Triphasic: Preeclampsia, Systemic Lupus Erythematosus, and Severe Neutropenia With Use of Granulocyte Colony Stimulating Factor in the Partum and Postpartum Period
Year: 2023
Type: article
Study design: Case Report
Abstract: A 28-year-old female who self identifies as White, non-Hispanic ethnicity with a diagnosis of childhood-onset systemic lupus erythematosus (SLE) presents with acute onset hypertension, lower extremity edema, shortness of breath, and headache during her second trimester of pregnancy. The patient was diagnosed at age 8 years in the setting of thrombocytopenia, hemolytic anemia, hypocomplementemia, elevated double-stranded DNA (dsDNA) antibody, anti-Ro/SSA positivity, and triple antiphospholipid antibody (aPL) panel positivity. At age 16 years, she developed hypertension, proteinuria, and hematuria and underwent renal biopsy that demonstrated class II lupus nephritis (LN). Additionally, in adolescence she was found to have mild mitral valve regurgitation stable on annual echocardiogram and previously followed by a pediatric cardiologist. Treatment for her SLE included monthly pulse-dose glucocorticoids, mycophenolate mofetil 1,500 mg twice a day and hydroxychloroquine (HCQ). Overall, SLE was clinically stable, but she continued to have serologic activity as noted by elevated dsDNA, hypocomplementemia, and elevated inflammatory markers. Prior to pregnancy, she was maintained on mycophenolate mofetil 1,500 mg twice a day, HCQ, lisinopril, and nifedipine until preconception counseling (Table 1). At age 28 years she underwent preconception counseling, and her mycophenolate mofetil was changed to azathioprine while HCQ was maintained and low-dose aspirin was started. Additionally, lisinopril was discontinued and the antihypertensive regimen was converted to monotherapy with nifedipine. Given the anti-Ro/SSA positivity, she was followed by Maternal-Fetal Medicine and underwent serial fetal cardiac ultrasounds from weeks 16 to 24 without evidence of a heart block. The first trimester of pregnancy was uncomplicated, with stable blood pressure and SLE clinical and serologic markers. During the second trimester, while creatinine and the glomerular filtration rate (GFR) remained stable, urinalysis revealed mild hematuria with a spot urine:protein:creatinine (UPC) ratio of 0.3 (Table 1). At 25 weeks gestation, she developed persistent hypertension, despite antihypertensive therapy with nifedipine, which was up-titrated with subsequent addition of labetalol. At 26 weeks gestation, given worsening proteinuria (24-hour urine protein of 1.3 grams) and precipitous thrombocytopenia (platelets 23,000/μl) (Table 1), her local health care team, including a rheumatologist, nephrologist, and Maternal-Fetal Medicine, were concerned for SLE flare versus preeclampsia and initiated a course of high-dose intravenous (IV) solumedrol 500 mg for 3 days, followed by oral prednisone 60 mg daily for 10 days, and subcutaneous enoxaparin 40 mg daily for deep vein thrombosis prophylaxis, given positive aPL and proteinuria in the second trimester of pregnancy. A course of IV immunoglobulin (IVIG) 1 gram/kg was administered for 2 days as treatment of thrombocytopenia. At 27 weeks gestation she presented to her outpatient obstetrician with acute onset of severe lower-extremity edema, shortness of breath, and headache requiring hospital admission. Vital signs showed blood pressure 160/110 and oxygenation saturation of 88% on room air. She was noted to have a cushingoid appearance without malar rash or nasal or oral ulcers. Diminished breath sounds were noted in bilateral lung bases. Lower extremities demonstrated 3+ pitting edema without overt synovitis, and there was no evidence of livedo reticularis on dermatologic examination. On admission she was noted to have acute kidney injury, with peak creatinine 4.5 mg/dl (baseline creatinine 0.74 mg/dl), 24-hour urine protein collection of 1.3 grams, hematuria, acute microangiopathic hemolytic anemia with hemoglobin 7.7 grams/dl, and worsening thrombocytopenia. Uric acid level was elevated up to 10.6 mg/dl (reference range 2.3–6.3 mg/dl) (Table 1) without evidence of a hepatocellular transaminitis, as aspartate aminotransferase (AST) was 60 U/liter and alanine aminotransferase (ALT) 52 U/liter. The primary clinical concern during the first admission was for: 1) severe preeclampsia