Sjögren’s Syndrome: Pathogenesis, Clinical Expression, and Management of Sicca Manifestations

What is Sjögren’s Syndrome (SjS) and SICCA Syndrome?

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Sjögren’s syndrome is a chronic autoimmune disease, classified under connective tissue diseases (collagenoses), characterized by lymphocytic infiltration and progressive destruction of exocrine glands, particularly salivary and lacrimal glands. Aberrant activation of the immune system generates an autoaggressive response against the body’s own tissues, leading to glandular hypofunction and the appearance of classic SICCA manifestations – xerophthalmia and xerostomia.

Two major clinical forms are distinguished: primary Sjögren’s, where symptoms appear in isolation, and secondary Sjögren’s, frequently associated with other systemic autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma. Regardless of the clinical form, the impact on quality of life is significant, with chronic fatigue, joint pain, and severe mucosal dryness being common symptoms.

It is important to note that SICCA syndrome is not specific to Sjögren’s alone. It can also occur secondary to other causes – medications (antihistamines, anticholinergics), head and neck radiotherapy, advanced age, or chronic metabolic conditions. Differential diagnosis must be rigorously performed, especially in atypical or early stages, as the autoimmune form carries additional risks, including systemic complications.

Extraglandular Manifestations in Sjögren’s Syndrome – Reflecting its Multisystemic Nature

In addition to SICCA manifestations, extraglandular involvement can occur, including cutaneous, pulmonary (bronchiolitis, interstitial fibrosis), renal (tubulointerstitial nephritis), peripheral nervous system (sensory neuropathies), or vasculitic manifestations. For this reason, Sjögren’s is recognized as a multisystemic disease and requires an integrated therapeutic approach.

As part of a supportive regimen, Omega-3 fatty acid supplementation can offer additional benefits due to their anti-inflammatory role, especially in the context of joint or systemic manifestations. For optimal intake, Omega-3 capsules with concentrated fish oil – 1000 mg/capsule, with a balanced content of EPA (455 mg) and DHA (230 mg) – can be an effective choice. Daily administration contributes to maintaining cognitive, cardiovascular, and joint functions, thereby supporting the body in combating the chronic inflammatory processes associated with the disease.

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The onset of the syndrome typically occurs between the 4th and 5th decades of life, with a higher prevalence among women (female:male ratio of approximately 9:1). Diagnosis is based on correlating clinical data with autoimmune serological markers (anti-SSA/Ro, anti-SSB/La), glandular functional tests (Schirmer, sialometry), and, when necessary, minor salivary gland biopsy.

Causes and Risk Factors of Sjögren’s Syndrome

The exact cause of Sjögren’s syndrome onset has not yet been fully identified, but current studies suggest the involvement of a combination of genetic, hormonal, immunological, and environmental factors that contribute to triggering the autoimmune response.

A hereditary predisposition has been observed in families with a history of autoimmune diseases, and genetic investigations have associated Sjögren’s syndrome with certain HLA haplotypes, particularly HLA-DR and HLA-DQ. This genetic susceptibility appears to promote the loss of immunological tolerance and the development of specific autoantibodies.

Hormonal factors, especially estrogen status, influence immune activity, which could explain the higher incidence of the disease in women, particularly after the age of 40. Hormonal imbalances occurring during perimenopause and menopause are correlated with an exacerbation of glandular and extraglandular symptoms.

Environmental Factors – The Role of Viral Infections in Triggering Lichen Planus

In addition to genetic predisposition and hormonal influences, certain environmental factors are thought to act as triggers for the disease. Among these, viral infections (such as Epstein-Barr virus, cytomegalovirus, hepatitis C virus) are most frequently mentioned. Furthermore, these viruses may contribute to abnormal lymphocytic activation and the initiation of the autoimmune response.

Additionally, factors such as prolonged exposure to environmental pollutants, toxins, or sustained oxidative stress could influence disease progression in susceptible individuals.

Furthermore, it should be noted that Sjögren’s syndrome often occurs in association with other systemic autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, or scleroderma), suggesting a common immune dysfunction affecting multiple autoimmune pathways.

Symptoms and Clinical Manifestations of Sjögren’s Syndrome

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Sjögren’s syndrome is characterized by predominant exocrine gland involvement, with the gradual onset of sicca syndrome, manifested by xerophthalmia and xerostomia.

