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\begin{document}

\title{Primary Sjogren's syndrome presenting as ptosis and eyelid swelling: A
case report.}



\author[1]{Alishba Ashraf  Khan}%
\author[1]{Shamaila Mumtaz}%
\author[1]{Javaria  Malik}%
\author[1]{Muhammad Shahzad Manzoor}%
\author[1]{Faran  Maqbool}%
\author[1]{Mudassir  Shafique}%
\author[1]{Maheen  Nazir}%
\author[2]{Zohad   Ibn-e-Shad}%
\author[3]{Kamal Kandel}%
\author[1]{Ayesha Farooq}%
\affil[1]{Rawalpindi Medical University}%
\affil[2]{Shifa International Hospitals Ltd}%
\affil[3]{Manipal College of Medical Sciences}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\textbf{Introduction:}

Primary Sj\selectlanguage{ngerman}ögren's syndrome(pSS) is an idiopathic, autoimmune disorder
characterized by both localized and systemic manifestations. The most
common clinical presentations include the ``sicca'' or ``dryness''
symptoms such as xerostomia and keratoconjunctivitis sicca due to
diminished salivary gland and lacrimal gland function, respectively.
Patients may also present with nonspecific symptoms such as fatigue and
arthralgia, as well as pulmonary, gastrointestinal, neurological and
renal involvement.\textsuperscript{1} Secondary Sjogren's syndrome can
coexist with other autoimmune disorders such as rheumatoid arthritis
(RA) and systemic lupus erythematosus (SLE). \textsuperscript{2}

According to literature, ocular signs and symptoms in pSS range from
foreign body sensations, punctate or filamentous keratitis, to overt
seborrheic blepharitis and eyelid swelling is reported to be
rare.\textsuperscript{3} We report an usual/rare presentation of
Sjogren's syndrome in which the patient developed severe evolving
mechanical ptosis and eyelid swelling to the extent that it impaired her
ability to lift open her eyes and see, along with a positive
anti-acetylcholine receptor antibody test.

\textbf{Case presentation:}

A 27-year-old woman presented to our Rheumatology department with the
complaint of periorbital swelling for the past five months. Prior to
coming to our clinic, she presented to the Neurology department of one
of our allied hospitals, Benazir Bhutto Hospital with a complaint of
drooping of eyelids for the last three months where she was presumed to
be a case of MG on the basis of positive anti-acetylcholine receptor
antibodies. She was given a therapeutic trial of pyridostigmine but she
failed to respond to the treatment and was referred to our rheumatology
clinic for an autoimmune workup.

The periorbital swelling was gradual, bilateral, and had progressed to
the degree that the patient could not lift open her eyelids and had to
open them with her fingers to be able to see. Figure 1 shows the extent
of her ptosis and eyelid swelling. It was not associated with any pain,
redness, discharge, loss of vision, or diplopia. Upon systemic inquiry,
she complained of undocumented weight loss, productive cough for the
past three months, dry gritty eyes, dry mouth, hair loss, and a
photosensitive facial rash. There was no significant family history of
disease other than her father who was treated for tuberculosis 10 years
back.

On clinical examination, our patient had periorbital puffiness with
closed palpebral fissures, there was no redness or discharge, and she
had normal extraocular eye movements. There was no assessable
lymphadenopathy and none of the salivary glands were palpable. On oral
examination, Schirmer test was positive with less than five mm tear
production in five minutes which is suggestive of dry eyes. On
respiratory examination, bilateral coarse crepitations were heard. Her
neurological examination was unremarkable and muscle strength and
endurance in all muscle groups was normal which was in contrast to the
symptoms of MG. We could not perform all the provocative maneuvers for
ocular MG (sustained upgazed, Herring's sign, peek sign) because of
marked eyelid swelling that impaired lifted the eyelids. There was no
fatigable diplopia. The rest of the systemic examination was normal.

Peripheral blood test results were as follows: hemoglobin 14.0 g/dl,
total leucocyte count 14000/mm\textsuperscript{3}, neutrophils 70.2\%,
lymphocytes 25.1\%, mixed 5.7\%, red blood cells 4.21
million/mm\textsuperscript{3}, platelets 223000/mm\textsuperscript{3},
hematocrit 38.9\%, erythrocyte sedimentation rate 44mm/hour, C-reactive
protein 4.1 mg/L, Serum biochemical testing results were as follows:
serum urea 3.0 mmol/L, serum creatinine 55 umol/L, serum sodium 137
mmol/L, serum potassium 4.6 mmol/L, alanine aminotransferase 15 U/L,
alkaline phosphatase 86 U/L, total bilirubin 0.4 mg/dl. \emph{The
results of her autoimmune workup are displayed in Table 1} . Repetitive
nerve stimulation showed no significant decremental or incremental
response which helped rule out generalized myasthenia gravis but not
ocular myasthenia.