given the degree of hypertension, proteinuria ≥300 mg/day, a doubling of the creatinine, severe thrombocytopenia, and new onset severe headache, versus 2) SLE/LN flare, as mean 24-hour proteinuria exceeded 2.9 grams, with hypocomplementemia, elevated dsDNA, thrombocytopenia, and microangiopathic hemolytic anemia, versus 3) obstetric aPL antibody syndrome (obstetric-APS) in the setting of aPL positivity, preterm birth <34 weeks with features of severe preeclampsia, and concern for thrombotic microangiopathy. On first admission, she was treated with pulse-dose IV solumedrol 1 gram, IV magnesium and IV diuretic. Given concern for severe preeclampsia with systolic blood pressure ≥160 mm Hg and diastolic blood pressure ≥110 mm Hg on 2 separate occasions at least 4 hours apart while at rest, severe thrombocytopenia, proteinuria, and cerebral symptoms of severe headache, she underwent emergent cesarean section (1). Following the cesarean section, her symptoms progressed and she developed acute hypoxic respiratory failure, with plain films demonstrating diffuse, bilateral pulmonary infiltrates requiring intubation and mechanical ventilation. No computed tomography (CT) was obtained outside prior to transfer. Following the cesarean section, laboratory results were notable for progression of thrombocytopenia, with nadir to 11,000/μl from 57,000/μl prior to admission. Given the complexity of her care, she was transferred to our facility for further management. She arrived at our facility on postoperative day 1 from emergent cesarean section and remained intubated in the setting of diffuse bilateral airspace disease consistent with acute repository distress syndrome. At our facility, initial vital statistics were notable for blood pressure at 99/69, heart rate 49, respiratory rate 14, and sating 94% on mechanical ventilation. Physical examination was notable for anasarca, livedo reticularis, and a new holosystolic apical murmur in a mechanically ventilated patient. Other pertinent positive findings included elevated jugular venous pressure and 3+ peripheral edema of the bilateral upper and lower extremities. Examination did not reveal hepatosplenomegaly. Laboratory results were notable for progressive hemolytic anemia, thrombocytopenia, leucopenia, proteinuria, hypocomplementemia, and elevated dsDNA (Table 2). Imaging included CT of the chest that demonstrated diffuse centrilobular ground-glass, bilateral pleural effusions and body wall anasarca. A transthoracic echocardiogram (TTE) revealed severe mitral valve stenosis and regurgitation (Table 2). When compared to her previous echocardiograms from 2013, 2014, and 2015, a significant worsening in mitral valve regurgitation was noted and a new, severe mitral valve stenosis was identified, with a rheumatic-appearing mitral valve. No valvular vegetations were identified on TTE. TEE was deferred at this time as the patient was extubated. Given her new mitral valve findings, progression of hemolytic anemia, thrombocytopenia, proteinuria, obstetric-APS, and hypocomplementemia, we formulated a differential diagnosis of SLE/LN flare versus thrombotic microangiopathy with coexisting Libman-Sacks endocarditis, considering the degree of severe mitral valve regurgitation. Other differential diagnoses included culture-negative infective endocarditis and lupus valvulitis. When she arrived at our facility, she was continued on treatment with pulse-dose steroids with IV solumedrol 1 gram daily until extubated and then transitioned to 40 mg every 8 hours for 10 days, followed by prolonged oral regimen taper and diuretics, and initiated on plasma exchange daily for 3 days. Despite therapy, she continued to have progressive thrombocytopenia and hemolytic anemia requiring an additional course of IVIG for 5 days and ultimately rituximab dosed at 375 mg/m2 weekly for 4 weeks, with gradual improvement of cell counts. Her prepartum mycophenolate mofetil was resumed (Table 2). Additionally, she was treated with a 7-day course of antibiotic therapy as sputum cultures returned positive for methicillin-sensitive S. aureus. Blood cultures were negative and formal bronchoscopy with bronchoalveolar lavage was not pursued at this time. Given ongoing anasarca and acute repository distress syndrome, she ultimately required continuous hemodialysis that was transitioned to intermittent as