Reduced tear secretion leads to severe dry eyes, perceived as a persistent gritty sensation, burning, or itching, often accompanied by photophobia and blurred vision. In the oral cavity, decreased salivary flow causes discomfort during chewing and swallowing, altered taste perception, and increased susceptibility to cavities, oral candidiasis, and halitosis.

Dryness can also affect other mucous membranes – nasal, pharyngeal, laryngeal, and vaginal – causing symptoms such as hoarseness, a sensation of a foreign body in the throat, chronic nasal dryness, dyspareunia, and vaginal itching (in women).

Extraglandular Manifestations — Clinical Spectrum and Diagnostic Importance

Extraglandular manifestations are variable but can be significantly severe. Joint pain of arthralgic type or symmetric, non-erosive polyarthritis are frequently reported. Myalgias, pronounced fatigue, or cutaneous involvement such as xerosis, palpable purpura, or Raynaud’s phenomenon may also occur.

Pulmonary involvement includes persistent dry cough, wheezing, or, in advanced cases, bronchiolitis obliterans or diffuse interstitial infiltrates. The renal system can be involved through chronic tubulointerstitial nephritis, sometimes clinically silent. Peripheral nervous system involvement (sensory or motor polyneuropathies) and central nervous system involvement (demyelinating lesions) can also complicate the clinical picture.

Inflammation of the salivary glands, particularly the parotid glands, often causes a visible, bilateral, and symmetrical enlargement, which is suggestive for diagnosis.

Chronic fatigue, fever of unknown origin, and unintentional weight loss are other frequently encountered systemic symptoms that require careful evaluation.

Diagnosing Sjögren’s Syndrome: Analyses, Laboratory Investigations, Functional Tests, and Imaging Methods

Establishing a diagnosis of Sjögren’s syndrome requires a complex approach. The approach is staged. The approach begins with a thorough medical history. The approach continues with a detailed clinical assessment. The approach continues with specific paraclinical investigations.

The physician will review the history of SICCA-type symptoms (xerophthalmia and xerostomia). They will assess their duration. They will assess their severity. They will assess any associated systemic manifestations. Examples of systemic manifestations include chronic fatigue. Other examples include arthralgias. Other examples include neurological symptoms. The clinical examination will include inspection of the oral cavity. It will include evaluation of the salivary glands (parotid and submandibular). It will include assessment of the conjunctiva. It will include assessment of tear secretion.

Biological investigations play an essential role in guiding the diagnosis. Among the immunological markers frequently associated with Sjögren’s syndrome are antinuclear antibodies (ANA), anti-SSA/Ro, and anti-SSB/La. Measuring serum immunoglobulin levels (polyclonal hypergammaglobulinemia) and rheumatoid factor can provide additional information about disease activity. Additionally, non-specific inflammatory markers, such as ESR and C-reactive protein (CRP), as well as liver and kidney functions, will be assessed in the context of potential systemic involvement.

Functional Tests for Exocrine Glands are Indispensable:

• The Schirmer test quantifies lacrimal secretion by placing a filter paper strip under the lower eyelid for 5 minutes and measuring the degree of wetting.
• The lissamine green or fluorescein staining helps visualize corneal and conjunctival lesions, completing the ophthalmological evaluation.

For salivary function, the following can be used:

• Sialometry (measurement of unstimulated salivary flow);
• Sialography (radiographic examination of salivary ducts after contrast agent injection) or salivary scintigraphy, which evaluates the functional activity of the parotid and submandibular glands in real time by administering a radioactive substance.

Modern imaging, such as ultrasound of the salivary glands, allows for the detection of structural changes (hypoechogenicity, presence of cystic areas, or heterogeneous appearance), being a non-invasive and accessible method. MRI may be indicated in cases of suspected systemic involvement or for staging purposes.

Histopathological diagnosis is confirmed, in certain cases, by biopsy of minor salivary glands (usually from the lower lip), where periductal lymphocytic infiltrate is evaluated, and the focus score is established, a defining element in the ACR/EULAR criteria for Sjögren’s syndrome diagnosis.

Depending on the clinical context, additional investigations may be recommended, such as:

• Periungual capillaroscopy, to identify any signs of microvascular damage,
• or sudomotor function testing using Sudoscan, useful in cases with suspected associated dysautonomia.

In conclusion, diagnosing Sjögren’s syndrome requires careful correlation between clinical, serological, imaging, and histopathological data, with a multidisciplinary assessment (rheumatological, ophthalmological, ENT, and dental) being essential for a comprehensive and personalized patient approach.

