Sj ogren s syndrome in women presenting with chronic dyspareunia

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1 British Journal of Obstetrics and Gynaecology September 1997, Vol. 104, pp Sj ogren s syndrome in women presenting with chronic dyspareunia *Diarmuid M. Mulherin Senior Registrar (Rheumatology), *Thomas P. Sheeran Senior Registrar (Rheumatology), * *Dinakantha S. Kumararatne Consultant (Immunology),?Bernard Speculand Consultant (Oral and Maxillofacial Surgery), $David Luesley Professor (Gynaecological Oncology), *R. Deva Situnayake Consultant (Rheumatology) Departments of *Rheumatology, **Immunology,?Oral and Maxillofacial Surgeg and SGynaecologv, City Hospital, Birmingham; Objective To identify cases of Sjogren s syndrome among women with chronic dyspareunia who did not already have a diagnosed rheumatological disorder. Design Prospective recruitment over 12 months. Setting Tertiary referral service for the assessment of vulva1 disease. Participants Women with chronic dyspareunia who had musculoskeletal symptoms, Raynaud s phenomenon or symptoms of ocular or oral dryness. Methods The women underwent a Schirmer tear test and a comprehensive auto-antibody screen including latex fixation test for rheumatoid factor, antinuclear, anti-ro, anti-la and anti-salivary duct antibodies. A labial salivary gland biopsy and vaginal biopsy were taken for routine histological analysis. Main outcome measures Cases of definite and probable Sjogren s syndrome were identified using the European criteria. Results Eleven women were assessed for features of Sjogren s syndrome. Four had definite primary Sjogren s syndrome, two had probable primary Sjogren s syndrome and one had probable secondary Sjogren s syndrome. Among these seven women the median duration of vaginal symptoms was seven years (range ), of ocular symptoms was one year (range -2) and of oral symptoms was 1.5 years (range 0-6). In all but one woman dyspareunia presented before ocular or oral symptoms, often by many years. Conclusions Although well-recognised as a feature of established Sj ogren s syndrome, this study emphasises that chronic dyspareunia can be a presenting feature in these women, antedating the emergence of ocular or oral symptoms by many years. Symptoms of ocular or oral dryness, Raynaud s phenomenon or musculoskeletal symptoms should be sought in women with chronic dyspareunia to identify those who merit further investigation. INTRODUCTION Henrik Sjogren described the association of keratoconjunctivitis sicca with oral dryness and rheumatoid arthritis in It was subsequently recognised that Sjogren s syndrome could occur alone (primary) or in association with a wide variety of other connective tissue diseases (secondary). The condition is characterised by widespread exocrine gland lymphocytic infiltration which can lead to thyroid, pulmonary, gastrointestinal and renal pathology as well as involvement of skin and the genital tract. Whilst primary Sjogren s syndrome can affect people of all ages, it is primarily seen in women in the fourth and fifth decades of life with a female : male ratio of 9: 1. Diagnosis of Sjogren s syndrome may be Correspondence: Dr R. D. Situnayake, Department of Rheumatology, City Hospital NHS Trust, Dudley Road, Birmingham B 18 7QH, UK. delayed for many years and it may go unrecognised if ocular and oral dryness are not prominent. Most women, however, have symptoms of decreased lacrimal and salivary gland function which usually precede involvement of other exocrine glands such as the upper airway (xerotrachea), gastrointestinal tract (atrophic gastritis, pancreatitis), and the external genitalia (dyspareunia). A small number may present with extraglandular manifestations including arthralgia, myalgia, Raynaud s phenomenon or a nonerosive arthropathy. For many years there was little concensus on appropriate criteria for the diagnosis of Sjogren s ~yndrome *~-~. While it was generally agreed that Sjogren s syndrome ought not be diagnosed on the basis of symptoms of oral and ocular dryness alone, there was disagreement on the relative diagnostic importance of objective ocular tests (Schirmer tear test, rose Bengal staining), measures of oral dryness, evidence of 0 RCOG 1997 British Journal of Obstetrics and GynaecologV 1019

