Sjögren syndrome and systemic lupus erythematosus are distinct conditions

Noah Scheinfeld MD

Dermatology Online Journal 12 (1): 4



Department of Dermatology, St Lukes Roosevelt Hospital Center, New York NY. Scheinfeld@earthlink.net

Abstract

Sjögren syndrome (SS) and systemic lupus erythematosus (SLE) are both collagen vascular diseases that can be accompanied by Ro antibodies. Clinical evidence suggests that they are wholly distinct diseases. SS is strongly linked to lymphoma while lupus is not. SS patients do not commonly exhibit photosensitivity even though anti-Ro antibodies circulate in their blood; SLE patients generally exhibit photosensitivity. SS does not respond to hydroxychloroquine in a reproducible fashion whereas SLE does. SS has not been linked to parvovirus B19, but SLE has. However, SS and SLE do have similarities. Their autoantibody profiles are similar. They effect women more than men and have similar HLA haplotypes and autoantibodies; this is not likely coincidence but it may not clinically relevant.

Introduction

Sjögren syndrome is a chronic disorder that results in insufficient secretion of certain glands of the body. Sjögren syndrome occurs when a person's normally protective immune system attacks and destroys moisture-producing glands, including salivary (saliva-producing) glands and lacrimal (tear-producing) glands. The lungs, intestines, and other organs are less often affected by Sjögren syndrome. Although physicians have had a useful and internationally agreed-upon definition of Sjögren syndrome (SS) for more than 30 years, even in the 1990s there was no agreed upon criteria for diagnosing SS [1]. Doctors parse SS into primary, which occurs by itself, or secondary disease, which manifests with another pathologic etiology such as rheumatoid arthritis or lupus. Primary and secondary SS are systemic diseases, although the symptoms in primary SS tend to be more circumscribed. Seeking to define the relationship of primary and secondary SS requires explication of the relationship of systemic lupus erythematosus (SLE) to Sjögren syndrome. This paper investigates some of the findings of SS and SLE in an effort to better understand their relationship.

History

In 1929 Henrik Sjögren, a Swedish ophthomologist, noted a patient with dry eyes, dryness in the mouth, and pain in the joints [2]. This observation had been made also by Henri Gougerot in 1925 (some refer to this disease as Sjögren-Gougerot syndrome) who had described three cases of progressive atrophy of the salivary glands associated with dry eyes, dry mouth, and dry vagina. Sjögren examined and assembled data on more patients with this symptomatic constellation and collected samples of exocrine glandular tissue with lymphocytic infiltrates. Sjögren described his syndrome in 1933 in his doctoral thesis, Zur Kenntnis der keratoconjunctivitis sicca. His thesis was not of a sufficiently high standard for him to be awarded the title of docent, and thus he was denied the opportunity for a career in academic ophthalmology. In 1943, however, Sjögren's paper was translated into English, a fact that contributed to establishing the eponym. In France, however, the term Gougerot syndrome has been used for decades because he in 1925 had described three cases of atrophy of the salivary glands associated with dry eyes, dry mouth, and dry vagina. Sjögren's very comprehensive and important work justifies the now accepted designation of Sjögren disease.

Etiology

The etiology of Sjögren syndrome is undefined but seems different from the etiology of SLE. As with SLE, the etiology of SS has yet to be fully defined. The etiology of SS remains unknown but the pathogenesis of exocrine cell damage is apparently multifactorial, involving immunological, genetic, hormonal, and viral components.

These etiologies have been extensively outlined [2, 3] Viral infection may be involved in the induction of SS. Epstein-Barr virus (EBV), human T-lymphotrophic virus 1 (HTLV-1), human herpesvirus 6 (HHV-6), human immunodeficiency virus 1 (HIV-1), hepatitis-C virus (HCV), and cytomegalovirus (CMV) may have a role but the findings are not consistent [3].

