Introduction
KEY TEACHING POINTS
•
Congenital atrioventricular block (AVB) is the most recognized consequence of the
transplacental passage of anti-Ro/SSA antibodies from the mother to the fetus. Although
traditionally considered invulnerable, the adult conduction system also may represent
a target for these antibodies.
•
Recent data suggest 2 possible forms of anti-Ro/SSA–associated AVB in adults: (1)
an acquired form, resulting from a direct and reversible autoantibody-mediated electrophysiological
inhibition of cardiomyocyte calcium channels, and (2) a late-progressive congenital
form related to a subclinical, prenatally established structural damage induced by
maternally acquired anti-Ro/SSAs, with a subsequent autoantibody-independent worsening
with age until a diagnosis in the patient’s adulthood. Nevertheless, in some patients
both the pathogenic mechanisms are concomitantly involved (mixed form).
•
Whereas in the acquired form the patient shows circulating anti-Ro/SSAs, only the
patient’s mother is seropositive in the late-progressive congenital form. Thus, a
recovery potential of immunosuppressive therapy is expected in the acquired form only.
•
In adults with unexplained AVB, even in the absence of signs of connective tissue
disease, a specific anti-Ro/SSA testing (enzyme-linked immunosorbent assay + Western
blot) in the patient and patient’s mother may be of diagnostic value. If anti-Ro/SSAs
are detected in the patient, immunomodulating therapy may induce a rapid AVB recovery,
thus avoiding or delaying pacemaker implantation.
A large body of evidence links the presence of circulating anti-Ro/SSA antibodies
(anti-Ro/SSAs) in a mother with the risk of her newborn developing neonatal lupus,
a paradigmatic model of transplacental passively acquired autoimmunity whose main
cardiac manifestation is congenital complete atrioventricular block (congenital-III°AVB).
1
Although the precise underlying mechanisms of the block have not been fully elucidated,
many experimental studies have demonstrated the ability of anti-Ro/SSA to biochemically
cross-react with L-type and T-type calcium channels and thus significantly inhibit
the related currents, both of which play a key role in the slow action potential of
the conduction system cardiomyocytes.2, 3 This interaction, at least in the initial
acute phase, is electrophysiologically reversible (spontaneously or after appropriate
immunosuppressive treatment of the mother), and in some cases may progress to an inflammatory-driven
irreversible structural damage of the conduction system (ie, the findings characterizing
the congenital-III°AVB).2, 4
Anti-Ro/SSAs, including the anti-Ro/SSA-52kD and anti-Ro/SSA-60kD subtypes, are frequently
found in patients with connective tissue diseases (CTDs), particularly in those with
Sjögren syndrome (30–95%) and systemic lupus erythematosus (30–50%), but also in 0.5–2.7%
of the healthy population.
4
Although it is believed that adult heart does not represent an immunologic target
for anti-Ro/SSA, increasing data indicate that these autoantibodies may also affect
the adult conduction system, although to a lesser extent than the fetal heart.
5
Accordingly, we have recently proposed the existence of 2 possible forms of anti-Ro/SSA–associated
atrioventricular block (AVB) in adults: (1) a first type resulting from an immunomediated
conduction-system interference secondary to anti-Ro/SSA developed during adulthood
(acquired form) and (2) a second type representing the late progression of a subclinical
anti-Ro/SSA–induced congenital damage of the conduction system (late-progressive congenital
form).
6
In the acquired form, characterized by the presence of anti-Ro/SSAs in the affected
subject, the conduction defect seems to be related to a direct autoantibody-mediated
inhibition of calcium channels in cardiomyocytes, and their effect is potentially
reversible. Intrinsic age-related differences (lower calcium channel reserve and underdeveloped
sarcoplasmic reticulum in the fetal heart)
4
may explain why anti-Ro/SSAs induce only an electrophysiological effect in adults,
without evolving to an inflammatory-driven heart injury as in newborns.
