Sjögren's syndrome in dermatology☆
Introduction
Sjögren's syndrome (SS) is an autoimmune disorder characterized by dry eyes (keratoconjunctivitis sicca, KCS) and dry mouth due to lymphocytic infiltrates of lacrimal and salivary glands. The symptoms of dryness result from glandular destruction and the dysfunction in residual glands due to local production of cytokines and metalloproteinases. When the condition occurs without association with other autoimmune diseases, it is classified as primary SS (“1° SS”). Sjögren's syndrome is often found in conjunction with other autoimmune disorders such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis, scleroderma (progressive systemic sclerosis, PSS), and primary biliary cirrhosis, and in these cases is termed secondary SS (2° SS).
The dermatologist and rheumatologist should be aware that although many clinical and laboratory features in patients with 1° SS are similar to patients with SLE, because of the low recognition of SS as a clinical entity among referring primary physicians who note a positive antinuclear antibody (ANA) and label the patient as SLE, many patients (especially among the older patients) who are labeled as SLE would better fulfill the criteria for SS than for SLE (discussed below). There are overlaps of SS with other autoimmune diseases such as scleroderma (PSS), dermatomyositis, and RA. There is also a significant overlap with patients who have “fibromyalgia,” a poorly defined disorder characterized by fatigue and a centralized pain syndrome.
This presentation will concentrate on dermatologic manifestations of primary SS with emphasis on the ocular surface, oral manifestations, and cutaneous findings.
Therapies will be reviewed and concentrate on 4 basic areas:
- 1.
methods to improve lubrication of local manifestations of dryness involving the eye and mouth;
- 2.
recognition of associated problems of xeropthalmia and xerostomia, such as oral yeast infections, ocular blepharitis, and gastro-tracheal reflux;
- 3.
recognition and treatment of systemic manifestations of SS including vasculitis and lymphoproliferative features;
- 4.
assessment and therapy of fatigue and vague cognitive symptoms that are not clearly the result of a systemic autoimmune process, but are similar to symptoms of patients with “fibromyalgia.”
Section snippets
Background
The first description of SS is generally credited to Johann Mikulicz who in 1892 described a 42-year-old farmer with bilateral parotid and lacrimal gland enlargement associated with a small round cell infiltrate.1 Because the term Mikulicz's syndrome could encompass so many different entities including tuberculosis, other infections, sarcoidosis, and lymphoma, the term Mikulicz syndrome fell into disuse because it did not provide sufficient prognostic or therapeutic information.2 The term is
Criteria for diagnosis
There is relatively little disagreement among rheumatologists regarding the clinical diagnosis of SS in a patient with:
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florid physical exam findings of keratoconjunctivitis on ocular exam
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dry mouth (xerostomia) and parotid swelling;
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positive ANA and anti–SS-A/SS-B antibodies.
Until recently, there were multiple sets of diagnostic criteria for primary SS including those by American2, 9 and European (EEC) groups10 that were so radically different, diagnoses of “SS” rendered by European physicians
Pitfalls in diagnosis and methodology
There are 2 common areas of confusion in clinical diagnosis regarding the specificity/sensitivity of the ANA and of the minor salivary gland biopsy.
The ANA frequently is used as a “screening” test in patients with fibromyalgia. Tan et al21 reported that the frequency in “normal individuals” of a positive ANA titer using Hep 2 cells at titer 1:40 was 31.7% of individual, at 1:80 was 13%, at 1:160 was 5%, and at 1:320 was 3.3%.
Using a Bayesian analysis, Lightfoot22 found similar results and
Overview of pathogenesis and correlation with clinical symptoms
Despite the extensive effort spent in studying the underlying cause of SS, the pathogenesis remains obscure.
In broad terms, SS can be considered a multifactor complex disease in which environmental factors are thought to trigger inflammation in individuals with a genetic predisposition for the disease. In comparison to many other organ-specific autoimmune disorders, the relative ease of minor salivary gland biopsy in SS provides researchers an opportunity to study the interaction of the immune
Ocular symptoms and signs in patients with SS
The characteristic ophthalmologic finding in SS is KCS, due to destruction of the lacrimal glands, leading to decreased lacrimal secretions. Patients may complain of dry eyes, irritation, soreness, foreign-body sensation, pain, or photophobia. In severe cases, patients may have strings of mucous filaments attached to the cornea.
When evaluating the patient with a complaint of dry eyes, it is important to determine whether the objective signs of dry eyes are commensurate with the patient's
Oral symptoms and signs in patients with SS
Xerostomia is caused by destruction of the major and minor salivary glands. Dryness of the mouth can make it difficult to swallow food or even to talk, because of dryness of the buccal mucosa. Patients may have difficulty wearing dentures, mucosal surfaces in advanced dryness may become dry and wrinkled, and saliva can become thick and stringy. As saliva also functions to protect the mouth from infection due to antimicrobial properties and mechanical flushing, patients with SS are at risk for
Cutaneous symptoms and signs in patients with SS
Cutaneous manifestations of SS include dry skin, immunologic inflammatory conditions such as vasculitis, and other associated skin conditions.