Polyclonal B lymphocyte hyper-reactivity is one of the most important immunologic phenomena in SS [3]. It results in hypergammaglobulinemia and the presence of the following immune complexes and various antibodies: anti-Ro/SS-A antibodies, anti-La/SS-B antibodies (95 %), rheumatoid factor, antithyroglobulin antibodies (25 %), antimicrosomal antibodies, antihistone antibodies (occasionally), anti-U4/U6snRNP-specific antibodies (uniquely), autoantibodies against platelet GPIIb-IIIa complex, anti-ssDNA antibodies, cryoglobulins, both cytoplasmic and perinuclear antineutrophil cytoplasmic antibodies (ANCA), and precipitating antibodies to extracts of lacrimal and salivary glands [3, 4].

An autoimmune etiology also is demonstrated by the occurrence of a Sjögren-type syndrome after allogenic bone marrow transplantation. A selective defect in aquaporin-5 is thought to contribute to decreased lacrimation and dry eyes in patients with SS. An anti-120-kDa α-fodrin immune response plays a critical role in the development of primary SS. Alpha-fodrin proteolysis and tissue destruction are attributed to apoptosis activated by EBV infection (among other causes) [3, 4].

In salivary gland epithelial cells, there is pronounced expression of the proapoptotic molecules Bax and caspase-3. Intense B-lymphocyte infiltration (20-25 %) and CD4+ T-cell infiltration (70-8 %) centered in the salivary glands promotes the eradication of epithelial cells [3]. The role of various cytokines, such as tumor necrosis factor-α (TNF-α), is also considered in the development of SS. High expression of the intercellular adhesion molecule 1 (ICAM-1) by the salivary epithelium in patients with SS suggests that it has an important role in the pathogenesis of the disease [3, 4]. Neither of these mechanisms have not been described in SLE.

Recent research also includes the neurogenic aspects of exocrine gland dysfunction, including the interference of immune mediators with the glandular response to neurotransmitters released from nerve fibers [1, 2, 3, 4]. This neurotransmitter linkage has not been described in SLE.

Mortality and morbidity

The prognosis with SS is generally better than that of other autoimmune diseases such as lupus. Patients with just exocrine gland involvement do not appear to have increased mortality. No published data concerning mortality and morbidity rates in SS appears to exist. A diagnosis of SLE greatly increases patients' mortality rates.

Laboratory data and SS

No single laboratory test allows the diagnosis of SS. A variety of test results are however abnormal. Erythrocyte sedimentation rate (ESR) is elevated in 80 percent of patients [3, 4]. Rheumatoid factor is present in 52 percent of cases of Sjögren syndrome and in 98 percent of patients with evidence of another collagen vascular disease. A mild normochromic normocytic anemia is present in 50 percent of patients [3, 4]. Leukopenia occurs in up to 42 percent of patients. Anti-SS-A (Ro) and anti-SS-B (La) antibodies are present in a majority of primary type Sjögren cases, but antisalivary duct antibodies are present in a majority of cases of the secondary type. Antinuclear antibodies of the speckled and homogeneous type are present in a majority of cases of Sjögren syndrome. Creatinine clearance may be diminished in up to 50 percent of patients. SLE is marked by a number of similar autoantibodies although the ANA is more often positive [3, 4].

The lack of photosensivity among patients with Sjögren syndrome gainsays that Sjögren syndrome is a variant of lupus

Unlike lupus, Sjögren disease is not marked by photosensitivity in most patients. High levels of Ro/SS-A antibodies with similar molecular specificities are encountered frequently in Sjögren syndrome, however photosensitivity is seen only infrequently. When patients with SLE have high levels of Ro/SS-A antibodies, photosensitivity is almost always present [3, 4].