6
However, a prenatally established structural (and irreversible) damage of immune origin
appears to be the pathologic basis of the late-progressive congenital form, with a
subsequent autoantibody-independent worsening with age. Accordingly, in late progressive
congenital form patients anti-Ro/SSAs are not detectable, despite the seropositivity
of their mothers. Thus, a recovery potential of the immunosuppressive therapy is expected
in the acquired form only. Preliminary data indicate a rapid recovery of the conduction
defects in patients with acquired anti-Ro/SSA–associated AVB after administration
of immunosuppressive drugs.
6
An extensive review of the putative mechanisms underlying these 2 forms is reported
elsewhere.
6
The epidemiologic impact of anti-Ro/SSA–associated AVB in adults is higher than expected,
probably because these patients (and their mothers) are frequently asymptomatic for
CTDs and are therefore difficult to identify. In fact, available retrospective population
studies indicate that the 2 forms, globally considered, may represent at least 20%
of all cases of isolated III°AVB of unknown origin in adults (approximately 10% of
cases attributed to each form).7, 8 Thus, the importance of considering the possibility
of anti-Ro/SSA–associated AVB and specifically testing for anti-Ro/SSAs in patients
with “idiopathic” AVB should be emphasized, particularly for the important benefits
coming from an early immunosuppressive treatment of the acquired form.
6
The clinical cases reported here provide further evidence in support of this view
and demonstrate how in some patients both the pathogenic mechanisms characterizing
the 2 forms of adult-onset anti-Ro/SSA–associated AVB may be concomitantly involved
(mixed form).
Case reports
Case 1
A 29-year-old woman presented with chest pain, faintness, paleness, and sweating that
had occurred acutely in the past few hours. An electrocardiogram (ECG) recorded at
the emergency department demonstrated III°AVB and wide QRS ventricular escape rhythm
with a rate of approximately 30–40 beats per minute (bpm), suggesting a conduction
impairment distal to the bundle of His (Figure 1A). The clinical history of the patient
was negative for relevant factors except for autoimmune thyroiditis, which was being
treated with thyroxine, and subclinical positivity for anti-Ro/SSAs (no sign of CTDs)
that had been incidentally detected 3 years before. As such, the patient had been
carefully monitored for the risk of neonatal lupus during 2 previous pregnancies that
delivered 2 healthy babies. Table 1
The patient was admitted to the intensive cardiac care unit. Laboratory investigation
did not show abnormalities in thyroid hormone or thyrotropin levels. As expected,
antinuclear antibody (ANA) testing results were positive (1:1280, speckled pattern),
with very high circulating levels of anti-Ro/SSAs, including both anti-Ro/SSA-52kD
and anti-Ro/SSA-60kD subspecificities, as assessed by an immunoenzymatic enzyme-linked
immunosorbent assay (ELISA) method (>240 U/mL, reference values <7; fluoroenzyme immunoassay
[FEIA] by a Phadia EliA system [Thermo Fisher Scientific, Waltham, MA]). The presence
of the anti-Ro/SSA-52kD subspecificity was confirmed by Western blot analysis (MarDx
Marblot HEp-2; Trinity Biotech, Carlsbad, CA).
Transthoracic and transoesophageal echocardiography were performed, and both excluded
significant structural heart abnormalities. The patient was closely monitored for
the following 12 hours, and then a permanent pacemaker was implanted (Figure 2B) to
address the persistence of symptomatic III°AVB. The day after, and in consultation
with the patient’s immunologist (A.B.), immunosuppressive therapy with corticosteroids
1 mg/kg/d was started (intravenous methylprednisolone for the first day, and then
oral prednisone). During the second day of treatment, III°AVB disappeared and a normal
AV conduction was present. The patient was discharged, and a short-time follow-up
ECG approximately 2 weeks later confirmed the persistence of a normal AV conduction
(Figure 2C). However, in consideration of the fact that a pacemaker had already been
implanted and the patient was totally asymptomatic for rheumatologic manifestations,
corticosteroids were progressively tapered until complete termination to avoid unjustified
side effects. A further follow-up visit 6 months later showed the presence of a rhythm
driven by pacemaker stimulation. Notably, clinical and instrumental monitoring in
the following years did not show the appearance of possibly concealed sarcoidosis
or other inflammatory/infiltrative cardiac diseases, despite persistent interruption
of immunosuppressive therapy.
