Key-words:
Antinuclear antibodies - autoimmune disease - rheumatoid arthritis - Sjögren's syndrome
- systemic lupus erythematosus
Introduction
Sjögren's syndrome (SS) is a systemic autoimmune disease that presents with Sicca
symptomatology of the main mucosa surfaces.[[1]] SS can present as an entity by itself, without an underlying autoimmune condition
– primary SS (pSS) – or may in conjunction with an underlying autoimmune condition
– secondary SS (sSS).[[2]] The main Sicca features (xerophthalmia and xerostomia) are confirmed by specific
ocular (Rose Bengal staining and Schirmer's test) and oral (salivary flow measurement
and parotid scintigraphy) tests. However, the gold standard for establishing a diagnosis
is a lip biopsy demonstrating the histologic hallmark of focal lymphocytic infiltration
of the exocrine glands, namely minor labial salivary glands.[[3]] Patients with SS present a broad spectrum of serologic features, and the presence
of autoantibodies including antinuclear antibodies (ANAs) and SSA can further support
the diagnosis autoantibodies, of which ANAs are the most frequently detected, anti-Ro/SS-A
the most specific, and cryoglobulins and hypocomplementemia the primary prognostic
markers.[[4]] The disease spectrum extends from Sicca syndrome to significant systemic involvement
(extraglandular manifestations).[[5]] SS is a heterogeneous disease that can be expressed in many guises.[[6]] The variability of its presentation may significantly delay the diagnosis after
the onset of symptoms.[[1]] Besides, the presentation may vary depending on multiple factors, including genetic
factors, ethnicity, immunologic profile, and others. These factors have been analyzed
in various studies[[7]],[[8]] with differing results, which may be due to the small number of patients included
and the different sets of classification criteria used. The aim of the current study
to represent the clinical and serological demographics in Libya, whether there are
differences compared to other cohorts in the region and internationally.
Patients and Methods
Patient population
We studied 60 consecutive patients (55 females and 5 males) attending the rheumatology
clinics at Benghazi Medical Center, who were diagnosed as having SS according to European–American
consensus criteria for the classification of pSS 2016.[[9]] The exclusion criteria include chronic hepatitis C virus, human immunodeficiency
virus infection, and previous lymphoproliferative processes.
Clinical assessments and investigations
Patients' clinical manifestations were recorded at baseline and follow-up period in
the rheumatology clinic. Articular involvement was defined as joint swelling, pain,
and stiffness of the hands' small joints for more than 6 weeks. Persistently altered
electrocardiographic examinations indicated heart involvement and/or structural abnormalities
detected by echocardiography. Pulmonary involvement was indicated by a persistent
cough and/or dyspnea with chronic diffuse interstitial infiltrates on chest X-rays,
altered patterns on pulmonary function tests, and/or evidence of lung alveolitis or
fibrosis in computed tomography (CT) scans. Chronic kidney disease was defined as
persistent proteinuria (>0.5 g/day), abnormal urine analysis (hematuria, pyuria, and
red blood cell casts), a persistently elevated serum creatinine level, renal tubular
acidosis, interstitial nephritis, or glomerulonephritis. Liver involvement was indicated
by altered serum hepatic function test results (aminotransferase, alkaline phosphatase,
gamma-glutamyltransferase, and bilirubin) and/or evidence of altered bile ducts in
imaging-based examinations (ultrasound, CT, or magnetic resonance imaging). Central
nervous system involvement was defined as the appearance of symptoms and signs associated
with a neurologic deficit (sensory and/or motor). All patients underwent routine biochemical
and serological testing, including erythrocyte sedimentation rate and C-reactive protein
levels. The immunological tests included ANA, rheumatoid factor (RF), extractable
nuclear antigens Ro (SSA) and La (SSB), and complement (C3 and C4) components. The
presence of a positive ANA or RF test was defined only if the titers were >1/80.
Data management statistical analysis
Data were analyzed using the Statistical Package for the Social Sciences (SPSS) 17.0
(SPSS; SPSS Inc., Chicago, IL, USA). Results are presented as frequencies in counts
and percentages or mean standard deviation and ranges. Subgroup analysis was performed
using the Chi-square test. In all cases, P < 0.05 was considered statistically significant.
Results
Demographic characteristics
Of the 60 patients, 55 (91.7%) were female and 5 (8.3%) were males with a female:male
ratio of 9:1. The mean age of the 60 patients at the time of diagnosis was 41.9 ±
9.9 years (25–56 years). Seventeen patients (28.3%) were diagnosed as having pSS,
and all were females. The sSS group included 38 females and all the five males of
the study. There was no difference in the age of onset between pSS and sSS (40 ± 8.9
vs. 43 ± 5 years, respectively, P + 0.439).
Glandular manifestations
At the time of diagnosis, 52 (86.7%) reported symptoms of dry mouth and 55 (91.6%)
of dry eye. Dental caries, oral candidiasis, and gingivitis, were seen in 25 (41.7%),
20 (33.3%), and 4 (6.7%) of patients, respectively. Positive Schirmer's test was observed
in seven patients (11.7%). In 14 patients (23.3%), the salivary gland biopsy was compatible
with Sjogren's syndrome [[Table 1]].
Table 1: Glandular manifestations of patients with primary and secondary Sjogren’s syndrome
Extraglandular manifestations
The most common extraglandular manifestations were arthralgia and arthritis in 49
(81.7%), Raynaud's phenomenon in 23 (38.3%), interstitial lung disease (ILD) in 9
(15%), and chronic hepatitis in 3 (5%). Three (5%) patients presented with neurological
symptoms (one peripheral sensory neuropathy and two with carpal tunnel syndrome).
