Dermatology

Sjögren’s Syndrome

Are You Confident of the Diagnosis?

What you should be alert for in the history.

Findings that should alert the practitioner to suspect the diagnosis of Sjögren’s syndrome include the following:

Oral

  • - Sensitivity to acids (in approximately 68% of patients)

  • - Difficulty eating dry foods (66%)

  • - Sensitivity to spicy foods (58%)

  • - Higher incidence of caries

  • - Fissured red tongue

  • - Difficulty swallowing solid food without concomitant water intake

  • - Frequent oral candidiasis (74%), especially angular chielitis

Ocular

- Dry gritty eyes, especially after the individual has spent several hours at a computer terminal. This has been attributed to the low humidity environment of many offices as well as the low blink rate during computer use.

Skin

- Skin dryness

Hair

- Dry, rough, coarse scalp hair

Other mucous membranes

- Vaginal dryness with secondary dyspareunia

Characteristic findings on physical examination

Oral Findings/Xerostomia

  • - Lack of salivary pool in the floor of the mouth

  • - Difficulty speaking without frequent sips of water

  • - Dry red fissured tongue (Figure 1, Figure 2, Figure 3)

  • - Candidiasis (in the form of both thrush and angular chielitis)

  • - High frequency of dental caries (the incidence of gingivitis is not increased)

  • - Swelling of the parotid gland (Figure 4)

Figure 1.

Dry, fissured, red tongue in woman with Sjögren's syndrome who also had dry eyes.

Figure 2.

Dry tongue and sclerodactyly in a patient with Sjögren's syndrome and calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST).

Figure 3.

Woman with Sjögren's syndrome. Note dry fissured tongue and surgical occlusion of the lateral eyelid margin.

Figure 4.

Woman with Sjögren's syndrome and marked swelling of the parotid glands.

Ocular Findings / Keratoconjunctivitis sicca

The tear film consists of water, proteins, mucin, and growth factors. Mucins are important for maintenance of the stability of the tear film and its mechanical functions such as allowing the upper eyelid to slide over the ocular surface. Patients with Sjögren’s syndrome have deficient mucin production, which results in symptoms of ocular discomfort.

The differential diagnosis of keratoconjunctivitis sicca includes conditions in which there is increased evaporative loss of water in the tear film secondary to dysfunction of meibomian glands such as that associated with blepharaitis, rosacea, and, less frequently, ocular pemphigoid.

Dermatologic Findings

The skin manifestations in patients with Sjögren’s syndrome are highly varied. Those that involve blood vessels have the most severe biologic consequences.

Vascular Lesions

Hypergammaglobulinemic purpura is seen frequently in patients with Sjögren’s syndrome and may lead to sensory peripheral neuropathy. Approximately 50% of patients with hypergammaglobulinemic purpura have Sjögren’s syndrome. Skin lesions are nonpalpable (unlike lesions of leukocytoclastic vasculitis) and are often associated with a monoclonal IgM kappa rheumatoid factor.

Leukocytoclastic vasculitis may be limited to the skin (Figure 5) or associated with internal organ involvement (such as the central nervous system or lungs). Some patients with leukocytoclastic vasculitis may have mixed cryoglobulinemia.

Figure 5.

Leukocytoclastic vasculitis of 10 years duration was the presenting complaint in this patient, who demonstrated xerostomia, keratoconjunctivitis sicca, and high titer antibodies to SS-A.

The presence of mixed cryoglobulinemia should lead to a search for occult hepatitis C infection. In a study of 558 consecutive patients with primary Sjögren’s syndrome, cutaneous involvement was present in 89 (16%) patients. Fifty-two of those patients had leukocytoclastic vasculitis. Of patients with leukocytoclastic vasculitis, 98% were female. Fourteen of the patients had cryoglobulinemia, and eleven patients had urticarial vasculitis. Twenty-six patients had (unspecified) purpura.

Patients with cutaneous vasculitis have a higher prevalence of joint involvement, Raynaud phenomenon, peripheral neuropathy, and renal involvement. Raynaud phenomenon occurs in approximately 30% of patients.

