Discussion
The patient was a young woman presenting with edema and renal failure.
Initial investigation showed multiple serous effusion and double
pneumonic exudation. Renal biopsy was chosen to confirm the diagnosis.
It is confusing that renal pathology revealed lupus-like nephritis but
this patient has not any typical lupus symptoms and all autoantibodies
were negative. Therefore, we must deliberate this patient’s diagnosis.
SLE was also considered in combination with the patient’s clinical
presentation (renal failure, multiple serous effusion and epilepsy) and
persistent hypocomplementemia, as well as the renal pathology of type IV
lupus-like changes. However, the 2019 EULAR/ACR SLE classification
Criteria project proposed that ANA is an entry criterion for
SLE4, 5. The patient’s autoantibodies (including ANA,
ds-DNA, ss-DNA, and Sm) were persistent negative. Hence, it proposed a
question that ANA negative Lupus-like syndrome: Is it lupus or not?
The decision that ANA was used as a screening test and an entry
criterion for SLE was made after the baseline facts had been worked up
thoroughly. Nicolai Leuchten, et al. showed ANA at a titer of 1:80 have
98% sufficiently high sensitivity in a systematic literature review and
meta-regression which included more than 13,000 SLE
patients6. A report showed that only 6.2% of patients
were ANA negative among more than 1000 SLE patients who fulfilled the
ACR classification criteria7. Therefore, ANA is a
useful and sensitive indicator for screening SLE. However, there are
also a minority SLE patient with ANA negative8, 9. It
has been reported that among patients with ”full-house”or “Lupus-like”
nephropathy but negative serology for lupus. Some of them developed
autoantibodies and other clinical manifestations of SLE during the
follow-up, while some of them remained seronegative and developed no
clinical findings of SLE other than full-house
nephropathy8, 10. Another report describes three
processes of autoantibodies in the development of
lupus11:Stage 1: patients had neither symptoms nor any
detectable autoantibody levels; Stage 2: patients develop detectable
autoantibodies without clinical manifestations; Stage 3: patients
presented obvious clinical symptoms of lupus with autoantibodies
positive11. According to the above description, ANA is
not only a diagnostic indicator of lupus, but also related to the
progression of the disease. Our patient presented with lupus-like
pathological and devastating features of SLE, but persistent negative
autoantibodies. This is different from the previous reports about
ANA-negative lupus.
In this patient, renal pathology is an important basis for lupus
diagnosis. SLICC (The Systemic Lupus International Collaborating
Clinics) used full-house staining as the sole criteria to diagnose
SLE3. However, It has been reported that the
prevalence of no-lupus full house nephropathy was
20%-30%12-15. “No-lupus full house nephropathy” is
an umbrella term for such patients who may exhibit “lupus-like”
nephropathy, but without presenting any extrarenal symptoms or
serologies suggestive of SLE. Pathologies of full-house nephropathy
should also be considered in the differential diagnosis of SLE,
including primary glomerular diseases (membranous nephropathy, C1q
nephropathy, IgA nephropathy), infections (endocarditis, HIV, HBV, HCV,
BK and CMV virus), diabetes mellitus, liver
diseases12-14. This patient had none any evidence of
these disease. For enhanced the sensitivity and specificity of
stand-alone kidney biopsy to diagnose lupus nephritis, another report
showed that five renal pathological features, which included
“full-house” staining, intense C1q staining, extraglomerular deposits,
combined subendothelial and subepithelial deposits, and tubuloreticular
inclusions, were selected to create a scoring system to define lupus
nephritis with reasonably high sensitivity and specificity16. According to this scoring system, this patient had
3 scores: “full-house” staining, subendothelial and subepithelial
deposits, and tubuloreticular inclusions, with sensitivity of 80% and
specificity of 95% for the diagnosis of lupus nephritis. However, there
is still a certain bias in the diagnosis of LN by renal biopsy pathology
alone. In the SLICC classification, If patients are ANA negative,
however, they have to fulfill at least four of the other 10 (or 16)
criteria, also biasing against ANA negative SLE3. At
the onset, the patient presented with multiple serous effusion, renal
failure, which had not yet met the diagnosis of ANA negative SLE. During
the follow-up, the patient developed new signs: epilepsy and
hypocomplement. Given excluding other possible diseases, combined with
the patient’s four clinical symptoms and lupus-like renal pathological
findings, the diagnosis of ANA negative SLE is considered.
In conclusion, the patient presented with chronic renal failure at the
time of diagnosis, and there was a lack of evidence and clinical
manifestations of secondary renal failure. If the patient was directly
treated with renal replacement therapy without renal biopsy, it would be
more difficult to diagnose. Therefore, the auxiliary role of
pathological manifestations in some intractable cases is crucial. ANA
screening for SLE is a good tool, but autoantibody testing should not be
overly relied upon when both pathological and clinical findings support
the diagnosis of SLE. In conclusion, this patient is a unique case of
ANA-negative severe lupus. For such cases, it is easy to be missed or
misdiagnosed, which is a challenge in diagnosis and treatment. How to
detect these diseases early still needs more research.