Retrospective reviews of the clinical findings of patients with lupus and Sjögren syndrome have borne out the weak link of photosensitivity and Sjögren syndrome as well as the strong link of SLE and photosensitivity. In a major study, the clinical and laboratory features of 89 patients with Sjögren syndrome (SS) were reviewed. SS alone was present in 48 of the patients (no internal findings on the ARA list, e.g., serositis) of whom 27 had antibodies to Ro or La. However, anti-Ro/La antibody positive patients showed a higher frequency of systemic clinical features, as well as high IgG levels and rheumatoid factors compared to those without the antibodies. Symptoms of SS were identified in 41 SLE patients; SLE patients developed symptoms of SS at the same age as those with SS alone, but facial rash, photosensitivity, and serositis were more common in those meeting criteria for both conditions [5].

Sjögren syndrome is a disease first and foremost of exocrine glands.

In Sjögren syndrome, the most prevalent organ involvement manifests with diminished lacrimal and salivary gland function, xerostomia, keratoconjunctivitis sicca, and parotid gland enlargement (collectively described as exocrine glands) [6]. That is, impaired gland function is assumed to be a result of progressive lymphocyte-mediated destruction of the exocrine gland tissue leading to the cardinal manifestations, hyposalivation and keratoconjunctivitis sicca (KCS), as well as devastating symptoms of oral and ocular dryness [7]. These findings are not confined to Sjögren syndrome. Sicca symptoms can be found in a number of other disorders including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis, and other rheumatic disorders [8].

Patients with Sjögren syndrome exocrine gland pathology can have pathology in other organs.

Patients with SS can have involvement of other organs in the same fashion as collagen vascular diseases. This is conventionally referred to as secondary Sjögren syndrome but perhaps is best conceived of as SS with extraglandular manifestations. In this broad array of pathological organ effects, SS and SLE become hard to distinguish. Neurologic involvement occurs in approximately 20 percent of patients with primary SS [9]. For example, a 28-year-old woman was described who presented with quadriparesis and respiratory failure and had severe hypokalaemia and distal renal tubular acidosis. Biopsy and scintigraphy of the minor salivary glands confirmed the presence of Sjögren syndrome [10].

Histology

The histology of SLE and SS shares the involvement of lymphocytes. However, whereas SLE skin biopsies can be marked by interface changes at the epidermal-dermal junction and dermal mucin deposition, SS primary involves changes in exocrine glands. Examination of small salivary glands in the biopsy of the lower lip represents the gold standard for diagnosis of SS. The growth and the dysfunction of salivary and lacrimal glands occurs in different pathologic states, but the most important diagnostic criterion in SS is considered to be the histologic focus score of the labial salivary glands. The focus score is defined as the number of lymphocytic foci per 4 mm² of the salivary gland according to the criterion of Chisholm and Mason. Histopathologic examination of incisional biopsies of the parotid and labial minor salivary glands can reveal focal periductal lymphocytic infiltrate and sialoduct ectasia [11]. This is also described as myoepithelial islands and severe lymphocyte infiltration with germinal centers or focal lymphoid sialoadenitis.

A single biopsy of tissue often does not fully confirm the diagnosis of SS. To assemble all possible diagnostic information and identify all cases, some recommend evaluating the presence of focal adenitis in labial salivary gland (LSG) and lacrimal gland (LG) biopsy specimens in all patients [12]. Furthermore, focal sialadenitis may occur in conditions other than SS. Therefore, it is preferable to assess the salivary component with other tests as well (sialometry and salivary scintigraphy in particular) because it has been demonstrated that the border between a normal and an abnormal test result may vary among investigators [13]. One study showed that immunohistologic criteria for SS, based on the percentages of IgA-containing and IgG-containing plasma cells, are able to 1) confirm the diagnosis of SS in labial salivary glands of KCS patients in the absence of grade IV lymphocytic adenitis; and 2) distinguish between a grade IV focal lymphocytic adenitis in the labial salivary glands of SS patients and of RA patients without SS [14].

