**6.1 Pregnancy and lupus nephritis**

#### *6.1.1 Pre-pregnancy*

*Lupus - Need to Know*

phase III trials [92].

ies had renal involvement [82, 83].

Another potent BAFF-inhibitor, Blisibimod, was associated with reduction in steroid use, decreased proteinuria and biomarker responses in a multinational phase III trial [81]. Tabalumab, a selective mAb that neutralises both membrane and soluble BAFF, despite having the same therapeutic class, on the contrary did not yield the expected positive statistical significance results in two phase III studies involving SLE patients; however, only approximately 10% of patients in these stud-

Voclosporin, a novel next generation CNIs (an analogue of cyclosporin) with enhanced calcineurin inhibition, better safety profile and consistent predictable dose response, despite initial safety concerns in the prior phase II study [84], has recently been demonstrated in a phase III trial to be highly effective for treatment of LN when combined with MMF, with acceptable safety profile, at least for the short term (52 weeks) [85]. More importantly, it has just received the approval by the United States' Food and Drug Administration (FDA) on the 22nd of January 2021, making it the only second targeted therapy approved specifically for LN [86]. There is emerging theoretical evidence for targeting autoantibody-secreting long-lived plasma cells (PCs) that recide in dedicated survival niches in the bone marrow or inflammed tissues of LN patients. Bortezomib, a proteasome inhibitor has been shown to be effective in both animal models and real-world setting but is limited by treatment related toxicity [87–89]. Recently, Ostendorf and colleagues have demosntrated succesful use of Daratumumab, a mAb that targets CD38 and depletes PCs with acceptable safety profile in a patient with refractory LN [90]. The

experience of its use however is still limited and more data will be required.

Obinutuzumab, a novel anti-CD20 mAb demonstrated encouraging sustained 18-months B-cell depletion and renal response in a phase II trial with further evaluation in phase III trial underway (can be accessed at ClinicalTrials.gov with identification number: NCT04221477) [91]. BI 655064 (anti CD40 mAb; NCT02770170) has recently completed a phase II trial as add-on therapy to SOC treatment in active LN and awaiting evaluation. Other biological agents currently undergoing clinical trials in the treatment of LN include Anifrolumab (Type I IFN receptor mAb; NCT02547922) in phase II, while Dapirolizumab (pegylated anti CD40 ligand; NCT04294667) and Secukinumab (anti-IL-17 mAb; NCT04181762) are both in

A pipeline of novel agents in LN are being developed or asssesed in clinical trials

including Ravulizumab (novel anti complement C5 antibody; NCT04564339), Guselkumab (IL-23 inhibitor; NCT04376827), Itolizumab, (anti CD6 antibody; NCT04128579), KZR-616 (proteasome inhibitor; NCT03393013), Iguratimod (novel small molecule; NCT02936375), and BMS-986165 (novel tyrosine kinase 2

Targeting the JAK/STAT signalling pathway with Tofacitinib, or CP-690, 550 have been shown to be effective in murine LN model and may potentially serve as therapeutic target in LN [93, 94]. Successful Bruton's Tyrosine Kinase (BTK) inhibition in several studies involving mice LN models supports *Kong et al.* finding of significantly upregulated BTK expression in glomerulus of LN patients and may

Despite looking promising in SLE, a placebo-controlled phase II/III study to evaluate Atacicept (recombinant fusion protein that inhibits BAFF/BLyS or APRIL) in combination with MMF and corticosteroids in active LN patients was prematurely terminated due to unexpected substantial decline in serum IgG and serious pneumonia infections in Atacicept-treated patients [98, 99]. Abatacept, a recombinant fusion protein co-stimulation modulator, trialled as add on to SOC in LN failed the primary end point of a phase III trial despite demonstarating more rapid

(TYK2) inhibitor; NCT03943147) among many others [92].

reduction of proteinuria and earlier sustained remission [100].

potentially be a therapeutic target in LN [95–97].