2 1020 D. M. MULHERIN ET AL. autoimmune activation or demonstrable lymphocytic infiltration of salivary glands. However, concerted action by specialists with an interest in Sjogren s syndrome, under the auspices of the European Community, has led to the publication of diagnostic criteria which have been comprehensively validated and have received broad support7. There are few reports in the literature which have examined the clinical or histological consequences of Sj ogren s syndrome in the female external genital tra~t.~.~. These studies have sought to characterise external genital involvement in women with diagnosed Sjogren s syndrome. It has been suggested that the histological changes described in the vagina and cervix are likely to reflect pathological processes similar to those seen in salivary and lacrimal tissues. The present study examined the relation between Sjogren s syndrome and the female external genital tract from a different perspective, seeking to identify cases of Sjogren s syndrome among women presenting with chronic dyspareunia. METHODS The University of Birmingham Department of Gynaecology at City Hospital provides a tertiary referral service to the West Midlands region for the assessment of vulva1 disease. Over a 12 month period all women attending the vulva clinic with chronic dyspareunia who had musculoskeletal symptoms, Raynaud s phenomenon or symptoms of ocular or oral dryness, but who did not have a diagnosed rheumatological disorder, were referred to a combined rheumatology-immunology clinic. Routine assessment at the vulva clinic included vaginal examination, a high vaginal swab for culture and a vaginal biopsy, to which all gave informed consent. At the combined rheumatology-immunology clinicwomen were evaluated using standard methodology, with a clinical assessment including a Schirmer tear test. A range of laboratory evaluations were completed, including a full blood count; plasma viscosity measurement; comprehensive auto-antibody screening, including latex fixation test for rheumatoid factor, antinuclear auto-antibody screening, anti-ro, anti-la, anticentromere, anti-scl-70, anti-salivary duct, antiparietal cell and thyroid antibodies; C-reactive protein (CRP) and immunoglobulin (IgG, IgA, IgM, and IgE) levels. Finally, a salivary gland biopsy was taken from the lip following local anaesthesia following informed consent. Routine histological analysis of material from both salivary and vaginal biopsies was performed in the departments of pathology at the University of Birmingham Dental Hospital and City Hospital respectively. The European criteria for the classification of Sjogren s syndrome were employed. These criteria define six features of Sjogren s syndrome, including ocular and oral symptoms, ocular signs, salivary gland histology, other evidence of salivary gland involvement, and the presence of auto-antibodies (e.g. anti-roy anti- La and antinuclear antibodies and rheumatoid factor). The presence of four features represented definite and, of three features, probable, primary Sjogren s syndrome. For the diagnosis of secondary Sjogren s syndrome, the diagnostic criteria did not consider the presence of auto-antibodies; instead, ocular or oral symptoms, combined with any two of the other three features, such as ocular signs, salivary gland histology or other evidence of salivary gland involvement, allowed a diagnosis of definite secondary Sjogren s syndrome; if only one of these latter criteria were satisfied, a diagnosis of probable secondary Sjogren s syndrome was allowed. RESULTS During the period of the study 238 women attended the vulva clinic and 11 women with chronic dyspareunia were referred for further rheumatological and immunological assessment. Median age was 42 years (range 29-58) and duration of vaginal symptoms was six years (range -25). Four women had definite primary Sjogren s syndrome, satisfying four diagnostic criteria; a further three patients had probable Sjogren s syndrome: two with probable primary and one with probable secondary Sj ogren s syndrome. The remaining four did not meet the criteria for the diagnosis of Sjogren s syndrome. Among those with definite/probable Sjogren s syndrome, median of vaginal symptoms was seven years (range -20), of ocular symptoms was one year (range -2) and of oral symptoms was 1.5 years (range 0-6). In all but one woman vaginal symptoms antedated ocular and oral symptoms, by four years (range 0-195). The salient clinical, laboratory and histological details of all women are outlined (Table 1) and brief case histories of patients with definite or probable Sjogren s syndrome follow. Case 1 A 46 year old patient presented with a 20-year history of vaginal symptoms and long-standing scalp psoriasis treated with coal tar preparations. Five years previously she had undergone a hysterectomy followed by hormone replacement therapy. Persistently gritty eyes and a dry mouth had been present for six months. She had no articular symptoms or Raynaud s phenomenon. The Schirmer test was abnormal and salivary gland biopsy demonstrated a focal lymphocytic infiltrate, with ductal atrophy. A chronic lymphocytic infiltrate was also seen in vaginal tissue underlying stratified squamous epithelium. Antinuclear auto-antibody screening was positive