Complaints of dry skin occur in about 50% of patients with SS.4, 72, 73 It is unclear whether the xerosis is due to infiltrate of the eccrine or sebaceous glands, or dysfunctional sweating.30 In some cases, dryness of the skin has been associated with lymphocytic infiltrates in the eccrine glands.74
The vascular findings of SS include benign
Systemic findings in patients with SS
Extraglandular disease manifestations (Table 4) are subdivided into nonvisceral (skin, arthralgia, myalgia) and visceral (lung, heart, kidney, gastrointestinal, endocrine, central, and peripheral nervous system). Cutaneous manifestations are discussed above. There is often a close overlap in the symptoms/signs between patients with SLE and those with SS.105 Particular attention below is paid to conditions more common in patients with SS.
The symmetric distribution and appearance of
Differential diagnosis
When approaching a patient with possible SS, it is important to rule out other causes of KCS, xerostomia, and parotid gland enlargement (reviewed in Kassan and Moutsopoulos 2004).223 Dry eyes can be caused by sarcoidosis, amyloidosis, medications, trauma or scarring, infection, inflammatory conditions such as blepharitis or pemphigoid, neurologic conditions impairing eyelid or lacrimal gland function, or hypovitaminosis A. Dry mouth can be caused by medications (antihypertensive,
Cutaneous therapy
Local treatment for cutaneous symptoms of SS focuses on dry skin. If patients have more serious skin findings such as vasculitis, their disease may warrant systemic management (reviewed in a subsequent section).
Treatment of dry skin in SS is similar to managing xerosis in other conditions. The patient should moisturize with a nonfragranced cream moisturizer once or twice a day. Moisturizing is performed immediately after bathing or showering, while the skin is still damp, to prevent further
Artificial lubricants
Patients can use over-the-counter preservative-free artificial tears, lubricating ointments, and methylcellulose. The latter 2 are usually used at night as they are viscous. Preservatives can lead to topical irritation, especially in the dry eye, where the concentration can become high. Other prescription ophthalmologic drops (such as antibiotics and glaucoma drops) may still have irritating preservatives.
Various measures are used to conserve the tear film for as long as possible:
- •
Side shields
Punctal occlusion
If frequent installation of artificial tears is inadequate or impractical, punctal occlusion is the treatment of choice. It is a highly effective method for maximizing the preservation of tears. This technique involves sealing of the lacrimal puncta, through which the tears normally drain away to the nose; 90% of drainage occurs through the inferior punctum. Several different types of punctual plugs are available, and plugs (called intra-cannicular plugs) that do not protrude onto the corneal
Topical cyclosporine
The United States Food and Drug Administration approved the use of a cyclosporine ophthalmic emulsion (0.05%) based upon 4 studies that compared this agent to a castor oil–based vehicle in 1200 patients.1 One of the studies presented in abstract form noted a decrease of 38% in infiltrating CD3-positive T cells in the conjunctival biopsies of 293 subjects receiving cyclosporine vs a 15% increase in those receiving the vehicle alone.2
Among 877 patients randomly assigned to receive twice-daily
Topical tacrolimus
Berdoulay et al180 reported the use of 0.02% tacrolimus in aqueous suspension on tear production in dogs with KCS. They suggest that this agent (which is water soluble, in contrast to relatively insoluble cyclosporin) may be a promising alternative to topical cyclosporine A for treatment of KCS and may be beneficial in patients with less than optimal response to topical cyclosporine A.
Topical nonsteroidal eye drops (such as indomethacin) have been found to provide symptomatic relief, but they
Blepharitis management
Blepharitis commonly occurs with dry eyes, and detection and management can aid SS symptoms. The source of lipids in the tear film is the meiobian glands that are predominately located in the margin of the eyelids near the eyelashes. In patients with SS, inflammation of the lower glands is common and may be caused by “plugging” by viscous secretions (including the overuse of ocular lubricants and ointments). Application of warm compresses followed by eyelid scrubs comprises the most critical
Conclusions
Treatment of SS is generally symptomatic, with most patients requiring treatment only for dryness. Adequate explanation is essential; many subjects, for example, may not realize that their central heating or air conditioning creates a drying environment or that a windy day is likely to make their eyes dryer. Simple measures such as humidifiers, sips of water, chewing gums, and simple replacement tears will be adequate in the majority of subjects. The rest should be told of the wide range of
Acknowledgment
Carla I Fox, RN, who proofread and clinically amended this manuscript, as well as adding insight from the critical questions that patients ask the nurse about treatment of Sjögren’s syndrome. As with all chronic diseases, it is critically important that we educate our nursing staff, as they will be fielding most of the day-to-day questions on therapy and referring to relevant online sites such as the Arthritis Foundation, the Sjögren's Syndrome Foundation, or the web site http://www.dry.org.
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2022, Journal of the American Academy of DermatologyCitation Excerpt :However, given the ongoing nature of the active clinical trials, close attention should be paid on whether other small molecular inhibitors may be useful in CLE. Cutaneous manifestations are seen in many patients diagnosed with primary Sjögren syndrome (pSS), which at times precede the associable sicca symptoms of ocular and oral dryness.79,80 Xerosis and Raynaud's phenomenon are the most common, whereas cutaneous vasculitides, SCLE-like annular erythema, and localized cutaneous nodular amyloidosis are also strongly associated.79,80
Skin manifestations associated with systemic diseases – Part I
2021, Anais Brasileiros de DermatologiaSjögren Syndrome
2019, Clinical Immunology: Principles and Practice
- ☆
Sjögren's syndrome in Clinics in Dermatology issue entitled “Rheumatology and Dermatology Interface” (edited by Jane M Grant-Kels, MD [[email protected]], Marti J Rothe, MD [[email protected]], and Philip Mease, MD [[email protected]]).