Maternal Sjögren’s Disease and Its Long Shadow: Adult-Onset Seronegative Lupus Nephritis Following Congenital Heart Block

Abstract

Congenital complete atrioventricular block (CCAVB) is a well-recognized manifestation of neonatal lupus erythematosus (NLE), caused by transplacental transfer of maternal anti-Ro/Sjögren's Syndrome Type A (SSA) and anti-La/Sjögren's Syndrome Type B (SSB) antibodies. Although non-cardiac manifestations of NLE typically resolve within the first year of life, the long-term autoimmune risk in affected offspring remains unclear. We report a 24-year-old woman with CCAVB secondary to maternal Sjögren's disease who presented with acute heart failure, nephrotic-range proteinuria, bicytopenia, pericardial effusion, and findings concerning for Libman-Sacks endocarditis. Despite negative conventional lupus serologies, renal biopsy demonstrated Class IV/V lupus-like immune-complex glomerulonephritis with full-house immune complex deposition, leading the multidisciplinary team to favor seronegative lupus nephritis. This case demonstrates the diagnostic limitations of serology-based approaches in atypical lupus presentations and underscores the critical role of tissue biopsy. The case also raises questions regarding long-term autoimmune risk after autoimmune congenital heart block, an area for which prospective data and evidence-based surveillance strategies remain limited.

Introduction

Congenital complete atrioventricular block (CCAVB) is a rare but serious manifestation of neonatal lupus erythematosus (NLE), a passively acquired autoimmune disease caused by the transplacental passage of maternal Anti-Ro/Sjögren's Syndrome Type A (SSA) and Anti-La/Sjögren's Syndrome Type B (SSB) antibodies, most commonly seen in mothers who have Sjogren’s disease or systemic lupus erythematosus (SLE) [1]​. The prevalence of NLE is estimated to be one in 20,000 live births [2]. Although rare, the neonatal cardiac manifestations of passive autoantibody transmission exposure are well described, but the long-term autoimmune implications of NLE remain incompletely understood [3]. Because most non-cardiac NLE manifestations resolve after six to nine months, evidence-based recommendations for long-term autoimmune surveillance of affected offspring beyond this period are lacking [4]. Additionally, seronegative lupus nephritis is an uncommon and diagnostically challenging entity in which renal biopsy reveals histopathology, including the characteristic “full-house” immunofluorescence pattern, despite negative conventional SLE serologies such as antinuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) [5]. The frequency of ANA negativity in established SLE ranges from 4.9-22.3% based on the assay method, with two classic presentations: (1) renal-limited disease with persistent negative serologies and (2) patients with negative serologies who develop positive serologies on follow-up [6,7]. The development of seronegative lupus nephritis in a patient with a history of CCAVB has rarely been reported and serves to further question whether exposure to maternal antibodies may predispose to future autoimmune disease, warranting long-term clinical awareness and patient education.

Case presentation

A 24-year-old woman with a medical history of CCAVB with a permanent dual-chamber pacemaker secondary to maternal Sjogren’s disease presented with four weeks of progressive dyspnea on exertion and at rest, orthopnea, and paroxysmal nocturnal dyspnea (PND). In the five days prior to her admission, she had worsening bilateral leg swelling, which prompted her to seek medical attention. The patient's medical history was notable only for iron-deficiency anemia, but she had not had routine medical care since childhood. Family history was significant for Sjogren's disease in her mother and SLE in her maternal grandmother.

Her physical exam on admission was significant for anasarca with 2+ bilateral pitting edema, left lower sternal border diastolic murmur, and bibasilar lung crackles with diminished breath sounds bilaterally. An initial work-up on the day of admission showed anemia and thrombocytopenia with a normal white blood cell count. She also presented with acute kidney injury, with a 24-hour urine study showing nephrotic-range proteinuria of 11 g/24h (Table 1).

Table 1. Laboratory workup findings on initial presentation.

WBC: white blood cells; RBC: red blood cells; MCV: mean corpuscular volume; BUN: blood urea nitrogen; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; TBC: total iron-binding capacity; INR: international normalized ratio; aPTT: activated partial thromboplastin time; BNP: B-type natriuretic peptide.