Models to define Sjögren syndrome

Martin-Martin et al. developed a simple mathematical score that uses clinical and laboratory variables for diagnosing SS, thereby reducing the need of minor salivary gland biopsy [15]. The model tracked the following laboratory values: ANA, SS-A/SS-B, Schirmer's Test/BUT, C3/C4, serum gammaglobulin levels. Martin-Martin studied 100 consecutive patients noting clinical syndromes consistent with a sicca syndrome. Martin-Martin's multifactorial mathematical construction demonstrated a high predictive value for SS as compared with controls or as compared with persons with other autoimmune disorders (Sensitivity 93 %, Specificity 100 %), with an estimated minor salivary gland reduction of 77 percent. Martin-Martin et al. concluded that their mathematical construction might be considered a useful noninvasive approach for diagnosing Sjögren syndrome. They recommend its study on a larger scale. Using the criteria of Martin-Martin model would not result in a diagnosis of SLE [15].

Viruses and Sjögren syndrome

A review of research on the relationship between viruses and SS or SLE suggests they are different processes. The linkage of SS and viral infection is tenuous. Notably there are parallels in presentations of SS and hepatitis C. HCV-infected patients frequently may have Sjögren-like sialadenitis with mild clinical symptoms [16].

HCV infection appears to account for a subgroup of patients with sicca syndrome in which half the cases meet the definition for SS; this subgroup is characterized by the constant finding of xerostomia, the absence of classic systemic manifestations observed in primary SS, and the absence of anti-SSA or anti-SSB antibodies. This syndrome is likely not true SS but a viral syndrome [17]. Patients with SS have HCV infection no more frequently than controls.

There is no association between human parvovirus B19 infection and SS [18, 19]. Isolated cytopenia due to parvovirus B19 in patients with Sjögren syndrome can occur [20]. Parvovirus B19 DNA was detected in 17 of 72 patients with SLE (and none of 18 patients with Sjögren syndrome) [21]. It is interesting to note that parovirus B19 can mimic SLE and the foregoing study suggests that parvovirus B19 might be linked to SLE etiology, continuation, and propagation.

SLE and SS have similar HLA II markers but the clinical significance of this remains undefined

SLE and SS demonstrate similar HLA Class II markers, but this may result from the generation of anti-Ro/La antibodies rather than from the diseases themselves [3]. The strongest contributors to the formation of an anti-Ro/La response included components of the DRB1*03-DQB1*02-DQA1*0501 haplotype. This haplotype can subsume the transethnically-associated DQ-β-DI motif. In addition, the dose-dependent contribution of DQ-α-34Q and DQ-β-26L suggest that there is a recessive contribution of HLA-DQ to the formation of an anti-Ro/La response.

Others have found similar HLA h types in SS [22]. In an investigation to understand the impact of HLA class-I alleles upon predisposition to SS, 46 patients who fulfilled the European criteria and 222 healthy unrelated Caucasians were analyzed. In these patients data was gathered regarding their HLA class I and class II haplotypes. The results confirm the association of the DRB1*03-DQB1*02 haplotype with SS-A/SS-B autoantibody-positive SS. This association demonstrated a significant association of HLA-A24 with the with SS. Moreover, HLA-A24 is more often associated with DRB1*11-DQB1*0301 and/or DRB1*0301-DQB1*02 in SS patients than in patients without SS.[22]

Treatment data

There is no consistently effective treatment in Sjögren syndrome. The current therapy is primarily symptomatic. Current therapeutic measures include means to increase secretion, relieve symptoms, and repair damage of the ocular surface. Controlled studies show that oral pilocarpine significantly improves sicca symptoms in the eyes, mouth, and other sites. In one case, researchers have reported the reversibility of histological and immunohistological abnormalities in sublabial salivary gland biopsy specimens following treatment with corticosteroids [23].

