Continuing Education Activity

Primary Sjogren syndrome is a systemic autoimmune disorder commonly presenting with dryness involving the eyes and mouth due to inflammation and resultant pathology of the lacrimal and salivary glands. Up to one-half of affected individuals also develop extra-glandular involvement in organs such as the joints, skin, lungs, gastrointestinal (GI) tract, nervous system, and kidneys. This condition is frequently associated with other autoimmune disorders including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Sjogren syndrome is managed by replacing moisture at affected glandular sites and diminishing the autoimmune response locally as well as systemically. This activity reviews the evaluation and management of Sjogren syndrome and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe how patients with Sjogren syndrome will most likely present.
• Identify the pathophysiology of Sjogren's disease and the most common presentation.
• Outline the treatment of Sjogren syndrome.
• Summarize the importance of improving care coordination among the interprofessional team in enhancing the delivery of care in those with Sjogren syndrome.

Introduction

In the early 1900s, Swedish physician Henrik Sjögren (SHOW-gren) first described a group of women whose chronic arthritis was accompanied by dry eyes and dry mouth. Today, Rheumatologists know more about the syndrome that is named for Sjögren and—most significantly for patients—can offer advice about how to live with it.

Primary Sjogren syndrome is a systemic autoimmune disorder most commonly presenting with sicca symptoms. Sicca refers to dryness most often involving the eyes and mouth due to inflammation and resultant pathology of the lacrimal and salivary glands. Up to one-half of affected individuals also develop extra-glandular involvement implying the occurrence of signs and symptoms in organs distinct from the salivary and lacrimal glands including the joints, skin, lungs, gastrointestinal (GI) tract, nervous system, and kidneys. Sjogren syndrome frequently occurs in conjunction with other autoimmune disorders including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this setting, authors will refer to it as secondary Sjogren or Sjogren-overlap syndrome. Therapies are directed toward replacing moisture at affected glandular sites and suppressing the autoimmune response locally as well as systemically.[1][2][3]

Etiology

As is the case with the majority of autoimmune disorders, the precise etiology of Sjogren syndrome is unknown. A genetic predisposition involving the major histocompatibility (MHC) locus is likely with individuals sharing haplotypes in the HLA-DQA_DQB_ region having an increased relative risk, although the diseases are described worldwide. These major histocompatibility haplotypes are hypothesized to result in an aberrant immune response in conjunction with certain environmental triggers. Laboratory studies, as well as some indirect epidemiologic evidence, implicates viruses, including Epstein-Barr virus (EBV) as participants in disease pathogenesis.[4][5]

Epidemiology

Sjogren syndrome is far from a rare disorder with an incidence approaching approximately one-half of that of rheumatoid arthritis (RA) or affecting 0.5% to 1.0% of the population.

Between 400,000 and 3.1 million adults have Sjögren's syndrome. This condition can affect people of any age, but symptoms usually appear between the ages of 45 and 55. About half of patients also have rheumatoid arthritis or other connective tissue diseases, such as lupus.

Sjogren has been reported worldwide in adults and more rarely in children, and there appears to be no racial, or geographic bias in incidence. The disorder, however, has a marked predilection for women and similar to SLE, the female:male ratio is approximately 9:1. The disease usually presents in middle age but may occur in children as well as the elderly.[6][7]

As there is no evidence-based standardized screening tool to decide which dry eye patients to refer for Sjogren syndrome workup, there is an underreferral of dry eye patients for Sjogren syndrome workups: hence there is continued underdiagnosis of the disease.  [8]

Pathophysiology

The characteristic lesion of Sjogren syndrome is focal lymphocytic sialadenitis (FLS). FLS is a lesion of exocrine glands. Foci of lymphocyte-rich mononuclear cells infiltrate exocrine glandular tissue adjacent to blood vessels and excretory ducts. The foci are comprised predominantly of T lymphocytes. However, B lymphocytes, plasma cells, and other cell types are seen. With more severe disease the foci may become confluent. The infiltrating mononuclear cells, humoral factors such as antibodies and cytokines, or both are hypothesized to cause exocrine gland dysfunction resulting in diminished tear production by the lacrimal glands and diminished saliva production by salivary glands. Also, exocrine glands outside the head and neck may be involved resulting in skin, tracheobronchial and vaginal dryness as well as lung and kidney dysfunction. Rarely, malignant transformation of B lymphocytes can result in non-Hodgkin lymphoma. Immune complexes may deposit in skin, joints and other organs resulting in a systemic vasculitis.[9]

Histopathology

Biopsy of the minor salivary glands is the ideal test to confirm the diagnosis of Sjogren syndrome. The minor salivary glands are accessed by making an incision in the inner lip. However, a biopsy is not mandatory in all cases if the clinical and laboratory features are suggestive of the syndrome. The typical findings on a biopsy will reveal aggregates of more than 50 lymphocytes, some macrophages and plasma cells. CD4 cells are predominant, and about 10% of lymphocytes will be CD5 positive B cells that produce IgG and IgM antibodies.

History and Physical

The patient will often complain of a foreign body sensation in their eyes and a dry mouth. On eye exam, the absence of tears may be noted in the inferior conjunctival sac, and the eyes may appear injected. However, referral to an ophthalmologist is mandatory for a slit-lamp exam to be performed. This examination in the presence of vital dye staining is necessary to demonstrate KCS (keratoconjunctivitis sicca) which is the most characteristic ophthalmologic lesion of Sjogren. A Schirmer test will also help confirm ocular dryness. The mouth may appear parched, with a smooth tongue, and thin mucosae. Approximately 50% demonstrate enlarged parotid, and/or submandibular glands at some point.  Extraglandular involvement often manifests in polyarthritis, lower extremity purpura, and/or evidence of peripheral neuropathy.