Specific skin lesions

- Xerosis

- Coarse, rough, unmanagable scalp hair (Figure 6)

Figure 6.

A woman with Sjögren's syndrome and CREST. Note dry, coarse hair, sclerodactyly, and fingertip scar secondary to prior ulcer.

Nonspecific skin lesions

Multiple nonvascular lesions or disorders have been reported in patients with Sjögren’s syndrome, with variable frequency. None of these is specific to Sjögren’s syndrome. These include:

  • - Erythema annulare, which tends to favor the face and is indistinguishable from gyrate erythema clinically and histologically (tight perivascular lymphocytic infiltrate)

  • - Erythema nodosum

  • - Erythema multiforme-like lesions

  • - Erythema perstans

  • - Sweet syndrome

  • - Red plaques with dermal neutrophilic infiltrate

  • - Eruption indistinuishable from bullous systemic lupus erythematosus (SLE) with subepidermal neutrophil-mediated bullae

  • - Localized subcutaneous amyloid deposit

  • - Anetoderma

  • - Calcinosis cutis

  • - Perniosis

Expected results of diagnostic studies

Histopathology

A minor salivary gland biopsy is one of the six criteria for the diagnosis of Sjögren’s syndrome. A vertical incision is made in the wet (inner) mucosa of the lower lip and five glands are excised with scissors. A “focus” of lymphocytes refers to a cluster of fifty or more lymphocytes in a salivary gland.

The average number of foci in four glands is the focus score. A focus score of more than 1 is one of the essential criteria for the diagnosis of primary Sjögren’s syndrome. (The alternative to a positive salivary gland biopsy is the presence of antibodies to SS-A or SS-B.)

Skin biopsies of hypergammaglobulinemic purpura reveal occlusion of blood vessels and rupture resulting in purpura.

Lesions of leukocytoclastic vasculitis reveal a neutrophil-mediated necrotizing vasculitis that favors the dermal venules.

In biopsies of dry skin, a lymphocytic infiltrate adjacent to eccrine glands has been seen in a few patients. This may explain, at least in part, the skin dryness.

Serologic Testing

Approximately 70% of patients with primary Sjögren’s syndrome have antibodies to SS-A. Approximately half of patients with antibodies to SS-A also have antibodies to SS-B. It is rare to have antibodies to SS-B in the absence of antibodies to SS-A.

The SS-A antigen contains a 60 kD and a 52 kD molecule that associate with a tRNA-like structure (called hYRNA) that serves a function in mRNA processing. The 48 kD SS-B molecule is associated with the SS-A/hYRNA complex.

Other, less specific, antibodies include a positive screening fluorescent antinuclear antibody (ANA), antibodies against endothelial cells, anti-cardiolipin antibodies and, rarely, antineutrophil cytoplasmic antibodies, usually of the perinuclear pattern.

Genetic Studies

The presence of antibodies to SS-A/SS-B is closely associated with specific HLA-DR loci. In Caucasian populations, the association is with the extended HLA-DR3 locus that also includes specific DQ and complement 4 (C4) alleles.

Diagnosis confirmation

The diagnosis of Sjögren’s syndrome should be made after the exclusion of other possible causes of dry eyes or dry mouth. These include previous radiotherapy to the head and neck, lymphoma, sarcoidosis, graft-versus-host disease, and infection with hepatitis C virus, human T-lymphotrophic virus type I, or human immunodeficiency virus (HIV).

Symptoms of dry eyes may result from increased evaporative loss secondary to dysfunction of meibomian glands, which may be seen in patients with blepharitis, rosacea, and (less frequently) ocular pemphigoid.

Distinction between Sjögren’s syndrome and other causes of dry eyes or dry mouth is based on the international criteria for the diagnosis of Sjögren’s syndrome. The six criteria are:

  • - symptoms of dry eye

  • - signs of dry eye (confirmed by the Schirmer or Rose-Bengal test)

  • - symptoms of dry mouth

  • - salivary gland function test (scialogram)

  • - minor salivary gland biopsy

  • - antibodies to SS-A or SS-B

For the diagnosis of primary Sjögren’s syndrome to be made, patients must fulfill four criteria, one of which should be either a positive salivary gland biopsy with a focus score of more than 1, or presence of antibodies to SS-A or SS-B.