We proceeded with a High-Resolution Computed Tomography (HRCT) scan of
her chest which revealed bilateral cylindrical bronchiectasis involving
all lung lobes, consolidation in the right lower lobe, and mild pleural
effusion. PCR was negative for COVID-19, sputum for Gene Xpert, and
QuantiFERON TB gold test were also negative. Sputum culture revealed
heavy growth of Candida and Klebsiella Pneumoniae. Magnetic Resonance
Imaging MRI of the brain and orbits revealed bilateral symmetrical
homogenous enlargement of lacrimal glands with accompanied symmetrical
swelling and edematous changes in bilateral pre-septal and para-septal
soft tissues. \emph{Figure 2 shows these MRI images prior to commencing
therapy} .

We considered primary Sjogren syndrome, systemic lupus erythematosus as
she gave a history of a photosensitive facial rash, ocular myasthenia
with idiopathic orbital inflammation as she gave a history of ptosis and
periorbital inflammation, sarcoidosis, ANCA associated vasculitis and
IgG4 related orbital pseudotumor as our differential diagnoses. We had
ruled out SLE, sarcoidosis, ANCA associated vasculitis on the basis of
autoimmune investigations all of which were negative for corresponding
antibodies. Myasthenia Gravis was ruled out on the basis of
electrodiagnostic studies. As she tested positive for Anti SSA
antibodies, we proceeded with a lip biopsy to confirm the diagnosis of
primary Sjogren's syndrome and to rule out IgG4-related disease. The lip
biopsy indicated normal-looking mucinous acini with lymphocytic
infiltrate. There were four microscopic foci of lymphoid aggregates per
4 mm\textsuperscript{2}, with no evidence of plasma cells and fibrosis
(hence ruling out IgG4-related disease), suggestive of primary Sjogren
syndrome (pSS). \emph{Figure 3 shows the histopathological images of her
lip biopsy} .

Pulmonology consultation was sought and she was started on an antibiotic
cover to control infective pulmonary etiology prior to beginning
immunosuppressive treatment for pSS. The patient was advised
Acetylcysteine, Azithromycin 250mg for three months along with Influenza
and Pneumococcal vaccine. After her chest infection subsided, we started
her on Hydroxychloroquine 200 mg/day, Azathioprine 2.5 mg/kg/day, and
Prednisolone 0.5 mg/kg/day. Cyclophosphamide was deferred because we
believed it would worsen her bronchiectasis. The patient was referred
for an ophthalmology consultation for her persistent eyelid swelling and
the consensus was to control her primary disease process which would
ultimately resolve her swelling. As the persistent swelling was
hampering her ability to see, she underwent a sling procedure to open
her eyelids.~\emph{Figure 4 shows an image of the patient after her
sling procedure} . Though the swelling had considerably subsided on
therapy, her lacrimal gland were persistently inflamed, we shifted her
towards a biological agent Rituximab, 1g IV infusion. She has received
two doses and the next dose is scheduled for after 6 months.

\emph{Figures 5 and 6 show MRI of her brain and orbits after starting
treatment.}

\textbf{Discussion}

This case highlights a rare presentation of pSS. The patient developed
bilateral ptosis along with prominent eyelid swelling which evolved to
the extent that she could not lift her eyelids to see. Eyelid swelling
has been reported in primary Sjogren's syndrome but to our knowledge,
this is the first case in which the swelling has evolved to the extent
that impairs the patient's ability to lift open her
eyes.\textsuperscript{4} Sjogren syndrome has a multitude of
ophthalmological manifestations ranging from chronic conjunctivitis,
sterile keratolysis, and non-healing corneal ulcers, but lacrimal gland
involvement is reported to be rare.\textsuperscript{1,5}