Laboratory test	Patient value	Reference range
WBC (×10³/µL)	4.01	3.5–10.5
RBC (×10⁶/µL)	3.49	3.90–5.03
Hemoglobin (g/dL)	8.4	12.0–15.5
Hematocrit (%)	27.8	34.9–44.5
MCV (fL)	79.7	81.6–98.3
Platelets (×10³/µL)	48	150–450
Absolute lymphocyte count (×10³/µL)	1.2	0.9–2.9
Sodium (mmol/L)	135	136–145
Potassium (mmol/L)	4.8	3.5–5.3
Chloride (mmol/L)	110	98–110
Bicarbonate (mmol/L)	18	20–31
BUN (mg/dL)	54	6–24
Creatinine (mg/dL)	2.68	0.5–1.0
AST (U/L)	17	10–36
ALT (U/L)	9	6–29
Alkaline phosphatase (U/L)	71	33–115
Total bilirubin (mg/dL)	0.3	0.2–1.2
Total protein (g/dL)	6.8	6.4–8.4
Albumin (g/dL)	1.9	3.6–5.1
ESR (mm/hr)	87	2–15
CRP (mg/dL)	1.7	<0.8
Ferritin (ng/mL)	310	11–307
Serum iron (µg/dL)	28	35–145
TIBC (µg/dL)	208	250–400
Iron saturation (%)	13.5	20–55
Urine pregnancy test	Negative	Negative
Urinalysis	4+ protein, 3+ blood, many RBCs, few WBCs	—
Urine microalbumin/creatinine ratio (mg/g)	8,058	<30
Prothrombin time (s)	11.3	9.0–13.4
INR	1.04	0.8–1.2
aPTT (s)	46.7	23–33
D-dimer (ng/mL FEU)	1,996	0–500
BNP (pg/mL)	1,146	<100
Troponin (ng/L)	202	<51
Hepatitis serologies	Nonreactive	Nonreactive

Blood cultures collected on admission remained negative at five days. A 2-D transthoracic echocardiogram (TTE) showed a decreased left ventricular ejection fraction (LVEF) of 30 to 35%, mild pericardial effusion, and severe aortic regurgitation with a flat vegetation on the non-coronary cusp of the aortic valve (Figure 1). 

Figure 1. 2D echocardiogram.

Parasternal long axis view of flat vegetation of the non-coronary cusp of the aortic valve.

She received care for fluid overload with intravenous loop diuretics in the setting of heart failure exacerbation and nephrotic syndrome. Given the presence of bicytopenia, kidney involvement with nephrotic-range proteinuria, an echocardiogram with pericardial effusion, and a strong autoimmune family history, a workup for autoimmune conditions was initiated (Table 2).

Table 2. Serologic and immunologic profile at presentation.

AI: antibody index; anti-dsDNA: anti-double-stranded DNA; ANA: antinuclear antibody; RNP: ribonucleoprotein; C3: complement component 3; C4: complement component 4; anti-SSa: anti-Sjögren's-syndrome-related antigen A; anti-SSb: anti-Sjögren's-syndrome-related antigen B; anti-GBM: anti-glomerular basement membrane; M2 antibody: antimitochondrial M2 antibody; C-ANCA: cytoplasmic antineutrophil cytoplasmic antibody; P-ANCA: perinuclear antineutrophil cytoplasmic antibody; TPO: thyroid peroxidase.