she stabilized. Due to the severity of her cardiopulmonary disease, cardiothoracic surgery was consulted in the setting of persistent hypoxemia and recurrent flash pulmonary edema, prompting removal to the operating room for mitral valve replacement surgery. Following mechanical mitral valve replacement, she was initiated on lifelong anticoagulation therapy with Warfarin. Final mitral valve pathology was consistent with Libman-Sacks endocarditis and healed valvulitis (Figure 1). Final mitral valve tissue and fungal cultures were negative. Repeat blood cultures and serum testing for Bartonella, Coxiella, Mycoplasma hominis, Brucella, histoplasmosis, and blastomycosis were obtained and were negative. Final 16S rRNA gene sequencing for bacterial identification of the mitral valve was negative. During admission, a renal biopsy was not pursued given the degree of thrombocytopenia, anticoagulation, and ongoing hemodialysis, indicating high bleeding risk. Following acute prolonged hospitalization, her renal function improved, and she no longer required hemodialysis at the time of discharge. Two weeks following discharge, she was readmitted to our facility with acute onset fever and found to have new severe leucopenia (Table 3). Vital signs were notable for fever to 103.2° F and tachycardia. A sternotomy incision was clear, dry, and intact without drainage. Mechanical heart sounds were appreciated. The abdomen was notable for suprapubic erythema at the Pfannensteil surgical site, with purulent drainage and surrounding induration with tenderness to palpation (Table 3). Laboratory results demonstrated leukopenia (white blood cells ↓1,100/μl) with neutropenia (absolute neutrophil count [ANC] ↓600/μl), acute kidney injury (creatinine ↑2.08 mg/dl, GFR ↓32 ml/minute/1.73 m2) with proteinuria (UPC ↑2.33 grams) in addition to elevated ferritin (↑1,250 ng/ml), fibrinogen (↑511 mg/dl), triglycerides (↑295 mg/dl), and a pattern of hepatocellular transaminitis (AST ↑156 U/liter, ALT ↑472 U/liter) (Table 3). CT of the abdomen and pelvis noted inflammatory changes of the skin and subcutaneous fat consistent surrounding the Pfannensteil surgical site (Table 3). The primary clinical concern at the time of the third admission was for severe neutropenic fever in the setting of a surgical site infection in an immunosuppressed patient. However, given laboratory findings of neutropenia, hypertriglyceridemia, and hyperferritinemia a concern for early macrophage activation syndrome/hemophagocytic lymphohistiocytosis was raised. A soluble interleukin-2 was not obtained, given a prolonged turn-around time of approximately 1 week at our institution. Further bone marrow biopsy was deferred by the hematology team given higher concern for neutropenic fever in a setting of infection and immunosuppression. The patient was treated with IV antibiotics and transitioned to oral antibiotics at the time of discharge (Table 3). Given a suspicion for neutropenic fever, hematology was consulted and recommended initiation of granulocyte colony stimulating factor (G-CSF) for management of severe leucopenia. She received 2 doses of G-CSF with recovery of the cell count. At 1.5 weeks following discharge and the last dose of G-CSF, the patient presented to our specialty Lupus Nephritis clinic with severe proteinuria as demonstrated by progression from 2.33 grams to 9.97 grams, consistent with SLE/LN flare. Given concern for flare, mycophenolate mofetil dosing was judiciously increased, and oral glucocorticoids were continued with close laboratory and clinical monitoring. Pregnancy in patients with existing SLE, LN, and/or APS is prone to complications, including disease flare, preeclampsia, and preterm birth, to name a select few that were demonstrated in our patient's case. Furthermore, active LN during the partum period poses the greatest risk to maternal-fetal complications and requires a multidisciplinary team approach to guide disease management and treatment (3, 4). Below, we propose our main take-away points from each dilemma complicating this case. Pregnancy in the setting of SLE is prone to a 20-fold increased risk in maternal mortality with an odds ratio of 2.4 for preterm birth and 3.0 for preeclampsia (5), and with approximately 25% of patients experiencing a lupus flare during pregnancy (3). As 15% to 30% of SLE patients with a flare