Due to her initial presentation with ptosis and eyelid swelling along
with a positive anti-acetylcholine receptor antibody test, we presumed
her to be a case of MG and she was given a therapeutic trial of
pyridostigmine to which she failed to respond. This made us reconsider
her initial diagnosis of MG and we started her autoimmune workup. Our
case is unique in this aspect as well because MG and Sjogren's syndrome
very rarely co-exist in the same patient and very few cases have been
reported in the current literature. \textsuperscript{6,7,8} There are
many diagnostic modalities for MG including Ice pack test, Tensilon
test, Anti-acetylcholine receptor antibodies, Repetitive nerve
stimulation, and Electromyography, all with varying sensitivity and
specificity.\textsuperscript{9} Of these, the positive titer of
anti-acetylcholine receptor antibodies has the highest specificity
(97-99\%) for the diagnosis of MG. \textsuperscript{10} Our patient had
no typical signs or symptoms of MG aside from ptosis but she had a
positive titer of anti-acetylcholine receptor antibodies. We proceeded
with repetitive nerve stimulation tests which showed no incremental or
decremental response hence ruling out generalized MG but not ocular MG.
A positive titer for this assay in the absence of typical signs and
symptoms, a negative therapeutic trial of pyridostigmine and
electrodiagnostic studies ruling out generalized MG could mean that the
test result was spuriously positive in our patient. The pathogenesis of
false positive antibody test results in the context of autoimmune
diseases is very interesting and has been reported in a number of other
autoimmune diseases as well \textsuperscript{11,12}. These false
positive antibody results can be attributed to the phenomenon of
heterophil antibody interference in which some of the patient's
antibodies react with the immunometric sandwich assays and cross-link
the assay antibodies yielding a false positive test
result.\textsuperscript{13} Heterophil antibody interference has been
well documented in the literature and there are examples of catastrophic
patient outcomes due to this phenomenon such as the HCG scandal in which
false positive HCG levels, later attributed to heterophil antibodies,
caused unnecessary treatment in a number of
women.\textsuperscript{14}Heterophile antibodies are common in
autoimmune diseases and should be suspected in cases of positive
antibody titers in absence of a solid clinical picture of the disease
and clinicians need to be made aware of this phenomenon. If such a
spurious test result is encountered either on a single occasion or
repeatedly, it should be followed by confirmatory testing and taking the
clinical context into account. Our case thus highlights the importance
of interpreting antibody test results in the context of clinical
findings as our patient did not have MG despite a positive
anti-acetylcholine receptor antibody test result indicated by a negative
therapeutic trial of pyridostigmine and electrodiagnostic studies.

The recent 2016 ACR-EULAR Classification Criteria for primary Sjögren's
Syndrome is most commonly used to establish a diagnosis of
pSS.\textsuperscript{15} On the basis of focal lymphocytic sialadenitis
upon labial salivary gland biopsy, positive Anti-SSA(RO) antibodies, and
positive Schirmer test, our patient scored seven out of nine where a
score of 4 or more is required for a definite diagnosis of pSS.

Based on the HRCT findings, our patient was also had co-existent
bronchiectasis, because of which she could not be started on
immunosuppressive therapy for pSS immediately until the pulmonary
infection had been resolved. Pulmonary involvement is an extraglandular
manifestation of pSS and it can be in the form of both interstitial
parenchymal disease and airway disease. Bronchiolitis and bronchiectasis
are the common airway lung diseases seen in pSS. The prevalence of
bronchiectasis is up to 10\% with involvement of the inferior lobes
being more common.\textsuperscript{16} Cylindrical bronchiectasis is the
most common type seen and patients of bronchiectasis have a higher
frequency of respiratory infections and
pneumonia.\textsuperscript{17}Our patient similarly had bilateral
cylindrical bronchiectasis involving all of the lung lobes along with a
positive sputum culture for Klebsiella pneumoniae thus indicating an
infective etiology coexisting with her autoimmune pulmonary
manifestation. The pathogenesis of pulmonary involvement in pSS seems to
involve epithelial damage due to any environmental factor such as
infection or an extension of the primary immune response in salivary
glands, followed by epitope spreading, antigen presentation and
lymphocyte activation, formation of antibodies and release of cytokines
leading to an inflammatory state damaging airways and lung
parenchyma.\textsuperscript{16} Pulmonary involvement also proved to be
a challenge in management as we had to control the infective etiology
with antibiotics prior to commencing immunosuppressive therapy to avoid
a flare-up of the lung disease.

\textbf{Conclusion:}

Our case highlights a unique ophthalmological manifestation of pSS and
provides key insight into managing this autoimmune disease. We must
always look at the clinical picture of a disease instead of relying
solely on investigations as elucidated in our case where a positive
anti-acetylcholine receptor antibody test led to a misleading diagnosis
of MG which was ruled out subsequently.

\textbf{Acknowledgements:}

None.

\textbf{Conflict of Interest:}

The authors declare that there are no conflicts of interest in the
publication of this paper.

\textbf{Informed Consent:}

Informed consent was obtained from the patient prior to writing this
report in accordance with journal's patient consent policy.

\textbf{Author's Contribution:}

\emph{Alishba Ashraf Khan:} Conceptualization, Investigation,
Methodology, Writing -- original draft.

\emph{Shamaila Mumtaz:} Conceptualization, Investigation, Methodology,
Writing -- original draft.

\emph{Javeria Malik:} Investigation, Methodology, Writing -- Reviewing
and editing

\emph{Muhammad Shahzad Manzoor:} Investigation, Methodology, Writing --
Reviewing and editing

\emph{Faran Maqbool:} Investigation, Methodology, Writing -- Reviewing
and editing

\emph{Mudassir Shafique:} Investigation, Methodology, Writing --
Reviewing and editing

\emph{Maheen Nazir:} Investigation, Methodology, Writing -- Reviewing
and editing

\emph{Zohad Ibn e Shad:} Investigation, Methodology, Writing --
Reviewing and editing

\emph{Kamal Kandel} : Methodology, Writing -- Reviewing and editing

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