The weight of evidence is that hydroxychloroquine is not an effective treatment for SS. In a prospective, placebo-controlled, 2-year double-blind crossover trial in 19 patients, the use of hydroxychloroquine at a dose of 400 mg daily taken over a 12-month period failed although a slight improvement in hyperglobulinanemia, ESR and IgM levels occured [24]. Despite this study, antecdotal reports continue to be published on hydroxchloroquine effectiveness for SS. Hydroxychloroquine was prescribed with clinical improvement in a 13-year-old girl with Sjögren syndrome manifested by recurrent parotitis [25]. In an open label study of hydroxychloroquine, several SS patients improved [26]. A retrospective study of patients with SS found (a) sustained improvement of local symptoms (painful eyes, painful mouth) and improvement of systemic manifestations (arthralgias and myalgias) after treatment with hydroxychloroquine 6-7 mg/kg/day over a mean three-year follow-up; (b) a significant improvement in ESR and quantitative IgG levels; (c) no significant late toxicity [27].

SLE is effectively treated with hydroxychloroquine. This has been demonstrated in large double blind placebo controlled studies [28]. This large difference in response to hydroxychloroquine suggests that SLE and SS are significantly dissimilar.

Sexual Epidemiology

Both SLE and SS are much more prevalent in women than in men. Women are affected by SS more often than men; the female-to-male ratio is 9:1. SLE has a similar sexual ratio. There is a lower prevalence of SS-related clinicopathologic and sialographic changes and autoantibodies in men with SS than in women with the same condition [1, 3]. Sexual epidemiology does not help distinguish these diseases.

Lymphoma and SS

There is clinical evidence that SS and lymphoma are linked. The occurrence of B-cell non-Hodgkin lymphoma (NHL) is the major complication in the course of disease in patients with SS. The risk of B-cell NHL is 44 times greater in patients with SS than in a healthy population; NHL affects about 5 percent of patients with SS. NHL occurs preferentially in the salivary glands and in other mucosa-associated lymphoid tissue. However, it can also occur in the lymph nodes or bone marrow. In an immunopathological study of 113 patients with non-Hodgkin lymphoma and Sjögren syndrome, 10 of the patients cured of lymphoma still had a lymphocytic infiltrate of salivary glands indicative of SS [29]. There is an increased risk of lymphoma in SLE but not nearly to the extent as in SS.

Sjögren syndrome and the skin

Cutaneous findings linked to SS include: xerosis, epidermal IgG deposits in non- specific eruputions, vasculitis, cutaneous B cell lymphoma, alopecia, vitiligo and papular lesions [30]. Annular erythema of Sjögren syndrome has been reported in Japanese and Polynesian patients and can resemble the annular lesions of subacute lupus erythematosus [31]. Four of the defining manifestions of lupus: discoid lesions, oral ulcers, photosensitivity and malar rash are mucocutaneous findings. The cutaneous findings of SLE are manifold and include[32]

Confluent erythema and edema

Erythematous macules and papules that eventually become confluent

Bullous lesions resembling TEN

Morbilliform macules/papules in a generalized photo-distributed pattern

Malar eminence eruption(representing the wings of the butterfly) and the nasal bridge (representing the body of the butterfly) typically are involved.

Superficial ulceration primarily involving the posterior surface of the hard palate. Occasionally, buccal and gingival mucosae and the tongue may be involved.

Conclusion

The weight of evidence is that SS and lupus are distinct conditions. SS does not manifest with photosensitivity even though it commonly manifests with anti Ro antibodies whereas SLE is a photosensitivity disease. SS does not respond to hydroxychloroquine in a reproducible fashion whereas SLE usually responds to hydroxychloroquine in a reproducible fashion. SLE is linked to parvovirus B19 and SS is not. SS is linked to lymphoma very strongly and SLE is not. SLE has a variety of cutaneous findings and SS has few cutaneous findings. SS and SLE do have similarities. Their autoantibody profiles are not dissimilar. They affect women more than men and have similar HLA haplotypes and autoantibodies. These similarities are not likely a coincidence but do not appear to be clinically relevant.

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