Case 2
An I°AVB (PR interval 320 milliseconds) was demonstrated in an asymptomatic 23-year-old
woman who underwent a routine screening ECG in the course of a preemployment visit
(Figure 2A). The following 24-hour ambulatory ECG showed intermittent II°AVB and episodes
of high-grade AVB with wide QRS escape beats (Figure 2B). The block appeared more
likely to be at the AV nodal level, because of the narrow QRS complexes when conducted.
The patient’s clinical history was negative for any relevant disease. The retrospective
analysis of a previous ECG performed at 9 years of age demonstrated that I°AVB was
already present at that time. The patient was not taking any drugs, and there was
no instrumental evidence of structural heart disease. Laboratory data, including thyroid
hormone levels, were normal. The patient was specifically tested for ANA and anti-Ro/SSAs,
and results of both tests were negative. However, the results of the same tests were
positive in the patient’s mother, a 51-year-old woman who was otherwise healthy except
for a euthyroid multinodular goiter, under thyroid stimulating hormone–suppressive
treatment with thyroxine. Indeed, FEIA displayed high levels of anti-Ro/SSAs (128
U/mL), with positivity for anti-Ro/SSA-60kD. Moreover, Western blot results revealed
the presence of the subspecificity anti-Ro/SSA-52kD.
The patient underwent close clinical and electrocardiographic follow-up in the next
months, until episodes of dizziness led to the insertion of a backup permanent pacemaker.
Case 3
A 21-year-old woman presented with asymptomatic high-grade AVB, incidentally diagnosed
during an endocrinology medical examination. ECG at rest showed III°AVB, narrow QRS,
and a ventricular rate of approximately 45 bpm (Figure 3A). A 24-hour ambulatory ECG
confirmed the presence of high-grade AVB for the most part of the day, with episodes
of II°AVB (Mobitz type 1–2).
The patient had a history of autoimmune thyroiditis, which was being treated with
thyroxine. A subclinical positivity for autoantibodies to gastric parietal cells was
also reported. Family history was negative for heart disease or autoimmune disorders.
The patient had no history of cardiac surgery, ablation procedures, or drug use. There
was no evidence of infiltrative heart diseases or myocardial ischemia. Transthoracic
echocardiography and cardiac magnetic resonance imaging were unremarkable. No clinical
manifestations of rheumatologic disease were present. Levels of thyrotropin were normal.
Laboratory evaluation demonstrated a positive test for anti-Ro/SSA-52kD (Western blot),
although FEIA testing was negative. Despite the patient’s negative history for conduction
disturbances, a retrospective evaluation of available previous ECGs (recorded at ages
7 and 15) revealed the presence of a previously unrecognized I°AVB (PR interval 240
milliseconds) (Figure 4).
Laboratory testing of the mother, who was asymptomatic for CTDs, showed a positive
result for ANA at a titer of 1:320, with a homogeneous pattern (ie, diffuse nuclear
fluorescence), and anti-Ro/SSA-52kD (Western blot). Also in this case, FEIA results
were negative.
Intravenous methylprednisolone was started for the patient at an immunosuppressive
dose of 1 mg/kg/d, resulting in a rapid (within a few days) and significant improvement
of ECG findings(disappearance of high-grade AVB; presence of I°AVB) (Figures 3B and
Figure 4). Maintenance oral immunosuppressive therapy with azathioprine (100 mg daily)
and prednisone (progressively reduced to 6.25 mg daily) was started. After 1, 3, and
6 months, new 24-hour ambulatory ECGs confirmed the absence of high-grade AVB, and
the persistence of I°AVB (although with phases of II°AVB, Mobitz type 1–2) (Figure
4). At this time (3 months), Western blot results were negative for anti-Ro/SSA-52kD.
However, since the patient was persistently asymptomatic and reluctant to long-term
immunosuppressive therapy, the treatment was stopped. 2 months later, the patient
presented persistent presyncopal symptoms, particularly in standing or sitting positions.