Category	Lab  value	Normal range	Category	Lab value	Normal range
ANA	<1:80	<1:80 negative	Antiscleroderma-70 antibody	<0.2	0-0.9 AI
Anti-dsDNA	2	<5 negative	M2 antibody	<20	0-20 Units
Anti-smith	<0.2	0-0.9 AI	C-ANCA	<1:20	<1:20
Anti-histone	1.6	Negative <1  Weak positive 1-1.5  Moderate Positive 1.6-2.5  Strong positive >2.5	P-ANCA	<1:20	<1:20
RNP antibodies	0.2	0-0.9 AI	Atypical P-ANCA	<1:20	<1:20
C3	88	82-167 mg/dL
C4	14	12-38 mg/dL	TPO antibody	12	0-24 IU/mL
Actin antibody	6	0-19 Units	Cardiolipin IgG	32.9	Positive if >20
Anti-Jo-1	<0.2	0-0.9 AI	Cardiolipin IgA	19.2	Borderline if 15-28
Anti-Ro/SSa	0.2	0-0.9 AI	Cardiolipin Igm	negative	Negative if   < 10
Anti-La/SSb	<0.2	0-0.9 AI	Lupus anticoagulant	positive	negative
Direct antiglobulin test Coombs	Negative	Negative	Beta-2 glycoprotein antibodies (IgG, IgA,IgM)	negative	negative
Anti-GBM	<0.2	0-0.9 AI

Additionally, the 2D TTE findings with a flat vegetation and thickening of the aortic valve were concerning for Libman-Sacks endocarditis secondary to autoimmune disease after two blood culture samples remained negative for infection, and transesophageal echocardiogram (TEE) was planned once clinically stable. 

On day three of hospitalization, the patient also underwent a right renal biopsy with pathology showing immunofluorescence, demonstrating a “full-house” pattern of glomerular immune complex deposition, consistent with diffuse lupus. Light microscopy was consistent with combined diffuse proliferative lupus nephritis (International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class IV) [8] (Figure 2) and membranous lupus nephritis (ISN/RPS Class V) (Figure 3).

Figure 2. Light microscopy showing diffuse endocapillary hypercellularity consistent with diffuse proliferative lupus nephritis ISN/RPS Class IV.

ISN/RPS: International Society of Nephrology/Renal Pathology Society.

Figure 3. Glomerular capillary wall thickening with spike-and-pinhole formation along the glomerular basement membranes, supporting a membranous pattern of injury.

The modified National Institutes of Health (mNIH) activity index was seven out of 24, indicating moderately active disease, and the chronicity index was six out of 12, placing the patient in the high-chronicity category [9,10].

The renal biopsy demonstrated Class IV/V lupus-like immune-complex glomerulonephritis with a full-house immunofluorescence pattern. In the context of thrombocytopenia, serositis, antiphospholipid antibodies, and systemic illness, the multidisciplinary team favored seronegative SLE with lupus nephritis. Although the patient did not meet the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria because of ANA negativity, these criteria are intended for classification rather than diagnosis; the working diagnosis therefore relied on the total clinicopathologic presentation. The patient was administered pulse-dose intravenous methylprednisolone 500 mg daily from hospital day four to six. With the combined management of immunosuppression for SLE and aggressive diuresis for fluid overload due to congestive heart failure and nephrotic syndrome, the patient's clinical status improved dramatically with resolution of shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), and complete discontinuation of supplemental oxygen. Thereafter, mycophenolate mofetil and a prednisone taper were initiated, with plans to discharge the patient with close follow-up by rheumatology, nephrology, and cardiology for a follow-up TEE. 

About one month after she was discharged, she presented newly to the emergency department with worsening anasarca, shortness of breath, progressive bilateral lower limb edema, and worsening renal function after a scheduled TEE. The 2D TEE showed a stable LVEF of 30-35%, a trileaflet calcified aortic valve without valvular vegetations, moderate to severe aortic regurgitation, mildly dilated ascending aorta of 3.6 cm, and no pericardial effusion. Initially, the patient was hypotensive (93/35 mmHg; abnormal blood pressure is <90/60 mmHg or mean arterial pressure <65 mmHg), raising concern for developing cardiogenic shock, for which she was admitted to the medical intensive care unit for inotropic support.

On day two of her readmission, anticoagulation with heparin infusion was initiated due to the development of a large deep venous thrombosis (DVT) of the right common femoral vein. The combination of acute DVT and previously detected antiphospholipid antibodies raised strong concern for thrombotic antiphospholipid syndrome (APS). On day three of readmission, she developed gastrointestinal bleeding for which she underwent colonoscopy, which was remarkable for pseudomembranous colitis later confirmed to be due to Clostridium difficile infection and findings of discontinuous areas of ulcerated colonic mucosa.