Who is at Risk for Developing this Disease?

Sjögren’s syndrome affects women preferentially with a ratio of 9:1 (which is similar to SLE). The incidence is approximately 1 in 200 women. The human leukocyte antigen (HLA)-DR3 allele is present in approximately 18% of patients with primary Sjögren’s syndrome, compared to 3.5% of controls.

What is the Cause of the Disease?

Etiology

Normal lacrimal and salivary flow is regulated through feedback mechanisms. The lacrimal and salivary nuclei are located in the medulla and are part of the autonomic nervous system. They are influenced by higher cortical inputs, including taste, smell, and anxiety.

The efferent neurons innervate both glandular cells and local blood vessels. Blood vessels provide water for tears and saliva, as well as growth factors. In response to neural stimulation through muscarinic M3 receptors and vasoactive intestinal peptide (VIP) receptors, glandular acinar and ductal cells secrete water, proteins, and mucin. This complex mixture forms a hydrated gel, which lubricates both the ocular mucosa and the oral mucosa.

The exact cause of Sjögren’s syndrome is not fully known. It is believed that both genetic and environmental factors play a role in the pathogenesis of Sjögren’s syndrome. Genetic factors have already been alluded to. Suspected environmental factors include multiple viral infectious agents that have been weakly linked to Sjögren’s syndrome. These include human T-lymphotropic virus Type I, HIV, and Epstein-Barr virus.

Pathophysiology

Although the exact pathogenesis of glandular dysfunction in Sjögren’s syndrome is not fully known, there is evidence for the following chain of events:

  1. Initial changes in glandular cells and gland vasculature secondary to “innate dysfunction” (of the salivary and lacrimal glands)

  2. Activation of the innate HLA-independent immunity that may respond to products of apoptosis, including RNA-protein complexes such as SS-A or SS-B

  3. Activation of the acquired HLA-DR-dependent immunity, with a close correlation between the HLA-DR haplotype and the pattern of antibodies against SS-A and SS-B

  4. Inflammation resulting in degradation of salivary and lacrimal glands by metalloproteinases, leading to glandular dysfunction

  5. Partial (almost never complete) destruction of glandular tissue by granzyme/perphorin mechanisms

  6. Dysfunction of the residual gland (approximately 50% of the original) due to cytokines such as interleukin-1 and tumor necrosis factor alpha, autoantibodies, and interruption of matrix-glandular signaling by metalloproteinases. This results in decreased release of neurotransmitters by residual neurons in the gland and decreased response to available neurotransmitters in the residual glands.

The failure of residual glands to function adequately may be partly due to loss of neural innervation, as evidenced by decreased neural staining by immunohistochemistry. Acetylcholine is required for normal acinar secretion. Release of cytokines, particularly interleukin-1 and tumor necrosis factor alpha, may be toxic to local nerves or acini. Interleukin-1 or tumor necrosis factor alpha in amounts similar to the levels found in the salivary glands or saliva of patients with Sjögren’s syndrome are toxic to nerve cells in vitro.

In short, it is highly likely that the lacrimal and salivary gland dysfunction in patients with Sjögren’s syndrome is due to inadequate response to neural signals, secondary to a local immune response and associated cytokines.

Systemic Implications and Complications

Mutliple internal organs may be involved in patients with Sjögren’s syndrome:

Musculoskeletal

  • - Arthralgia

  • - Myalgia

  • - Fibromyalgia

Gastrointestinal

  • - Autoimmune cholingitis with histology similar to that of primary biliary cirrhosis

  • - Watery diarrhea secondary to multiple causes, including collagenous colitis, ulcerative colitis, ischemic colitis associated with vasculitis, or lymphocytic infiltration of the intestine

  • - Chronic atrophic gastritis may result in anemia and epigastric discomfort

Renal

- Renal tubular acidosis and nephrocalcinosis

Hematology/oncology

- A 33-40-fold increased risk of lymphoma, particularly mucosal-associated lymphoid tumors. Patients at risk include those who have persistent adenopathy, recurrent parotid swelling, vasculitic leg ulcers, circulating paraproteins, and antibodies against gastric parietal cells.