during pregnancy had severe disease manifestations commonly involving the kidney and other internal organs, SLE flare during pregnancy associated with poor maternal and fetal outcomes again reiterates the importance of well-controlled SLE/LN prior to conception (6). In a single-center retrospective study of 72 patients, the study authors identified a prevalence of preterm delivery, before 37 weeks of gestation, to be 38% in SLE, as seen in our patient's case. Further, adverse outcomes are associated with active LN and hypertension during the first trimester, and such patients have a higher risk of developing preeclampsia subsequently during the later trimesters (7). Approximately 30–40% of patients with SLE are positive for aPL antibodies, with approximately 40% of patients with SLE with aPL positivity developing clinical features of APS, and with venous thromboembolism as the most common manifestation (8, 9). Pregnancy morbidity in APS includes miscarriage, late intrauterine fetal demise, and severe preeclampsia. Thus all patients with SLE should be screened for aPL positivity during prepartum management, including β2 glycoprotein IgG and IgM, anticardiolipin antibody IgG and IgM, and lupus anticoagulant (8-11). Key attention should be given to lupus anticoagulant, as it carries the strongest association with thrombotic disease and adverse pregnancy outcomes after 12 weeks of pregnancy as seen in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus study of pregnancy morbidity due to aPL antibodies (12-14). With regard to treatment of aPL-positive patients without a history of thrombosis during pregnancy, low-dose aspirin should be initiated to reduce the risk of preeclampsia (12). If the patient has a history of obstetric complications, including late fetal demise (>10 weeks), multiple early losses, intrauterine growth restriction, and a history of severe preeclampsia, the treatment of choice includes prophylactic dosing of low molecular weight heparin (dosed twice daily) in addition to low-dose aspirin, which should be initiated as soon as pregnancy is confirmed and switched to unfractioned heparin 4 weeks prior to delivery, with continuation of heparin 6 weeks postpartum (15, 16). Finally, if there is a history of a known postthrombotic event, the recommendation is to initiate full-dose heparin and low-dose aspirin (16). Patients with well-controlled LN should be transitioned to azathioprine therapy during preconception counseling, and angiotensin converting enzyme inhibitor/angiotensin receptor blocker should be discontinued (11). Our expert panel established that this transition should occur at least 3 months prior to pregnancy to ensure that LN remains controlled (as monitored by urinalysis, urine protein:creatinine ratio, creatinine, and eGFR) following alteration in pharmacotherapy. As previously described by Smyth et al, active LN poses the greatest risk to the outcome of pregnancy in women with lupus (3). As 15% to 30% of patients with SLE who have a flare during pregnancy had severe disease manifestations, commonly involving the kidney and other internal organs, SLE flare during pregnancy associated with poor maternal and fetal outcomes again reiterates the importance of well-controlled SLE/LN prior to conception (6). Moreover, among women with SLE, active LN, and serum creatinine of >2.8 mg/dl at the time of conception, up to 85% develop maternal complications, including preeclampsia, 60% develop intrauterine growth restriction, and 70% experience preterm labor (17). Other factors that determine the risk of preeclampsia in patients with SLE include hypertension and thrombocytopenia (18). Differentiation between preeclampsia and active SLE/LN continues to be a diagnostic quandary, as both may present with progressive proteinuria, declining renal function, hypertension, lower-extremity edema, and thrombocytopenia (19). Preeclampsia is defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg on at least 2 occasions at least 4 hours apart after 20 weeks of gestation in a previously normotensive patient AND the new onset of 1 or more of the following: proteinuria ≥0.3 grams or dipstick ≥2+ if a quantitative measurement is unavailable, platelet count <100,000/μl, serum creatinine >1.1 mg/dl or doubling of the creatinine concentration (absent other renal disease), liver function tests >2 times