3 ~~~ ~~ ~~ ~~ ~ SJOGREN S SYNDROME IN WOMEN WITH DYSPAREUNIA 1021 Table 1. Clinical and laboratory details of I1 women (case nos ) with chronic dyspareunia assessed for evidcnce of Sjogren s syndrome. SS = Sjogren s syndrome; ND = not done; NSpec = nonspecific; ANA= antinuclear antibody; RF = rheumatoid factor; IgG = immunoglobulin G; FCLI = focal chronic lymphocytic infiltration; CII = chronic inflammatory cell infiltrate; LS = lichen sclerosus; Strep. = streptococcal; Stuph. =staphylococcal. Details I I1 Diagnosis of SS Age (years) Dypareunia (years) Ocular dryness (years) Oral dryness (years) Raynaud s (years) Arthralgia (years) Schirmer tear test (m/5 min) Salivary gland biopsy Vaginal biopsy Autoantibodies Vaginal culture Definite Definite Definite Definite Probable Probable Probable Not SS I FCLI, FCLI, NSpec NSpec NSpec NSpec NSpec ND fibrosis duct CI1 CII, CII, CII, dilated CII, atrophy plasma cells fibrosis ducts fibrosis CII CIl C1I Acanthosis ND ND LS ND ANA Parietalcell RF,Ro Ro ANA Salivary RF?IgG f IgG thyroid Salivary duct duct Candida No Candida No No No Candida Strep. spp growth spp growth growth growth spp spp NotSS NotSS NotSS ND Lichen Normal planus ND Acanthosis Normal None ANA None Staph. No Candida SPP growth SPP at low titre but other auto-antibodies were negative, and full blood count, plasma viscosity, immunoglobulin and C-reactive protein levels were normal. Definite primary Sj ogren s syndrome was diagnosed. Case 2 A 35 year old woman presented with a 10-year history of vaginal symptoms and Raynaud s phenomenon. She had a six-year history of a persistently dry mouth and a two-year history of dry eyes and arthralgia, with no clinical evidence of synovitis. The Schirmer test was abnormal and a labial biopsy demonstrated a focal lymphocytic infiltrate, with ductal atrophy. A chronic lymphocytic infiltrate was also seen in vaginal tissue underlying stratified squamous epithelium. Autoantibodies against gastric parietal cells only were identified. Full blood count, plasma viscosity and C-reactive protein levels were normal but polyclonal increased IgG was measured. Again, definite primary Sjogren s syndrome was diagnosed. Case 3 A 42 year old patient presented with a three-month history of vaginal symptoms. During the same period, she had noticed persistently dry eyes and mouth. She had a six-year history of Raynaud phenomenon and a six-month history of arthralgia, but no clinical evidence of synovitis. The Schirmer test was abnormal and a both labial and vaginal biopsies demonstrated a nonspecific chronic inflammatory cell infiltrate. Anti-Ro and anti- thyroid antibodies were identified and rheumatoid factor was positive (3 10 IU/mL). Other auto-antibodies were negative, and full blood count, plasma viscosity, C-reactive protein and immunoglobulin levels were normal. Again, definite primary Sjogren s syndrome was diagnosed. Case 4 A 33 year old woman presented with a six-year history of dyspareunia and Raynaud s phenomenon. She had a five-year history of a persistently dry mouth and arthralgia and a six-month history of gritty eyes. There was no clinical evidence of synovitis. The Schirmer test was abnormal and labial biopsy demonstrated a nonspecific chronic inflammatory cell infiltrate with prominent plasma cells. Biopsy of the vagina demonstrated acanthotic squamous epithelium. Anti-Ro antibodies were identified. Other auto-antibodies were negative, and full blood count, plasma viscosity, C-reactive protein and immunoglobulin levels were normal. Again, definite primary Sjogren s syndrome was diagnosed, Cases 5-7 Three cases met criteria for the diagnosis of probable Sjogren s syndrome. The first patient, a 46 year old woman with a seven-year history of vaginal symptoms, had a five-year history of dry mouth, a two-year history of Raynaud s phenomenon and an 18-month history of

4 1022 D. M. MULHERIN ET AL. gritty eyes. The Schirmer test was normal and labial biopsy demonstrated a chronic inflammatory cell infiltrate with fibrosis. Both antinuclear and salivary duct antibodies were positive. Probable primary Sjogren s syndrome was diagnosed. The second patient, a 50 year old woman with a 10-year history of vaginal symptoms, had a two-year history of Raynaud s phenomenon and an 18-month history of a persistently dry mouth and gritty eyes. The Schirmer test was abnormal and labial biopsy demonstrated a chronic inflammatory cell infiltrate with dilated ducts. Salivary duct antibodies were positive. Probable primary Sjogren s syndrome was again diagnosed. The third patient, a 58 year old woman with a five-year history of vaginal symptoms, had a one-year history of dry eyes and Raynaud s phenomenon and a six-month history of an inflammatory arthritis, subsequently