Hematologically, both pSS and sSS were associated with a lymphocytosis with leukocyte
count more than 15,000/dl which was reported in 16 (26.7%) [[Table 2]].
Table 2: The frequency of extraglandular manifestations and immunological characteristics
in the whole cohort and primary and secondary Sjögren’s syndrome separately
Associations of Sjogren's syndrome
SSS was associated with rheumatoid arthritis in 28 (46.7%) patients, followed by systemic
lupus erythematosus (SLE) 11 (18.3%) and systemic sclerosis and mixed connective tissue
disease in 3 and 1 patient, respectively. Thyroid disease was reported in 14 (23.3%),
nine of them were hypothyroid [[Table 2]]. Immunologically, 53 patients (58.3%) presented positive RF and 18 patients (30%)
had positive ANA. RF was strongly associated with sSS and Sicca symptoms (P = 0.004
and P = 0.001, respectively), while ANA positivity was strongly associated with pSS
and other glandular manifestations (P = 0.001 and P = 0.003, respectively).
Discussion
Due to the wide variety of signs and symptoms, patients with SS may see a diverse
range of healthcare practitioners, including family physicians, ophthalmologists,
ENT specialists, and dentists, at the first consultation. Thus, physicians of various
specialties must be informed about current aspects of clinical manifestations of the
disease, the revised classification criteria, and current treatment options.[[10]] As for many autoimmune diseases,[[11]] most patients with SS are women, with an estimated female-to-male ratio of 9-14:1.[[11]],[[12]] Our current study revealed that SS by its two types is predominantly more frequent
among females. SSS coexisted especially with SLE (15%–36%), rheumatoid arthritis (20%–32%)
as well as limited and progressive systemic sclerosis (11%–24%). It occurred less
frequently with multiple sclerosis and autoimmune hepatitis and thyroiditis.[[13]] The current study shows a higher prevalence of RA as a cause of sSS, and RA patients
with sSS had worse joint damage, suggesting that sSS may be a marker of more aggressive
disease.[[14]],[[15]]
Sicca symptoms were more prevalent among patients diagnosed with sSS than pSS [[Table 1]]. Brito-Zerón et al.[[16]] found higher frequency Sicca symptoms to be the most common manifestation of SS,
with up to 98% of cases.
Compared with the general population, the prevalence of dental caries and early tooth
loss is about twice as high in patients with SS, and their oral health-related quality
of life is significantly reduced. Recurrent oral infections with Candida albicans
occur ten times more frequently than in the general population;[[17]] our results show a higher prevalence of oral complications among pSS compared to
sSS.
Up to 34% of patients with SS reported episodic or chronic, typically bilateral swelling
of the parotid glands.[[18]] In the current study, salivary gland enlargement was reported in 70.6% and 37.2%
of pSS and sSS. It is essential to exclude malignant non-Hodgkin lymphoma of B-cell
lineage, which occurs in about 5% of patients with pSS.[[19]]
The most common extraglandular manifestations are arthralgia and a usually nonerosive
polyarthritis which occur in approximately 50% of patients.[[18]] Our study findings show a higher prevalence of arthralgia among both pSS and sSS
(88.2% and 79%).
About 9%–20% of cases, SS is associated with various respiratory symptoms.[[18]],[[20]] The most typical manifestations are chronic ILD and tracheobronchial disease.[[20]] Subclinical lung disease is even more frequent, including small airway disease
and airway inflammation.[[21]] The presence of ILD is associated with impaired respiratory function. Importantly,
pulmonary involvement leads to an increased risk of mortality.[[22]] In the current cohort, ILD was reported among 15% of our patients, most of them
were sSS.
Gastrointestinal and hepatic involvement in the form of dysphagia and hepatitis was
found in 49 (81.7%) and 3 (5%), respectively; literature shows that esophageal dysmotility
has been reported in 36%–90% of patients.[[23]],[[24]]
Thyroid disease, usually hypothyroidism, accompanies SS in up to 20% of cases;[[25]] nearly, the same results are seen in our study (23.3%).
Over half of our patients have positive ANA, and almost one-third of the patients
had positive RF. A well-known characteristic of the systemic autoimmune diseases is
the possibility of evolution from one disease to another, and it is possible that
some of these ANA patients could evolve to a disease other than pSS over time, such
as systemic sclerosis or SLE, as suggested by Davidson et al.[[26]] Up to 20% of healthy people may have positive ANA, particularly in older people.[[27]],[[28]] In a large cohort of 400 patients with pSS, 72% had positive ANA and 38% had positive
RF.[[5]] These results support a possible role of RF in the diagnosis of pSS.
Conclusions
To the best of our knowledge, this is the first study looking into the clinical presentation
of SS in the Libyan population. Sicca symptoms and systemic manifestations are more
prevalent in patients with pSS than those with sSS similar to data from other world
regions. Despite the small number of patients and the single-center design of the
study, a more extensive multicentric series would be valuable further to elucidate
the clinical presentation of the disease in Libya.
Authors' contribution
Equal contribution to conception and conduct of the study, data analysis and drafting
and revision of the manuscript. All authors approved the final version of the article.
Compliance with ethical principles
The study was conducted according to the Declaration of Helsinki 1975. The study was
approved by the Research Ethical Board, Benghazi Medical Center (BMC) (2020.65.44),
and all participants provided informed consent.
Reviewers:
Ashraf Algul (Abu Dhabi, UAE)
Chanaveerappa Bammigatti (Puducherry, India)
Khadija Hafidh (Dubai, UAE)
Editors:
Salem A Beshyah (Abu Dhabi, UAE)
Rajaie Namas (Abu Dhabi, UAE)