Internal organ vasculitis

- Central nervous system vasculitis may present with neurologic deficits as well as behavioral changes. Patients with systemic vasculitis may present with persistent ulcerative skin lesions, digital gangrene, glomerulonephritis, mononeuritis multiplex, myositis, and mesenteric arteritis.

Cardiopulmonary

- Chronic cough, frequent sinus infections, bronchiectasis, obstructive airway disease, and interstitial lung disease that may progress to pulmonary fibrosis.

Treatment Options

Treatment of Sjögren’s syndrome is extremely variable and depends on the organ(s) involved, the severity of involvement, and associated factors such as concomitant illnesses. A list of treatment options and reference to the concept of a therapeutic ladder is not possible for this multiorgan disorder.

Internal organ involvement is managed by a specialist in the involved organ.

Ocular involvement is best managed by an ophthalmologist.

Oral involvement may be managed by a dental professional or a dermatologist.

Manifestations related to the skin may be managed by a dermatologist. Therapy for these symptons is similar to that for patients with the same disorders in the absence of Sjogren’s syndrome (e.g. Raynaud phenomenon or leukocytoclastic vasculitis are treated similarly, whether the patient has Sjogren’s syndrome or not).

The following is an outline of the discussion of treatment of patients with Sjögren’s syndrome:

MANAGEMENT OF GLANDULAR MANIFESTATIONS

Local therapies

  • - Ocular manifestations

  • - Oral manifestations

  • - Other glandular manifestations

Systemic therapies

  • - Nonimmunosuppressive therapy

  • - Immunosuppressive/Immunomodulatory therapy

MANAGEMENT OF EXTRAGLANDULAR MANIFESTATIONS

  • - Musculoskeletal

  • - Raynaud Phenomenon

  • - Gynecological complications

  • - Vasculitis

  • - Lymphoma

Optimal Therapeutic Approach for this Disease

Management of glandular manifestations

LOCAL THERAPIES

Oral manifestations

The principles of local treatment include the use of salivary substitutes as well as stimulating salivary flow.

Meticulous oral hygiene and frequent dental visits should be encouraged. The use of fluoride-containing dentifrices should be encouraged. Fluoride is essential for mineralization of the hydroxyapatite component of the enamel, which renders it less susceptible to decay. In patients with severe hyposalivation, fluoride gels, prescription-strength toothpaste, and/or oral rinses containing 0.4%-1.25% fluoride are recommended. Dentures should be cleaned with chlorhexadine 2% overnight. Dentures should be removed overnight.

Oral candidiasis may be treated with nystatin ointment or oral suspension. In resistant cases, systemic therapy with ketoconazole (Nizoral), fluconazole (Diflucan), or itraconazole (Sporanox) (all 200mg daily for two weeks) may result in long remissions.

Salivary substitutes are available as gels, mouthwashes, lozenges, and toothpastes, and are transiently effective.

Oral lubrication may also be accomplished by sipping water or sugar-free fluids frequently throughout the day. Salivary flow may be enhanced transiently with sugar-free chewing gum. Accupuncture treatments have been reported to result in increased salivary flow.

Ocular manifestations

Patients should avoid medications that exacerbate dry eyes, such as anticholinergics and antihistamines, and avoid environments in which dust or cigarette smoke is prevalent.

The patient’s environment should be humidified, and the patient should be advised to use eyeglasses with side shields and take regular breaks while reading or working at a computer.

Replacement therapy with artificial tears containing sodium hyaluronate may be helpful. Whenever possible, preparations that contain preservatives should be avoided. Thicker products, including methylcellulose inserts and lubricating ointments, may be used at night.

Topical corticosteroids are of limited value and should not be used routinely.

Cyclosporine emulsion 0.05% (Restasis) has been shown to be beneficial in multiple randomized double-blind studies.

Surgical intervention using punctual plugs has been used with success.

Other glandular manifestations

Dryness of the upper airways may be managed with a home humidifier and frequent sinus rinses with saline solution, in order to remove dry crusted secretions of the nasal and sinus mucosa.