diagnosed as seropositive rheumatoid arthritis. The Schirmer test was abnormal and labial biopsy demonstrated a nonspecific chronic inflammatory cell infiltrate with fibrosis. Vaginal biopsy demonstrated lichen sclerosus. Probable secondary Sj ogren s syndrome with rheumatoid arthritis was diagnosed. DISCUSSION The present study sought to identify cases of previously unidentified Sjogren s syndrome among a highly selected population of women presenting to a tertiary referral service for the assessment of vulval disease. Among over 200 women who attended during the 12-month period of the study, 11 with chronic dyspareunia were identified who admitted to musculoskeletal symptoms, Raynaud s phenomenon or symptoms of ocular or oral dryness and who did not already have a diagnosed rheumatological disorder. Following further assessment, four women were identified with sufficient features to allow a definite diagnosis of Sjogren s syndrome and a further three had probable Sjogren s syndrome. All of these women had long-standing symptoms of vaginal dryness and dyspareunia which, in most cases, antedated the onset of symptoms of ocular or oral dryness, often by many years. Vaginal dryness, as a presenting feature of Sjogren s syndrome, has not been highlighted previously and this again emphasises the difficulties in diagnosing women with Sjogren s syndrome, particularly where ocular or oral dryness are not prominent. Clearly, larger studies are needed to estimate the incidence and prevalence of Sjogren s syndrome in women with chronic dyspareunia. Until these are completed, medical practitioners treating a woman with dyspareunia should enquire about symptoms of ocular or oral dryness, Raynaud s phenomenon or musculoskeletal symptoms, in order to identify women who might warrant further assessment by a Schirmer tear test, appropriate auto-antibody measurement, and perhaps a labial salivary gland biopsy where there remains a strong clinical suspicion of Sjogren s syndrome. The vagina is lined by a deep layer of nonkeratinised squamous epithelium overlying a lamina propria of dense connective tissue, with numerous elastic fibres, polymorphonuclear leucocytes, lymphocytes and lymphoid nodules 0.. There are a variety of physiological mechanisms for vaginal lubrication. Whilst there are no secretory glands in the vagina, a fluid exudate seeps through the vaginal wall from the underlying richlyvascular stroma during sexual stimulation and is an important contributor to vaginal lubrication. In addition, vaginal epithelium is rich in glycogen stores during the reproductive years, and it undergoes a process of continuous desquamation, also making an important contribution to vaginal lubrication. Finally, cervical glands are another important source of vaginal secretions. Dyspareunia, or painful intercourse, in the absense of structural pelvic pathology, can reflect vaginal dryness as a result of a failure of the physiological mechanisms for vaginal lubrication. In women with Sjogren s syndrome, reduced vaginal secretions could reflect altered vaginal epithelium, chronic inflammatory changes in the vaginal wall or chronic cervicitis, or a combination of these factors. Only a small number of studies have examined the clinical or histological consequences of Sjogren s syndrome in the female genital In 1965 Bloch et al. described dyspareunia, vulval pruritus and vaginal dystrophy in most cases from a cohort of 62 women with Sj ogren s syndrome. They identified vaginal erythema and irritation on gynaecological examination and suggested that these features might reflect impaired function of vaginal and vulval exocrine glands due to Sjogren s syndrome. Capriello et a/.* found that 18/26 women (69%) with Sjogren s syndrome (nine postmenopausal) complained of vaginal dryness and dyspareunia. While these features were universally present in postmenopausal women, they were also frequent in women of reproductive age and thus could not be attributed solely to oestrogen deficiency. Cervical biopsy identified chronic nonspecific cervicitis in 11 women (42%), but no histological features pathognomonic for Sjogren s syndrome were identified. More recently Skopouli et al9 described their findings in 51 women with primary Sjogren s syndrome compared with healthy controls. Dyspareunia was more frequent among premenopausal women with Sj ogren s syndrome (8/20) compared with healthy premenopausal controls (1/35), although many of these had an obvious aetiology for this which was felt to be unrelated to Sjogren s syndrome (e.g. vaginitis or surgical trauma). Vaginal histology in a small number of patients revealed chronic inflammatory cell infiltrates underlying atrophic squamous epithelium. All of these studies have examined