**44**

Women of childbearing age with LN should understand and be counselled about the potential risks of pregnancy, even if she is in complete remission. Age, previous pregnancy complication, duration from last LN relapse, medication exposure, treatment adherence, blood pressure (BP) control and current disease status are among the important factors that may determine the outcome of future pregnancy. Baseline complement levels, antibody status for dsDNA, SS-A and SS-B, presence of antiphospholipid antibodies (aPL; notably lupus anticoagulant antibody) and urinalysis for proteinuria should be obtained prior to pregnancy.

Possible maternal complications include flare of nephritis, uncontrolled hypertension, pre-eclampsia, risk of Caesarean section, worsening renal function and thrombosis. Foetal risks include prematurity, growth retardation, congenital heart block and intrauterine death [108]. Patients with active disease at conception, uncontrolled hypertension, proteinuria of >1 g/day and abnormal renal function have the highest risk for complications; therefore, good control of disease prior to pregnancy is critically important to optimise pregnancy outcome and ideally the pregnancy should be planned.

Patients on MMF should be transitioned to pregnancy-safe immunosuppressive drugs such as AZA or TAC, while HCQ should be continued throughout pregnancy. MMF exposure especially after the first trimester increases the risk of miscarriage and congenital malformation [109], and practically should be stopped at least 3–6 months prior to conception to ensure disease control is maintained with the new agent(s) [47]. CYC is also teratogenic, associated with premature ovarian failure and increases miscarriage rate [110].

RAAS blockers should ideally be stopped before conception due to possible teratogenicity risk [111]; however, later publications seemed to suggest that they may be safe to be used until pregnancy is confirmed [112]. This is important especially for those who have residual proteinuria as attempt to conceive may take months or even years of effort. Stopping RAAS blockers early on in these patients would essentially exclude them from its' benefits.

#### *6.1.2 During pregnancy*

Multidisciplinary team approach is important during pregnancy and should ideally involve the obstetrician, neonatologist, nephrologist and rheumatologist. Majority of patients (80%) with quiescent LN would have successful pregnancies [113]; however, about a third may relapse during pregnancy [108]. Identification of patients who are at higher risk is important when pregnancy begins, as these patients will require closer observation to ensure good maternal and foetal outcomes (**Table 5**) [109, 114–118].


#### **Table 5.**

*Baseline risk assessment during pregnancy.*

During early pregnancy, BP would usually remain normal even in patients who required antihypertensive before pregnancy. Gradually, BP may rise as pregnancy progresses, requiring reintroduction of hypertensive medications such as labetalol, methyldopa or nifedipine. BP control should be targeted to be less than 140/90 mmHg [119]. As these patients are at higher risk to develop pre-eclampsia, high dose calcium supplementation and aspirin should be prescribed before entering 16 weeks of gestation [120, 121]. Ultrasound screening including uterine and umbilical artery Doppler to detect early signs of placental insufficiency may be performed at regular interval, especially in high-risk patients.

Hydroxychloroquine is safe during pregnancy and discontinuation has been associated with lupus flare. It also significantly reduces the risk of foetal congenital heart block in patients with positive SS-A (anti-Ro) [116]. Other drugs for consideration in LN and compatible with pregnancy include AZA, CNIs (TAC, Cys), plasma exchange and intravenous immunoglobulins. Data on RTX in pregnancy is limited, although some clinicians have used it safely in early trimester without apparent complication [122]. LN flare during pregnancy can be treated with drugs mentioned above and with addition or increased dosage of steroid. Pulsed intravenous methylprednisolone may be given during severe flares, followed by oral prednisolone [114]. While use of steroid is associated with elevated BP and new onset diabetes, it is probably not related to cleft lip and palate as previously thought [123, 124] (**Table 6**).