Electrocardiogram demonstrated the reoccurrence of high-grade AVB with marked bradycardia
(approximately 35 bpm) (Figure 3C). Administration of intravenous methylprednisolone
again rapidly improved the conduction disturbances: soon the patient become completely
asymptomatic and ECG tracings showed I°AVB with a mean heart rate of 50–60 bpm (Figure
3D). A new immuno-Western blot performed at that time revealed the reappearance of
anti-Ro/SSA-52kD positivity. The patient again underwent cardiac magnetic resonance
imaging, and in this instance no signs of infiltrative or inflammatory diseases, particularly
sarcoidosis, were detected. Currently, 1 month after restarting combined therapy with
azathioprine and prednisone, the patient is stably asymptomatic and ECG shows I°AVB
(with phases of II°AVB revealed by 24-hour ambulatory ECG) (Figure 4).The possibility
of implanting a pacemaker is still under consideration.
Discussion
The cases reported in this paper illustrate the different forms of anti-Ro/SSA–associated
AVB that can be observed in adults.
The first patient represents an acquired form, as indicated by circulating anti-Ro/SSAs.
The pathogenic relevance of these autoantibodies in AVB development is strongly suggested
by the complete recovery of the conduction disturbance soon after the onset of the
steroid treatment. Conversely, the detection of anti-Ro/SSAs in the mother, but not
in the patient, as well as the demonstration of signs of subclinical conduction system
damage already present at the childhood stage (I°AVB at 9 years of age), identify
the second case as a late-progressive congenital form.
Finally, in our opinion, the third case may represent a mixed form, in which both
the mechanisms are involved. Indeed, the data suggest that, in this case, a peculiar
“2-hits” autoimmune conduction system damage has developed. The first “hit” was the
result of the transplacental passage of anti-Ro/SSAs that may have induced a subclinical
congenital injury of the conduction system (incomplete AVB). The following development
of a multiorgan autoimmune response, including anti-Ro/SSAs, during the postnatal
life may have represented the second “hit” leading to the progression of the defect
to high-grade AVB. Interestingly, another case of an anti-Ro/SSA–positive congenital-III°AVB
(diagnosed as such at birth) followed by the development of anti-Ro/SSA in adult life
has been already described,
9
thus confirming the existence of this possibility as a probable result of the transmission
of a “genetic predisposition” to autoimmune response. The regression to incomplete
AVB after immunosuppressive therapy in this patient further confirms that adult-onset
anti-Ro/SSA–associated damage is reversible, whereas the fetal injury is permanent.
Noteworthy, in all the above-depicted cases, the presence of anti-Ro/SSA with pathogenic
effects on the heart was not associated with clinical signs of autoimmune disease.
In fact, patients 1 and 3 and the anti-Ro/SSA–positive mothers of patients 2 and 3
were totally asymptomatic. Although patients 1 and 3 had been previously diagnosed
with autoimmune thyroiditis, they did not have clinical manifestations of CTD. This
fact (in agreement with previous reports of anti-Ro/SSA–associated life-threatening
rhythm disturbances in adult patients10, 11), with the evidence that anti-Ro/SSA–positive
subjects in the general population are frequently asymptomatic for AD,
12
emphasizes the concept that in most cases only specific testing may reveal an anti-Ro/SSA–associated
mechanism of disease in adult patients with isolated AVB of unknown origin.
The level of the block in these patients represents another intriguing issue. Indeed,
whereas in children with congenital AVB it is generally localized at the AV node,
13
our and preliminary literature data
10
suggest that in adult patients (particularly in the acquired form) the level of block
may be more frequently distal to the bundle of His. It is currently unclear whether
this feature is dependent on age-related differences in calcium channel density at
the AV node vs the His-Purkinje system, and whether an electrophysiological study
may provide useful diagnostic and prognostic information.
Finally, our report (particularly case 3) also suggests that an ELISA method alone
is probably not able to detect all patients with anti-Ro/SSA–associated AVB, underscoring
the crucial importance of completing anti-Ro/SSA testing using Western blot analysis
in all patients whose ELISA results are negative. Further support of this view, also
substantiated by previous data demonstrating a higher sensibility of Western blot
in detecting anti-Ro/SSA-52kD with respect to immunoenzymatic methods,
14
another case of anti-Ro/SSA-52kD–positive (blot only) III°AVB fully reversing after
immunosuppressive therapy(acquired form) has been recently described.
10