Given rapidly evolving multiorgan dysfunction, DVT, distal ischemic and vasculitic skin changes (Figure 4), renal deterioration, and antiphospholipid antibody positivity, catastrophic antiphospholid syndrome (CAPS) was considered clinically.

Figure 4. Cutaneous and mucosal changes associated with suspected/probable CAPS.

(A) vasculitic changes involving the dorsal aspect of foot and distal foreleg; (B) Necrotic changes of the lips. CAPS: catastrophic antiphospholid syndrome.

However, histopathologic confirmation of small-vessel thrombosis was unavailable and several organ manifestations had plausible competing explanations; therefore, the presentation was treated as suspected/probable CAPS rather than definite CAPS. Repeat lupus anticoagulant and anticardiolipin antibody tests were positive when repeated at eight weeks, though the patient had already been started on heparin product at the time of testing. Other causes were considered unlikely, including ANCA vasculitis given the negative ANCA antibody results, disseminated intravascular coagulation given normal repeat d-dimer and fibrinogen levels, and heparin-induced thrombocytopenia, as the patient had not been exposed to heparin before symptom onset. 

The patient remained hospitalized, being treated for C. difficile infection with antibiotic therapy and antiphospholipid syndrome and probable CAPS with anticoagulation and steroids. Despite this, her condition continued to worsen, with the patient requiring continuous renal replacement therapy. She was eventually transferred to a tertiary center for rheumatologic management and plasma exchange (PLEX) with an anticipated plan for anti-CD20 therapy with rituximab if refractory. We were unable to obtain follow-up results after the transfer.

Discussion

Value of renal biopsy in seronegative SLE

This case highlights a rare presentation of maternal autoantibody-mediated congenital disease and severe adult-onset systemic autoimmunity. Our patient presented with acute decompensated heart failure, nephrotic-range proteinuria, cytopenias, pericardial effusion, and hematologic complications, raising suspicion for a systemic autoimmune condition. Despite negative conventional SLE serologies, renal biopsy demonstrated diffuse proliferative and membranous lupus nephritis (ISN/RPS Class IV/V) with "full house" immune complex deposition, strongly supporting a diagnosis of seronegative lupus nephritis [5]. The 2024 ACR guideline for lupus nephritis recommends prompt kidney biopsy whenever the condition is suspected, since histopathologic findings confirm the diagnosis, exclude mimicking conditions, and guide treatment [11]. This case underscores the limits of serologic testing alone for diagnosing SLE and reinforces the role of tissue biopsy when clinical suspicion is high. 

The characteristic histopathology of lupus nephritis is described as a "full-house" immunofluorescence pattern, defined by the glomerular deposition of IgG, IgM, IgA, C1q, and C3 [5]. Kudose et al. described five features that together help distinguish lupus nephritis: full-house staining, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions [12]. At least two of these five features yielded a sensitivity of 0.92 and a specificity of 0.89 for lupus nephritis, and four or more raised specificity to 0.98 [12]. These findings show that biopsy features can reliably distinguish lupus nephritis from other glomerulopathies even when serologies are negative, though rare mimics exist. 

In this case, the patient's history of CCAVB which itself is a manifestation of autoimmune injury in utero, raises the pre-test probability of autoimmune-mediated disease. A renal biopsy in such cases serves multiple important functions: it can confirm lupus nephritis even when serologies are negative, classify the disease by ISN/RPS histologic class to guide treatment planning, provide activity and chronicity scores, and rule out other glomerulopathies that can present similarly [5,11].

Current data and guideline recommendations for surveillance of patients with NLE

The development of systemic autoimmunity in this patient with prior autoimmune CCAVB raises questions regarding long-term autoimmune susceptibility in affected offspring; however, the relative contributions of prenatal autoantibody exposure and shared familial/genetic susceptibility remain uncertain. The 2020 ACR guidelines focus on prenatal screening with fetal echocardiography and early postnatal management, but stop short of recommending long-term surveillance for NLE offspring beyond six to nine months after birth [13]. The 2023 Society for Maternal-Fetal Medicine (SMFM) Consult Series notes that non-cardiac NLE manifestations (skin rash, anemia, thrombocytopenia, hepatitis) typically resolve within the first three to six months of life as maternal antibodies clear, but it likewise does not address longer-term surveillance [2]. Routine follow-up for transient noncardiac manifestations generally focuses on infancy, when maternally derived antibodies clear; however, evidence-based recommendations for long-term autoimmune surveillance of affected offspring are lacking.