Evaluation

Evaluation of a patient with suspected Sjogren syndrome should include an evaluation of oral and ocular dryness and function. In addition to the history, this may include the performance of a Schirmer test, slit-lamp exam with vital dye staining, salivary flow rate, and/or nuclear scintigraphic evaluation of the salivary glandular function. Assessment of autoantibodies (ANA, RF, SS-A, and SS-B) should also be performed. Of these, SS-A is probably the most sensitive and specific antibody for Sjogren's but alone is not diagnostic since it may be present in other autoimmune disorders and may be absent in up to a third of Sjogren cases. The most specific single test is a minor salivary gland (lip) biopsy which will demonstrate FLS in positive specimens.[10][11][12]

Treatment / Management

Treatment of sicca symptoms involves:

• Dry eyes usually respond to artificial tears applied regularly during the day or to gels applied at night. We usually have patients use a preservative-free drop during the day and a preservative-free gel or ointment at night.
• Punctal occlusion with plugs or cauterization is frequently needed in more severe cases. Cauterization should only be performed after a trial of plugs to ensure the patient is not left with excessive tearing.
• Eye drops that reduce inflammation in the glands around the eyes, such as cyclosporine (Restasis) are used to increase tear production.
• Many patients are helped by serum tears which are derived from their own blood. Most eye centers now have the capability of making these for the patient. 
• Drinking water, chewing gum, or using saliva substitutes may relieve dry mouth.
• Some patients benefit from using prescription medications that stimulate saliva flow, such as pilocarpine (Salagen) or cevimuline (Evoxac).
• If patients develop yeast infections, anti-fungal therapies may be used. Humidifiers and nasal saline irrigation may improve nasal dryness. Medications that reduce gastric acid (such as proton-pump inhibitors and H2 blockers) may lessen symptoms of acid reflux. Treatments may help relieve some of the dryness, but usually some dryness persists.
• The first approach to extra-glandular (systemic) major organ-system disease is oral/parenteral corticosteroids.
• Various DMARDs (methotrexate, azathioprine) have been successfully employed as steroid-sparing agents although none is specifically approved for Sjogren.
• Hydroxychloroquine is recommended to treat inflammatory polyarthritis. B cell depletion may have a role in certain severe extra-glandular manifestations (vasculitis). TNF-alpha inhibitors have not proved effective for Sjogren. [13][14][15]

Differential Diagnosis

• Sarcoidosis
• Rosacea
• Mumps
• Dehydration
• Use of medications-  antidepressants, anticholinergics
• Mouth breathing
• Lymphoma
• Advanced age
• Parkinson disease
• Scleroderma
• Rheumatoid arthritis
• AIDS
• Lupus

Pearls and Other Issues

Primary Sjogren patients have an increased relative risk for the development of B-cell non-Hodgkins lymphoma. Many of these lymphomas are extranodal and may involve the salivary glands. Risk factors include persistent salivary gland swelling, enlarging lymph nodes, leukopenia, palpable purpura and low complement C4 at presentation. These patients need to be carefully monitored and referred for oncologic evaluation when appropriate. Current guidelines by the Sjorgen Syndrome Foundation recommend 1) palliation of symptoms, 2) minimizing complications, and 3) proper patient selection when selecting immunosuppressive treatment. 

Biological Therapies are used to treat severe cases of Sjogren disease. Rituximab is an option for patients with keratoconjunctivitis sicca, vasculitis, xerostomia and severe parotid gland swelling. All patients on Rituximab must be closely monitored for tumor lysis syndrome (when patients have lymphoma), cytopenia, infusion reactions, hepatitis B reactivation and serious fungal, viral and bacterial infections.

Enhancing Healthcare Team Outcomes

Sjogren syndrome is a systemic disorder that affects many organs. There is no cure for the disorder. The management revolves around decreasing the morbidity of the symptoms. Besides physicians, both the pharmacist and nurse play a vital role in patient education.

• The patient should be educated on prevention of dental caries, using fluoride-containing toothpaste and using sugar-free chewing gums and lozenges to promote saliva production.
• For dry eyes, the pharmacists should educate the patient on changing the diet and eliminating medications that cause reduced secretions.
• In addition, the pharmacist should educate the patient on proper use of artificial tears and gels.
• Avoiding contact lenses, using warm compresses and seeing an ophthalmologist is the next step.
• Since these patients are also on a number of drugs to prevent arthritis pain, the pharmacist should educate the patient on compliance and what adverse reactions to anticipate.
• The patient should also be referred to a physical therapist to regain joint function and build on muscle strength.
• Finally, the disorder can affect mood and a referral to a mental health counselor may be required.[16][17][18] (Level III)

Outcomes

Mild Sjogren disease has a good prognosis but those with moderate to severe disease have a very poor quality of life. The dry mouth and eyes often cause irritable symptoms which are not well tolerated. In addition, many of these patients develop moderate to severe arthritis and ambulation can be difficult. With advancing age, as the function of the exocrine glands subsides, the symptoms also tend to worsen. In the long run, there is a risk that patients with Sjogren syndrome will develop a lymphoproliferative disorder which can lower the life expectancy. 

Women with Sjogren syndrome are also at a high risk for developing complications during pregnancy. Premature deliveries and spontaneous abortions are not uncommon. Finally, patients with Sjogren syndrome who have antiphospholipid antibodies are at risk for developing vascular thrombotic disorders and fetal demise. [19][20][13](level V)