transplantation in lupus nephritis

Patients with LN who reach ESRD can be managed by hemodialysis, peritoneal dialysis, or renal transplantation^[35]
The outcomes of hemodialysis and peritoneal dialysis are comparable; there is no preference regarding these two options^[36],[37]
In the absence of any contraindication, we recommend renal transplantation as the modality of choice for renal replacement therapy due to its association with better patient outcomes^[38]
We recommend preemptive renal transplant if the disease is clinically inactive for 3–6 months for the following reasons:

Preemptive transplantation is associated with a lower risk of recipient death and graft failure^[39]
Preemptive transplantation is not associated with recurrent LN in the majority of patients^[40]
Longer transplantation waiting times are associated with equivalent or worse graft outcomes among patients with LN and ESRD.^[41]

For patients undergoing dialysis, we suggest considering renal transplantation as soon as the disease becomes clinically quiescent^[41]
Anticoagulant treatment may be considered in LN patients with antiphospholipid antibodies when thrombosis of the vascular dialysis access becomes a recurrent issue. The benefit–risk ratio of anticoagulation must be considered
Antiplatelet/anticoagulant treatment may be considered in LN patients with antiphospholipid antibodies to minimize the risk of graft thrombosis. The benefit–risk ratio of anticoagulation must be considered.

Pregnancy and lupus nephritis

Preconception evaluation and counseling

The prevalence of LN flares during pregnancy in different lupus cohorts ranges 16%36%.^[42],[43]

lupus nephritis flare risk

Several studies have suggested that active renal disease at the time of conception and within 6 months before pregnancy are significant predictors of pregnancy complications and adverse outcomes.^[44],[45] The rate of relapse of renal disease during pregnancy in women with a prior history of LN is approximately 30%.^[46]

Maternal outcome

There is an increased risk of maternal complications in lupus compared with non-lupus patients. A higher frequency of maternal deaths has been documented among patients with active LN.^[47]

Defer pregnancy

Pregnancy should be avoided in patients with active disease during the 6 months of the preconception period in the presence of pulmonary hypertension, prior cerebrovascular event, or myocardial infarction as there is an increased risk of mortality and morbidity for the mother and baby.

Disease assessment during pregnancy

Laboratory testing

The assessment of disease activity before conception and during pregnancy is required for risk stratification of lupus activity and monitoring. We recommend a laboratory workup at each trimester in stable patients and more frequently in active patients [Table 1].

Table 1: Laboratory screening and monitoring of patients with lupus before and during pregnancy

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Medication management

Immunosuppressive therapy

HCQ should be continued as it is compatible with pregnancy and lactation
Patients who receive MMF should be switched to AZA 3–6 months before conception
Tacrolimus and cyclosporine are compatible with pregnancy and can be prescribed in response to proteinuria progression
Rituximab can be continued until conception and under life-threatening conditions
Cyclophosphamide should be discontinued 3 months before conception
Belimumab and voclosporin are not recommended for use in patients with lupus during pregnancy.

Anti-platelet/anti-coagulation management: it is recommended that all lupus patients with a history of LN receive a low-dose aspirin regimen during pregnancy regardless of the presence of antiphospholipid antibodies^[48]
Anti-hypertension management: Angiotensin- converting enzyme inhibitors and angiotensin receptor blockade must be discontinued before conception and during pregnancy.^[49] These agents must be replaced by methyldopa, labetalol, or a calcium channel blocker
All patients should be monitored closely, preferably by a multidisciplinary team (i.e., rheumatologist, nephrologist, and obstetrician)
Patients with antiphospholipid syndrome are at increased risk for adverse pregnancy outcomes. For such patients, anticoagulation therapy with low-molecular-weight heparin and/or acetylsalicylic acid should be considered depending on their history of obstetric and/or thrombotic events. Warfarin must be discontinued as soon as pregnancy is confirmed. Patients with nephrotic-range proteinuria are also candidates for anticoagulation.

Presence of anti-Sjögren's syndrome type A/Ro and anti- Sjögren's syndrome type B/La

Treatment with HCQ should be carried out during pregnancy^[50],[51]
In the absence of prior history of neonatal lupus: Serial (interval uncertain) fetal echocardiography should be performed in weeks 16–26^[52]
In the presence of prior history of neonatal lupus: Weekly fetal echocardiography should be performed in weeks 16–26^[53]
Abnormal fetal echocardiography: In the presence of first- or second-degree heart block, treatment with dexamethasone 4 mg daily should be initiated^[54],[55]
In the presence of isolated third-degree heart block (and no other cardiac inflammation), treatment with dexamethasone is not recommended.^[54],[55]

Management of lupus nephritis flare intrapartum

The definition of an LN flare in pregnant and non-pregnant women is identical (see definition of LN flare)
If a flare is suspected, the dose of prednisolone should be increased to 0.5–1 mg/kg (the indication of a pulse of methylprednisolone in pregnant and nonpregnant women is identical)
The current immunosuppression should be adjusted or a medication compatible with pregnancy (CNI or intravenous immunoglobulin) should be added on
BP should be controlled by adjusting the anti-hypertensive medication

Kidney biopsy may be needed to establish the diagnosis and can be performed safely up to 20 weeks of gestation.^[56]

Mode of delivery

This decision is reached by the multidisciplinary team and the patient^[16]
Delivery at a tertiary center with neonatologists and the availability of a neonatal intensive care unit is preferable
Cesarean section is generally indicated as for other obstetrical indications.

Clinical scenarios

Case 1

A 32-year-old woman with SLE and class IV LN for 2 years. Her disease has been in complete remission for the past 12 months. She receives maintenance with HCQ 400 mg daily, mycophenolate 500 mg twice daily, and perindopril 5 mg daily. The patient has expressed the desire to become pregnant in the near future. How should the medication regimen of this patient be modified?

Answer

Based on the aforementioned recommendations for the management of family planning for patients with SLE, the UPCR should be controlled (<500mg/g) without the use of renin–angiotensin–aldosterone system inhibitors. These agents are contraindicated in the first trimester due to the risk of teratogenicity
Withdrawal of MMF for a longer period (e.g., 3–6 months before attempting conception), provides time to assess the tolerability and efficacy of an alternative immunosuppressive agent (e.g., AZA and CNI)

Case 2

A 27-year-old woman was recently diagnosed with SLE based on arthritis, mucocutaneous manifestations, leukopenia, and positive serology. Her examination revealed BP of 160/90 mmHg and bilateral lower limb pitting edema. Her workup indicated 24-h urine protein collection equal to 5 g with normal renal function. The urgent kidney biopsy showed changes typical of pure membranous LN. In addition to HCQ, what other treatment options should be recommended?

Answer

Based on the aforementioned recommendations for the management of pure membranous LN, treatment with immunosuppressants should also be initiated since the patient has nephrotic-range proteinuria
MMF is recommended as a first-line option with a target dose of 2–3 g/day, combined with oral prednisone 0.5 mg/kg/day, tapered to ≤5 mg/day by 36 months
Alternatively, a cyclophosphamide-based regimen (Euro-Lupus protocol), multitarget therapy (MMF 500 mg twice daily + CNI [e.g., tacrolimus]), or CNI monotherapy can be used
Angiotensin-converting enzyme inhibitors should be co-administered.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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