Treatment of Sjögren’s Syndrome: Therapeutic Approaches for Symptom Relief

The treatment of Sjögren’s syndrome primarily aims at symptom control, protecting the function of affected organs, and preventing long-term complications. The therapeutic protocol is individualized based on the severity and type of clinical manifestations – localized or systemic.

For the management of SICCA symptoms, topical therapies are recommended to alleviate ocular and oral dryness:

• In cases of xerophthalmia, preservative-free artificial tears, gels, or long-acting ophthalmic ointments are used. For patients with chronic ocular inflammation, the ophthalmologist may prescribe topical cyclosporine A or tacrolimus, which reduce lymphocytic infiltration and improve tear secretion.
• In resistant forms, punctal occlusion may be indicated, a minimally invasive procedure aimed at preserving endogenous tear secretion.

For xerostomia, the following are recommended:

• salivary substitutes, oral moisturizing gels, sugar-free chewing gums, and cholinergic agents such as pilocarpine or cevimeline, which stimulate residual salivary secretion;

However, maintaining strict oral hygiene, preventing fungal infections, and regular dental check-ups are mandatory, given the increased risk of cavities and oral candidiasis.

In forms with mild joint, cutaneous, or systemic involvement, immunomodulatory drugs such as hydroxychloroquine may be used, with demonstrated efficacy in reducing joint pain and mucocutaneous manifestations.

In moderate to severe cases, refractory to conventional therapy, or with internal organ involvement (renal, pulmonary, neurological), systemic immunosuppressive therapy may be initiated. Corticosteroids and, depending on the indication, agents like methotrexate, azathioprine, or mycophenolate mofetil can be included in the treatment regimen.

Biologic therapy, such as rituximab (anti-CD20 monoclonal antibody), is reserved for severe forms with significant systemic involvement or cryoglobulinemia. Clinical studies support its efficacy in reducing lymphocytic infiltration and improving extraglandular manifestations, but its use requires careful evaluation of risks and benefits.

The association of Sjögren’s syndrome with other autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus, may necessitate treatment adjustments based on comorbidities and the patient’s inflammatory profile.

In cases of oral fungal infections, frequently associated with chronic xerostomia, topical or systemic antifungals are recommended, depending on the severity.

Adapting Diet and Daily Routine in the Context of Sjögren’s Syndrome

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Optimizing lifestyle helps reduce discomfort caused by Sjögren’s syndrome. Increasing dietary intake of omega-3 fatty acids through consumption of fatty fish or flaxseeds contributes to reducing inflammatory processes in the body. In the absence of sufficient dietary intake, omega-3 supplements can be administered, supporting the health of joints and affected mucous membranes.

Foods with antioxidant action, such as colorful vegetables and berries, provide additional benefits by reducing oxidative stress. This is important in autoimmune pathologies where chronic inflammation is a central mechanism.

Adequate hydration is essential for relieving dryness symptoms. Therefore, constant fluid intake throughout the day is recommended, even in the absence of thirst. For example, still water or herbal teas, without added sugar or caffeine, are perfect alternatives. Conversely, alcoholic and carbonated beverages should be avoided, as they worsen mucosal dryness.

For ocular and nasal comfort, a room humidifier can be used, especially during the cold season or in overly air-conditioned environments. It increases air humidity, preventing mucosal dehydration. When going outdoors, wearing protective eyewear is recommended, especially on windy or dusty days. Nasal mucosa can be protected by using nasal sprays with saline water.

For the oral cavity, artificial saliva is recommended, which maintains hydration longer than consuming liquids. Oral hygiene must also be rigorous – brushing teeth after every meal and regular dental check-ups are essential for preventing cavities. Smoking is contraindicated, as it further dries the mucosa and can lead to local complications.

Complications of Sjögren’s Autoimmune Disease and Their Impact on Quality of Life

Complications of Sjögren’s syndrome can extend beyond glandular manifestations and involve multiple systems and organs, some of which have a high potential for severity.

Ocularly, severe xerophthalmia can progress to chronic SICCA keratoconjunctivitis. In the absence of adequate treatment, it can lead to complications such as punctate keratitis, corneal ulcers, and, in severe cases, corneal perforation or loss of visual acuity. Therefore, periodic ophthalmological monitoring is essential.

In the oral cavity, the lack of salivary secretion compromises saliva’s protective function. This promotes the development of multiple dental caries, periodontal disease, and recurrent oral candidiasis. Difficulties in chewing, swallowing, and speaking may also arise, affecting nutritional status and quality of life.