5 SJOGREN S SYNDROME IN WOMEN WITH DYSPAREUNIA 1023 cohorts of women with diagnosed Sjogren s syndrome. Their findings emphasise the frequency of vaginal symptoms in these women, with disproportionately more premenopausal women affected, and provide levidence of chronic nonspecific inflammation in the vagina and cervix. The present study echoes their clinical and histological findings in the women with Sj ogren s syndrome who were identified among women with chronic dyspareunia. The aetiology of primary Sjogren s syndrome remains unknown. Considerable interest has focussed on a possible aetiological role for viral infection. In particular, the relation of hepatitis C and retroviruses have been evaluated. Jorgensen et al. l2 sought evidence of hepatitis C infection in a cohort of 62 women with Sjogren s syndrome using a recombinant immunoblot assay for the detection of anti-hepatitis C antibodies combined with polymerase chain reaction methodology to detect viral RNA in serum and saliva from these patients. Almost 20% of their patients had evidence of hepatitis C infection, with increased neurological and hepatic abnormalities and decreased anti-ro and anti- La serology in these patients compared with those who were hepatitis C-negative. Other authorsi3 have suggested a possible role for retroviruses, such as human immunodeficiency virus (HIV) and human T lymphotropic virus type 1 (HTLV-l), in the aetiology of Sjogren s syndrome. It has been suggested that there are many areas of clinical overlap between Sjogren s syndrome and manifestations of both HIV and HTLV-1 infection, including oral and ocular dryness, chronic lymphocytic infiltration of various tissues, lymphadenopathy, lymphoid malignancy and cachexia. In addition a number of small studies have identified HTLV-1 gene products expressed in salivary tissue of a subset of patients with Sjogren s syndrome. Clearly, more work is needed in this area. It may well be that manifestations of Sjogren s syndrome represent a final common pathological process following a variety of insults and in this context, it is possible that viral infection of the genital tract might be aetiologically important. If this were the case, such women could present with vaginal symptoms prior to the development of overt symptoms elsewhere. In this regard, future epidemiological studies of Sj ogren s syndrome in women with chronic dyspareunia could also be combined with viral studies of vaginal tisue and labial salivary glands. Acknowledgements The authors would like to thank Ms P. Connolly for her help in identifjmg patients for further evaluation, and the staff of the Department of Oral Pathology at the University of Birmingham Dental Hospital and the Departments of Immunology and Pathology at City Hospital NHS Trust, Birmingham, for their assistance in processing samples. References Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjogren s syndrome: a clinical, pathological and serological study of sixty-two cases. Medicine (Baltimore) 1965; 44: Fox RI, Howell FV, Bone RC, Michelson P. Primary Sjogren syndrome: clinical and immunopathologic features. Semin Arthritis Rheum 1984; 14: Fox RI, Kang HI. Sjogren s syndrome. In. Kelley WN, Harris ED, Ruddy S, Sledge CB, editors. Textbook ofrheumatology. Philadelphia: WB Saunders, 1993: Whaley K, Williamson J, Chisholm DM, Webb J, Mason DK, Buchanan WW. Sjergren s syndrome. I: Sicca components. Q J Med 1973; 42: Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjogren s syndrome. Proposed criteria for classification. Arthritis Rheum 1986; 29: Anonymous. Diagnosis of Sjogren s syndrome. Lancet 1992; 340: Vitali C, Bombardieri S, Moutsopoulos HM et al. Preliminary criteria for the classification of Sjogren s syndrome. Results of a prospective concerted action supported by the European Community. Arthritis Rheum 1993; 36: Capriello P, Barale E, Cappelli N, Lupo S, Teti G. Sjogren s syndrome: clinical, cytological, histological and colposcopic aspects in women. Clin Exp Obst Gyn 1988; 15: Skopouli FN, Papanikolaou S, Malamou-Mitsi V, Papanikolaou N, Moutsopoulos HM. Obstetric and gynaecological profile in patients with primary Sjogren s syndrome. Ann Rheum Dis 1994; 53: Junqueira LC, Cameiro JC, Kelley RO. editors. Basic Histolop. London: Prentiee-Hall International, 1992: Peel KR, Maclean AB. Benign and malignant disorders of the vagina. In: Whitfield CR, ed. Dewhursth Textbook of Obstetrics and Gynaecology for Postgraduates. Oxford: Blackwell Science, 1995: Jorgensen C, Legouffe MC, Perney Petal. Sicca syndrome associated with hepatitis C virus infection. Arthritis Rheum 1996; 39: Garry RF. New evidence for involvement of retroviruses in Sjogren s syndrome and other autoimmune diseases. Arthritis Rheum 1994; 37: Received 20 January 1997 Accepted 18 April 1997