Immunization with pneumococcal polysaccharide vaccine helps prevent pneumococcal pneumonia.

Chronic atrophic gastritis may require antacids.

SYSTEMIC THERAPIES

Nonimmunosuppressive therapy/secretagogues/cholinergic agonists

The mainstay of treatment of Sjögren’s syndrome is stimulation of secretory function. Pilocarpine and cevimeline are both United States Food and Drug Administration approved secretagogues/cholinergic agonists.

Pilocarpine (Salagen 5mg, 7.5mg), a natural alkaloid with cholinergic effect, was initially indicated for the treatment of radiation-induced xerostomia. In a large randomized controlled twelve-week trial of pilocarpine 5mg four times daily, symptomatic relief of dryness of the mouth, eyes, nose, vagina, and skin, as well as an increased level of saliva production was demonstrated. Pilocarpine 10mg three times daily was also found to be beneficial for ocular symptoms but not tear production.

Adverse effects of pilocarpine include excessive sweating, urinary frequency, flushing, and headache.

Cevimeline (Evoxac 30mg) has a high affinity for M3 muscarinic receptors, which are found in both salivary and lacrimal glands. It has a greater half-life (approximately 5 hours) than pilocarpine and may be given three times daily.

Three randomized controlled 6-week studies showed significant improvement in the symptoms of dry mouth and the need of artificial saliva, as well as increased salivary flow in patients who received cevimeline 20mg three times daily and those who received 10mg three times daily. A twelve-week multicenter study compared cevimeline 30mg and 15mg versus a placebo, and demonstrated a significant improvement in the subjective symptoms of dry eyes and dry mouth, as well as in the salivary and lacrimal flow rates in the 30mg group, compared to placebo.

Adverse effects were reported in the high-dose group and included nausea and increased sweating. The 15mg-daily group reported a subjective relief of sicca symptoms. In a subsequent 4-week study, cevimeline 20mg three times daily resulted in significant improvement in ocular subjective symptoms, tear dynamics, and condition of the corneal and conjuctival epithelium, compared to placebo.

Cevimeline gargle is effective in alleviating dry mouth symptoms.

Both pilocarpine and cevimeline are contraindicated in patients with uncontrolled asthma, acute iritis, and narrow-angle glaucoma.

Immunosuppressive/Immunomodulatory therapy

Cyclosporine: Because cyclosporine (Neoral, Seromycin, and Gengraf 25mg, 100 mg) acts by inhibiting interleukin-2 production by activated helper T-cells (which are present in involved salivary glands in patients with Sjögren’s syndrome), a double-blind study of cyclosporine 5mg/kg/day was performed. Subjective symptoms of dry mouth were improved, without significant changes of lacrimal and parotid flow.

Methotrexate is an immunomodulatory and anti-inflammatory agent. In an open trial, methotrexate 0.2mg/kg/week was found to be effective in improving the subjective symptoms of dry mouth and dry eyes, without an objective effect on the lacrimal or salivary flow rates.

Thalidomide is a potent inhibitor of tumor necrosis factor-alpha. It was used in a 12-week, randomized double-blind placebo pilot-controlled study with a starting dose of 50mg daily and an increase by 50mg daily to a maximum dose of 300mg, if tolerated. Significant improvement was noted in both oral and ocular symptoms; however, severe adverse effects, including sedation, orthostatic hypotension, and peripheral neuropathy, make thalidomide use unsuitable.

Corticosteroids: A randomized study suggested a beneficial role for systemic corticosteroids. The prolonged use of topical corticosteroids in the eyes is discouraged.

Azathioprine: Low-dose azathioprine (Imuran 50mg) (1mg/kg/day) did not reveal any therapeutic benefit in a double-blind placebo-controlled trial.

D-penicillamine was investigated in a prospective open study and was shown to be of little value regarding the salivary flow, stimulated parotid gland flow, and objective determination of tear flow.

Hydroxychloroquine (Plaquenil) was not found to be effective in alleviating the sicca symptoms.