**47**

*Lupus Nephritis: Current Updates*

*6.1.3 After pregnancy*

*DOI: http://dx.doi.org/10.5772/intechopen.96891*

commonly available in clinical practice.

of glomerular endotheliosis would suggest the latter [128].

again should be based on the usual indications accordingly [129].

or captopril can be safely used during breastfeeding [131] (**Table 6**).

having stable renal function during pregnancy [133].

**6.2 Renal transplantation in lupus nephritis**

Differentiating between pre-eclampsia and LN flare in pregnancy may be difficult, especially after 20 weeks gestation. Features like proteinuria, high BP, thrombocytopenia and renal impairment are common in both conditions. Red cell cast in urine, abnormal level of complements and anti-dsDNA may point toward LN flare [125]. Elevated soluble fms-like tyrosine kinase 1 (sFlt1)/placental growth factor (PlGF) ratio may assist in predicting pre-eclampsia [126, 127] although not

Renal biopsy may be required during pregnancy but poses increased risk of complications. In a systematic review involving data on renal biopsies performed during pregnancy, overall complication rate was higher at 7%, compared to 1% when performed post-partum. Importantly, 4 biopsies during pregnancy had major bleeding complications that required blood transfusion, with median gestational age of 25 weeks; hence, biopsy should only be considered early during the course of pregnancy when results may lead to changes in therapy. Biopsy should be considered if LN flare is suspected and to distinguish it from pre-eclampsia, with finding

Multidisciplinary team approach and patients' engagement are prudent during severe LN flare, as pregnancy termination may be considered with risks and benefits weighed carefully, so that patient can be treated with urgent cytotoxic drugs. Overall rate for preterm delivery and Caesarean section are higher in patients with LN. For patients with non-active disease, delivery at term should be aimed. In those likely to deliver prematurely, dexamethasone should be given to accelerate foetal lung maturation. Delivery should be aimed after 34 weeks to minimise neonatal adverse outcomes; nonetheless, this strategy relies on the overall clinical picture. Timing of delivery is determined by usual obstetric indications and risk of renal deterioration. Mode of delivery does not seem to affect maternal renal function and

The WHO recommends breastfeeding for all babies until 6 months of age, even in patients on immunosuppressive therapy. Although studies found trace amount of immunosuppressives excreted into breast milk, the amount absorbed by infant is negligible and do not exert any clinical effect [130]. Hence, immunosuppressives deemed safe during pregnancy such as corticosteroid, AZA and CNIs can be safely taken during breastfeeding [114]. Post-partum, regular antihypertensive drugs such as amlodipine or bisoprolol can be reinstated and RAAS blockers such as enalapril

Postpartum risk of thromboembolic disease increases in SLE especially in active LN patients with nephrotic-range proteinuria. Preventative measure with heparin during postpartum period is controversial, but may be considered in active LN patients with risk factors such as advanced age, obesity, Caesarean section delivery, and pre-eclampsia [132]. For patients with chronic kidney disease and significant proteinuria during pregnancy, careful monitoring after delivery is required as decline in renal function may accelerate within 6–12 months postpartum, despite

Approximately 10–20% of patients with LN will progress to ESRD, with young female of African ancestry having the highest risk [8, 134]. In general, outcome for renal transplant is better compared to dialysis particularly with preemptive transplantation, including in patients with LN [135]. However, many patients

#### **Table 6.**

*Summary of immunosuppressive drugs during perinatal period.*

#### *Lupus Nephritis: Current Updates DOI: http://dx.doi.org/10.5772/intechopen.96891*

*Lupus - Need to Know*

Mycophenolate exposure during

*\*IUGR: Intra-uterine growth retardation.*

*Baseline risk assessment during pregnancy.*

pregnancy

**Table 5.**

During early pregnancy, BP would usually remain normal even in patients who required antihypertensive before pregnancy. Gradually, BP may rise as pregnancy progresses, requiring reintroduction of hypertensive medications such as labetalol, methyldopa or nifedipine. BP control should be targeted to be less than 140/90 mmHg [119]. As these patients are at higher risk to develop pre-eclampsia, high dose calcium supplementation and aspirin should be prescribed before entering 16 weeks of gestation [120, 121]. Ultrasound screening including uterine and umbilical artery Doppler to detect early signs of placental insufficiency may be