the upper limit of normal, pulmonary edema, new-onset and persistent headache not due to alternative diagnoses and not responding to usual analgesic doses, or visual symptoms (1), whereas severe preeclampsia is defined as systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg on 2 separate occasions at least 4 hours apart while at rest, central nervous system dysfunction with new-onset cerebral or visual disturbances, impaired liver function >2 times the upper limit of normal or severe persistent right upper quadrant or epigastric pain, severe thrombocytopenia <100,00/μl, renal insufficiency with serum creatinine >1.1 mg/dl or a doubling of the serum creatinine, and pulmonary edema, of which 4 of the 6 features were present in our patient (1). As we learned from our expert panelists, a serum uric acid level >5.5 mg/dl, urinary calcium level <195 mg/dl, and elevated liver enzymes be in features of preeclampsia versus SLE/LN and disease activity and may guide treatment In a retrospective study of patients, women had preeclampsia with severe and a serum uric acid level mg/dl was associated with renal and preeclampsia with severe features Further, in a study of obstetric patients, 24-hour urine collection was and the 28 patients who developed preeclampsia had a urine calcium level of mg/dl between remains and an remains for has the of renal biopsy during the partum including the of for the management of LN and the and and LN not the clinical renal biopsy during pregnancy In a by et al, the study authors that patients who develop evidence of new or progressive renal disease in the partum period should be for renal biopsy if of diagnosis have and/or a renal biopsy management et the following to renal biopsy in patients with SLE during the partum 1) proteinuria 500 creatinine and results low aPL 2) of fetal on before and after biopsy fetal heart at weeks of gestation or 3) of bleeding risk by factors and platelet aspirin and for at least 1 week prior to the and biopsy if of anticoagulation are high a history of biopsy 28 weeks and if biopsy is not considering therapy and a biopsy during the postpartum period However, this study had a of women with SLE who underwent renal biopsy during pregnancy, and and further are to the and of renal biopsy in pregnancy. In a by et al, 2 patients with SLE were found to experience severe disease flare in association with the of G-CSF therapy The noted that both patients and in renal function following of G-CSF, indicating a and concern the of and for clinical In a study of 4 patients with SLE and an level to therapy and other of G-CSF was administered for of complications and/or as therapy during infection The study authors found that G-CSF be an and a treatment for neutropenia in patients with SLE with of SLE flare. If G-CSF is it should be at the dose and with close the level to In our patient the of active SLE/LN and of during her first pregnancy as she disease flare, preeclampsia, and preterm birth at 27 Patients with and elevated dsDNA antibody serologic as seen in our have an of a normal pregnancy, as we learned from our expert preconception counseling and pregnancy Further, testing for aPL antibody panel positivity should be in all patients with SLE considering pregnancy, with attention to lupus anticoagulant positivity, as it the risk of poor pregnancy outcomes results guide to prophylactic therapy in patients with a history of thrombotic or a previous pregnancy to the risk of and preeclampsia. Patients with evidence of active renal disease in the partum period who to et should renal biopsy during the first and second trimester to further the diagnosis and guide treatment as kidney biopsy has demonstrated to be and Finally, G-CSF should be with clinical in patients with known SLE, as it flare and renal function If G-CSF is the dose and should be with close of laboratory and the level The authors to the patient for to her case. to the expert and for of our during the of the on Lupus Nephritis in of authors were in the or it for and all authors the to be for had to all of the in the study and for the of the and the of the The is not for the or of by the should be to the for the
Source: Arthritis Care & Research
DOI: 10.1002/acr.25138
Institution: University of Wisconsin–Madison
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,640
OpenAlex ID: W4366822663