Management of extraglandular manifestations

There are no large controlled randomized studies for the management of systemic manifestations of patients with Sjögren’s syndrome.

MUSCULOSKELETAL

Patients with Sjögren’s syndrome may complain of arthralgias, myalgias, and fibromyalgia-like symptoms.

These symptoms respond well to nonsteroidal anti-inflammatory drugs (Naproxen, Ibuprofen), as well as hydroxychloroquine (Plaquenil).

Regular excercise such as walking and stretching, and low-dose tricyclic antidepressant (Doxepin, Amitryptiline), may improve sleep in patients with fibromyalgia symptoms. Higher doses of tricyclic antidepressants should be used with caution, as they may exacerbate sicca symptoms.

Some patients present with symmetrical polyarthritis indistinguishable from rheumatoid arthritis. These patients may be treated with methotrexate 0.2 milligram/kilogram/weekly.

RAYNAUD PHENOMENON

Management consists of avoidance of cold and physical and emotional stresses, along with the administration of calcium channel blockers (Diltiazem, Nifedipine) or angiotensin-converting enzyme inhibitors (Captopril, Lisinopril, Enalapril), and may be carried out by the dermatologist alone or in cooperation with the internist or rheumatologist.

GYNECOLOGICAL COMPLICATIONS

Dyspareunia secondary to poor vaginal lubrication is frequently seen in patients with Sjögren’s syndrome (40% compared to 3% of healthy controls) and may be managed with vaginal lubricants such as KY jelly. In post-menopausal women, topical estrogen preparations may be helpful. There is no need for topical steroids, and they should be avoided.

VASULITIS

Patients with systemic vasculitis are treated aggressively with prednisone 1mg/kg/day, intravenous cyclophosphamide (Cytoxan) 0.5-1 gram/m2 monthly, and plasmapheresis. A few reports suggested the beneficial role of rituximab (anti-CD20) therapy in the management of systemic vasculitis. Vasculitis limited to the skin may be managed conservatively with low-dose prednisone (1/2mg/kg/d), nonsteroidal anti-inflammatory medications, and leg compression.

LYMPHOMA

The management of lymphoma in patients with Sjögren’s syndrome is similar to that of lymphoma in the general population and depends on the histological type, location, and extent of involvement.

Patient Management

As mentioned under Treatment Options, the treatment of patients with Sjögren’s syndrome is extremely variable.

Unusual Clinical Scenarios to Consider in Patient Management

Rarely, patients with Sjögren’s syndrome had associated cutaneous T cell lymphoma or lymphomatoid papulosis.

What is the Evidence?

Fox, RI, Liu, AY. "Sjögren’s syndrome in dermatology". Clin Dermatol. vol. 24. 2006. pp. 393-413.

(Sjögren’s syndrome is a systemic autoimmune connective tissue disease characterized by dry mouth [xerostomia] and dry eyes [keratoconjunctivitis sicca]. There are six diagnostic criteria. For the diagnosis to be confirmed, the patient must have four criteria, one of which should be either a positive salivary gland biopsy or the presence of antibodies to SS-A and/or SSB. Sjögren’s syndrome may be primary or associated with other systemic autoimmune connective tissue disorders such as rheumatoid arthritis, diffuse scleroderma, SLE, or dermatomyositis. Patients have a markedly increased risk of lymphoma.)

Mavragani, CP, Moutsopoulos, HM. "Conventional therapy of Sjögren’s syndrome". Clinic Rev Allerg Immunol. vol. 32. 2007. pp. 284-91.

(This paper provides an extensive discussion on the management of patients with Sjögren’s syndrome. The authors admit the lack of strong evidence for the use immunosuppressive agents, which are the mainstay of treating other autoimmune connective tissue diseases. Keratoconjunctivitis sicca is managed with tear substitutes, as well as stimulators of tear secretion. Management of oral manifestations consists of intense oral hygiene, prevention and treatment of oral candidiasis, the use of saliva substitutes, and local as well as systemic agents that stimulate salivary secretion.)

Fox, RI, Tornwall, J, Michelson, P. "Current issues in the diagnosis and treatment of Sjögren’s syndrome". Curr Opin Rheumatol. vol. 11. 1999. pp. 364-71.