Chronic kidney disease Worsening renal function, prematurity, IUGR, preeclampsia [118]

ocular malformation [109]

Miscarriage and embryopathy involving ear, mouth, finger and

Active disease during conception Pregnancy loss, pre-eclampsia, IUGR, prematurity [114]

Proteinuria >1 g/day Worsening renal function, pre-eclampsia [115] Uncontrolled hypertension Pregnancy loss, IUGR, prematurity, pre-eclampsia [114]

Presence of SS-A antibody Neonatal lupus (congenital heart block) [116] History of recent acute kidney injury Pre-eclampsia, IUGR and prematurity [117]

Hydroxychloroquine is safe during pregnancy and discontinuation has been associated with lupus flare. It also significantly reduces the risk of foetal congenital heart block in patients with positive SS-A (anti-Ro) [116]. Other drugs for consideration in LN and compatible with pregnancy include AZA, CNIs (TAC, Cys), plasma exchange and intravenous immunoglobulins. Data on RTX in pregnancy is limited, although some clinicians have used it safely in early trimester without apparent complication [122]. LN flare during pregnancy can be treated with drugs mentioned above and with addition or increased dosage of steroid. Pulsed intravenous methylprednisolone may be given during severe flares, followed by oral prednisolone [114]. While use of steroid is associated with elevated BP and new onset diabetes, it is probably not related to cleft lip and palate as previously thought [123, 124] (**Table 6**).

**Medication Pregnancy Breastfeeding**

Mycophenolate Increased risk of congenital malformation and miscarriage Limited data, not

Azathioprine Relatively safe. Alternative to mycophenolate Relatively safe Hydroxychloroquine Relatively safe. Improve outcome in antiphospholipid syndrome Relatively safe

Calcineurin inhibitor Increase risk of high blood pressure and diabetes. Relatively safe Relatively safe

Immunoglobulin Safe in pregnancy. Headache & rash common side effect Relatively safe

Glucocorticoids Increase risk of hypertension, preeclampsia, GDM. May have neutral effect on cleft lip and palate

Rituximab Limited data. No teratogenic effect in animal. 1st trimester use

may be possible.

*Summary of immunosuppressive drugs during perinatal period.*

*\*GDM: Gestational diabetes mellitus.*

Cyclophosphamide Increased risk of teratogenicity, especially in 1st trimester May cause infants' bone

marrow suppression

recommended

Relatively safe

Limited data

performed at regular interval, especially in high-risk patients.

**Baseline risk assessment Possible complication**

**46**

**Table 6.**

Differentiating between pre-eclampsia and LN flare in pregnancy may be difficult, especially after 20 weeks gestation. Features like proteinuria, high BP, thrombocytopenia and renal impairment are common in both conditions. Red cell cast in urine, abnormal level of complements and anti-dsDNA may point toward LN flare [125]. Elevated soluble fms-like tyrosine kinase 1 (sFlt1)/placental growth factor (PlGF) ratio may assist in predicting pre-eclampsia [126, 127] although not commonly available in clinical practice.

Renal biopsy may be required during pregnancy but poses increased risk of complications. In a systematic review involving data on renal biopsies performed during pregnancy, overall complication rate was higher at 7%, compared to 1% when performed post-partum. Importantly, 4 biopsies during pregnancy had major bleeding complications that required blood transfusion, with median gestational age of 25 weeks; hence, biopsy should only be considered early during the course of pregnancy when results may lead to changes in therapy. Biopsy should be considered if LN flare is suspected and to distinguish it from pre-eclampsia, with finding of glomerular endotheliosis would suggest the latter [128].