Lichen Planus – Systemic Manifestations and Visceral Complications

Systemically, involvement of internal organs can occur in a subset of patients. Renal involvement, in the form of tubulo-interstitial nephropathy, manifests as urinary concentrating defects, renal tubular acidosis, and, rarely, chronic kidney failure. In the lungs, inflammation can lead to bronchiolitis, interstitial pneumonitis, or pulmonary fibrosis, requiring periodic imaging and spirometry assessments.

Hepatically, Sjögren’s syndrome can be associated with primary biliary cholangitis or autoimmune hepatitis, particularly in patients with secondary forms of the disease.

One of the most significant, although rare, complications is the development of non-Hodgkin lymphoma, especially B-cell types. It is estimated that patients with Sjögren’s syndrome have a 5 to 10 times higher risk than the general population of developing this hematological malignancy. Warning signs may include persistent lymphadenopathy, splenomegaly, unexplained weight loss, and marked fatigue. Regular clinical monitoring and periodic tests are essential for early detection of these complications.

Neurologically, peripheral neuropathies (tingling, numbness, burning sensations) can manifest, but also central nervous system involvement, including cognitive or affective dysfunctions.

Last but not least, the psychological impact is significant. Due to the chronic, progressive, and unpredictable nature of the disease, anxiety disorders, depression, and reduced quality of life may occur. Chronic fatigue and persistent pain can lead to social isolation and decreased work capacity.

Current Research Directions and Emerging Advances in Sjögren’s Syndrome Management

Recent advances in Sjögren’s syndrome research offer real hope for early diagnosis and more effective therapeutic approaches.

Currently, international scientific efforts aim to identify new serological biomarkers. They aim to identify new salivary biomarkers. These biomarkers would allow for early recognition of the disease. Recognition would occur even before the appearance of evident clinical symptoms. Thanks to modern genomic profiling technologies, attempts are being made to define a specific molecular profile. Thanks to modern transcriptomic profiling technologies, attempts are being made to define a specific molecular profile. Thanks to modern proteomic profiling technologies, attempts are being made to define a specific molecular profile. This profile would differentiate primary Sjögren’s syndrome from other related autoimmune diseases. Furthermore, among promising directions is saliva analysis. This would be a non-invasive method. The method has potential in population screening. The method has potential in monitoring disease activity.

Therapeutically, research focuses on targeted immunomodulation. This targets pathogenetic mechanisms involved in B-cell activation. This targets pathogenetic mechanisms involved in B-cell persistence. Molecules such as anti-BAFF monoclonal antibodies (belimumab) are in advanced clinical trials. JAK inhibitors (ruxolitinib, baricitinib) are in advanced clinical trials. Studies are evaluating their ability to reduce systemic autoimmunity. Studies are evaluating their ability to reduce glandular manifestations. In parallel, blocking the type I interferon pathway is becoming an increasingly clear therapeutic target. The type I interferon pathway is recognized as being hyperactivated in Sjögren’s.

Regenerative Medicine – Innovative Perspectives in Treating Sicca Symptoms

Increasing attention is also being given to the field of regenerative medicine. Experimental studies on the use of mesenchymal stem cells for repairing damaged glandular tissues could revolutionize the treatment of sicca symptoms. Additionally, tissue engineering projects aimed at regenerating salivary glands represent an area of research with significant clinical impact. This area is expanding.

Sjögren’s syndrome, despite its multisystemic nature, can be controlled. Sjögren’s syndrome, despite its unpredictable nature, can be controlled. Control is achieved through a careful combination of medical supervision. Control is achieved through tailored therapeutic interventions. Control is achieved through lifestyle modifications. Access to modern treatments helps reduce the disease’s impact on daily functioning. Active collaboration between the patient and the medical team contributes to reducing the disease’s impact on daily functioning. Last but not least, understanding the disease mechanisms allows not only for symptom relief. It also allows for long-term autonomy. It also allows for a balanced long-term life. Constant updating of care strategies allows not only for symptom relief. It also allows for long-term autonomy. It also allows for a balanced long-term life.

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3. Vivino FB, Bunya VY, Massaro-Giordano G, et al. Sjogren’s syndrome: An update on disease pathogenesis, clinical manifestations and treatment. Clin Immunol. 2019;203:81-121. doi:10.1016/j.clim.2019.04.009;

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