(This paper addresses the limitations of both the European and the American criteria for the diagnosis of Sjögren’s syndrome. The authors discuss the planned combination of the two sets of criteria. Patients tend to have a relatively strong association with the HLA-DR3 haplotype, which is associated with increased frequency of antibodies against SS-A and SS-B.Dryness of the eyes appears to be caused by deficiency or dysfunction in mucin production. Dermatologic manifestations may be divided into those that are related to blood vessel pathology [purpura, vasculitis, and Raynaud phenomenon] versus those that are not. Inflammation of the lacrimal and salivary gland almost never results in complete destruction, but instead, moderate destruction of the glands followed by their dysfunction. Hence, there is lack of correlation between the level of destruction and the degree of gland secretion.)

Fox, RI, Saito, I, Hertl, M. "Sjögren’s syndrome". Autoimmune diseases of the skin: pathogenesis, diagnosis, management. Springer-Verlag. 2005. pp. 261-89.

(This paper emphasizes the pathogenesis of Sjögren’s syndrome and the evidence for it. The initial change is believed to be in the glandular cells and blood vessels that precede lymphocytic infiltration. This is followed by activation of the innate HLA-independent immune system that may respond to apoptotic products, including the SS-A or SS-B RNA-protein complex. The HLA-DR-dependent acquired immune system is then activated, resulting in activation of metalloproteinases that degrade the matrix of the salivary and lacrimal glands.Partial dysfunction of the residual gland [that constitutes approximately 50% of the original number of ducts and acini] is due to inflammatory cytokines, autoantibodies, and interruption of matrix glandular signaling, which all result in decreased release of neurotransmitters by residual neurons in the gland and decreased response of the glandular cells to available neurotransmitters.)

Provost, TT, Watson, R. "Cutaneous manifestations of Sjögren’s syndrome". Rheum Dis Clin No Am. vol. 18. 1992. pp. 609-16.

(Patients with Sjögren’s syndrome have multiple mucocutaneous signs and symptoms. Dryness of the eyes may result in photophobia, burning, and itching. Dryness of the mouth may result in alterations of taste and smell. Dryness of the vagina may result in dysparunia. Dryness of the nasopharyngeal mucosa may result in recurrent sinusitis and rhinitis. Patients with Sjögren’s syndrome develop vascular disease, including vasculitis which is usually neutrophil mediated but may also be lymphocyte mediated.)

Soy, M, Piskin, S. "Cutaneous findings in patients with primary Sjögren’s syndrome". Clin Rheumatol. vol. 26. 2007. pp. 1350-2.

(The authors report two patients with Sjögren’s syndrome. One of the patients presented with perniosis and the other presented with red plaques over the face and upper extremities, with the histology revealing a dermal neutrophilic infiltrate.)

Brito-Zerón, P, Ramos-Casals, M, Bove, A, Sentis, J, Font, J. "Predicting adverse outcomes in primary Sjögren’s syndrome: identification of prognostic factors". Rheumatology. vol. 46. 2007. pp. 1359-62.

(The objective of this study was to identify features present at the time of diagnosis of Sjögren’s syndrome that were prospectively associated with adverse outcomes in a large cohort of patients with primary Sjögren’s syndrome. The outcomes measured in 266 patients were vasculitis, B-cell lymphoma, and death.Nine percent of patients developed vasculitis. Multivariate analysis identified abnormal parotid scintigraphy and low C4 level as variables predicting the development of vasculitis. Three percent of patients developed B-cell lymphoma. A low C3 level was a predictive factor for the development of lymphoma. Nine percent of patients died during follow-up. Independent predictive factors were systemic involvement, vasculitis, low C4 level, and presence of cryoglobulins. These predictors were independent of each other.)

Llamas-Velasco, M, Eguren, C, Santiago, D, García-García, C, Fraga, J, García-Diez, A. "Calcinosis cutis and Sjögren’s syndrome". Lupus. vol. 19. 2010. pp. 762-4.

(A patient with Sjögren’s syndrome who developed cutaneous calcinosis is reported.)
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