Unlike the self-limited non-cardiac manifestations, CCAVB is irreversible and requires lifelong cardiology follow-up. The 2021 Pediatric and Congenital Electrophysiology Society (PACES) Expert Consensus Statement on Cardiovascular Implantable Electronic Devices in Pediatric Patients offers the most detailed guidance, citing a class 1 indication for pacemaker placement in symptomatic bradycardia, wide QRS escape rhythm, complex ventricular ectopy, ventricular dysfunction, or asymptomatic neonates/infants with a mean ventricular rate ≤50 bpm [14]. Lifelong follow-up is key because some CCAVB patients develop left ventricular cardiomyopathy despite pacing, from either antibody-mediated myocarditis or pacing-induced dyssynchrony [14].

Swedish registry data by Mofers et al. show a 5.7-fold increased risk of autoimmune disease in congenital heart block patients, and a 3.6-fold increased risk in their unaffected siblings [15]. The increased risk observed in both affected individuals and their unaffected siblings suggests that long-term autoimmune susceptibility may reflect a combination of familial/genetic factors and prenatal immune exposures. Andreoli et al. (2024) synthesized these findings and confirmed that late cardiovascular and autoimmune manifestations tend to peak after age 17 and appeared to correlate with the severity of in utero disease and the duration of pacing [16]. 

Regarding SLE specifically, some reviews have estimated that approximately 5% of infants with NLE may subsequently develop SLE, although long-term cohort data are sparse and estimates remain uncertain [17]. In one cohort of 49 children followed for at least eight years, 12% developed a well-defined systemic rheumatic or autoimmune disease including juvenile idiopathic arthritis, psoriasis, thyroid disease, iritis, type 1 diabetes, and nephrotic syndrome [18]. Notably, none developed SLE during at least eight years of follow-up in that particular cohort, though the sample size was small and follow-up may have been insufficient to capture later-onset disease [18].

Conclusions

This case describes a rare and severe presentation of seronegative lupus nephritis with suspected/probable catastrophic antiphospholipid syndrome in a young adult with a childhood history of CCAVB secondary to in utero exposure to maternal anti-Ro/SSA antibodies. It underscores the limitations of relying on conventional serologic testing alone and highlights the critical role of renal biopsy when clinical suspicion for lupus nephritis remains high despite negative serologies. In this case, the combination of nephrotic-range proteinuria, cytopenias, pericardial effusion, and systemic illness warranted further evaluation with a tissue biopsy, which demonstrated Class IV/V lupus nephritis with full-house immune complex deposition. These findings strongly supported the working diagnosis, defined the disease severity, and helped guide treatment while excluding alternative glomerular disorders. The eventual adult-onset development of systemic autoimmunity in a patient with exposure to maternal autoantibodies in utero raises the possibility of persistent autoimmune susceptibility beyond infancy. Although long-term cohort data suggest increased rates of some autoimmune conditions among individuals with anti-Ro/SSA-associated congenital heart block, a specific increased risk of adult SLE has not been established. Close follow-up with cardiology throughout childhood and adulthood should be a priority to monitor symptoms and ensure that cardiac function and overall cardiovascular health remain stable, particularly in individuals with CCAVB.

Beyond cardiac monitoring, clinicians may consider maintaining awareness of possible autoimmune manifestations and pursuing targeted evaluation, including serologic testing and assessment for renal involvement, especially when symptoms, examination findings, or other clinical features raise concern. Patient and family education may similarly focus on recognizing symptoms that warrant medical evaluation rather than implying a defined or quantifiable risk of future autoimmune disease. Prospective longitudinal studies are needed to clarify whether neonatal lupus, particularly with congenital heart block, is associated with increased autoimmune risk in adulthood and whether any extended surveillance strategy improves outcomes.