Multidisciplinary team approach and patients' engagement are prudent during severe LN flare, as pregnancy termination may be considered with risks and benefits weighed carefully, so that patient can be treated with urgent cytotoxic drugs. Overall rate for preterm delivery and Caesarean section are higher in patients with LN. For patients with non-active disease, delivery at term should be aimed. In those likely to deliver prematurely, dexamethasone should be given to accelerate foetal lung maturation. Delivery should be aimed after 34 weeks to minimise neonatal adverse outcomes; nonetheless, this strategy relies on the overall clinical picture. Timing of delivery is determined by usual obstetric indications and risk of renal deterioration. Mode of delivery does not seem to affect maternal renal function and again should be based on the usual indications accordingly [129].

#### *6.1.3 After pregnancy*

The WHO recommends breastfeeding for all babies until 6 months of age, even in patients on immunosuppressive therapy. Although studies found trace amount of immunosuppressives excreted into breast milk, the amount absorbed by infant is negligible and do not exert any clinical effect [130]. Hence, immunosuppressives deemed safe during pregnancy such as corticosteroid, AZA and CNIs can be safely taken during breastfeeding [114]. Post-partum, regular antihypertensive drugs such as amlodipine or bisoprolol can be reinstated and RAAS blockers such as enalapril or captopril can be safely used during breastfeeding [131] (**Table 6**).

Postpartum risk of thromboembolic disease increases in SLE especially in active LN patients with nephrotic-range proteinuria. Preventative measure with heparin during postpartum period is controversial, but may be considered in active LN patients with risk factors such as advanced age, obesity, Caesarean section delivery, and pre-eclampsia [132]. For patients with chronic kidney disease and significant proteinuria during pregnancy, careful monitoring after delivery is required as decline in renal function may accelerate within 6–12 months postpartum, despite having stable renal function during pregnancy [133].

#### **6.2 Renal transplantation in lupus nephritis**

Approximately 10–20% of patients with LN will progress to ESRD, with young female of African ancestry having the highest risk [8, 134]. In general, outcome for renal transplant is better compared to dialysis particularly with preemptive transplantation, including in patients with LN [135]. However, many patients

may not be in complete remission despite dialysis initiation, making preemptive transplantation difficult. Current guidelines suggest that clinical lupus activity and ideally, serologically should be quiescent for 6 months and on no or minimal immunosuppression prior to transplantation [47, 136]. Even if on dialysis, the waiting time for transplant should be maximally shortened to reduce potential risk of graft failure [137].

Although the benefit of transplantation is clear, earlier studies have suggested that LN patients may have worse survival outcome compared to ESRD patients of other aetiologies; however, more contemporary studies seem to abrogate this finding [138]. Clinically relevant recurrence rate of SLE post transplantation is less than 5%, but it increases the risk of graft failure [136]. The rate may even be higher if electron microscopy finding is included and protocol biopsy implemented; nevertheless, the lower rate is probably due to the similar immunosuppressive therapy used in both transplant recipient and active LN.

During pre-transplant evaluation, particular attention should be given to screening of aPL as its' presence increases the risk of graft thrombosis. Patients with APS would require careful consideration of perioperative anticoagulation to prevent graft loss. Presence of anti-dsDNA or low complement level is not a predictor for renal transplant outcomes. SLE patients have higher risk for cardiovascular mortality hence will require careful cardiac evaluation prior to transplantation [138]. Recurrence of LN after transplantation can be treated by increasing the dose of the immunosuppressive drugs already being used post transplant. CYC may be considered in severe or aggressive disease while RTX has been used in resistant cases [139].

There is concern in LN patients of having higher risk to develop cancer with prolonged exposure to immunosuppression. Previous exposure to CYC doubles the risk for cancer post transplantation, primarily of the skin [140]. Prior use of immunosuppressive therapies before transplant also increases the risk for non-Hodgkin's lymphoma, anogenital, breast, renal and bladder cancers [141, 142]. Furthermore, prolonged corticosteroid exposure in transplanted SLE patients should adhere to the screening and treatment recommendations on bone health [143].
