Abstract
Objective: To assess the prevalence of Sjögren syndrome (SS) in patients with primary progressive MS (PPMS).
Background: SS may be considered in the differential diagnosis of MS. Age at onset and clinical presentation are similar in SS and PPMS. However, occurrence of SS in definite cases of PPMS has been recently reported.
Methods: Proposed clinical and laboratory diagnostic criteria for SS were systematically assessed in 60 consecutive patients with PPMS. The authors questioned all patients about xerophthalmia and xerostomia, biopsied minor salivary glands, and performed a Schirmer test, a salivary gland scintigraphy, and anti-Ro (SSa) and anti-La (SSb) serologies.
Results: Ten patients (16.6%) met four or more criteria for SS. This prevalence is higher than in the general population (1 to 5%) and implies that SS can mimic PPMS.
Conclusions: The authors propose that SS should be screened for systematically in patients with PPMS.
The relationship between MS and Sjögren syndrome (SS) is controversial. Two studies reported that CNS involvement occurs in approximately 20% of patients with SS and is usually misdiagnosed as MS at onset.1,2⇓ However, this study was performed before the advent of MRI and it was considered that one band in CSF on electrophoresis was sufficient for oligoclonal bands (OCB) to be defined. In contrast, two studies failed to demonstrate any association between MS and SS.3,4⇓ However, these studies were performed before the validation of new criteria for SS, which are now recognized as sensitive and specific.5 When four of these criteria are met, the sensitivity and specificity for the detection of SS are 93.5% and 94%. A previous study on patients with MS did not find any with SS but the authors did not perform the complete screening battery for SS; notably, salivary gland flow measurements and minor salivary gland biopsies.3 Another study found two patients (3.1%) with SS in a population of 64 patients with MS,4 which is within the generally accepted incidence in the general population (1 to 5%).6 We recently reported patients with SS with acute and chronic myelopathies, the most recent of whom presented clinical, laboratory, and MRI features very similar to those found in primary progressive MS (PPMS).7 We therefore decided to evaluate the prevalence of SS in 60 consecutive patients with PPMS by applying the revised European criteria for SS.5
Methods.
We studied 60 consecutive patients with PPMS as defined by recent criteria.8 Clinical, laboratory, and MRI findings in these patients are summarized in table 1. All patients underwent complete screening for PPMS, including brain and spinal cord MRI, visual evoked potentials (VEP), and CSF analysis. OCB were detected by an isoelectrofocusing method. Presence of three of more bands was required. We considered brain MRI abnormal (evidence of MRI lesions) when the patient had typical images (more than nine lesions).8,9⇓ Brain MRI was considered equivocal when there were between four and eight lesions and normal when there were fewer than four lesions. Disability was evaluated by the Expanded Disability Status Scale (EDSS).10 For all measurements the findings were similar to previous studies on PPMS.11-13⇓⇓ All patients were followed up for at least 1 year and showed a progressive disease course without relapses. Typical brain abnormalities were found in 80% of patients and spinal cord MRI abnormalities in 40%. VEP abnormalities were found in 80% of patients and OCB in 88%. Finally, according to the recently proposed criteria,8 77% of patients had definite PPMS, 21.3% had probable PPMS, and one patient (1.7%) had possible PPMS. For the SS screening, we used the revised European criteria.5 Patients had been free of medication capable of inducing xerostomia or xerophthalmia. Xerophthalmia was evaluated clinically and by bilateral Schirmer test without local anesthesia. Schirmer test was considered abnormal if less than 5 mm of filter was moistened after 5 minutes. Xerostomia was evaluated clinically and by salivary gland scintigraphy using Schall et al.’s classification.14 This examination was considered abnormal for grades III or IV. We also performed a salivary gland biopsy in all patients, scored according to Chisholm and Mason’s classification.15 This examination was considered abnormal for grades III or IV. We investigated other symptoms of the sicca complex (i.e., recurrent parotidis, Raynaud phenomenon, arthralgia). All patients were asked about specific manifestations of other autoimmune diseases (e.g., lupus, rheumatoid arthritis, or scleroderma). Laboratory investigations included complete blood count and erythrocyte sedimentation rate, and tests for rheumatoid factor by the latex method, considered positive at a dilution higher than or equal to 1/40. Antinuclear antibodies (ANA) were tested by indirect immunofluorescence with HEP-2 cell line as substrate, considered positive at a dilution higher than or equal to 1:80. The presence of Ro (SS-A) and La (SS-B) antibodies was evaluated by double gel immunodiffusion and by Western blotting. We considered patients meeting four or more criteria as having definite SS.5 Patients were also investigated for HIV, human T-cell lymphotrophic virus (HTLV)-1 and HTLV-2 serologies, and for neurosarcoidosis (chest X-ray and angioconvertase level). The latter are not sufficient to definitely exclude neurosarcoidosis, but as neurosarcoidosis with clinical features of PPMS has rarely been reported we did not perform any further examinations. The study was approved by the local ethics committee. All patients gave informed consent for the SS investigations. We statistically compared the subgroups of patients with PPMS with SS (Group 1) and without SS (Group 2) using nonparametric tests. We used a chi-square test for qualitative variables and a Mann-Whitney U test for quantitative variables. The degree of significance was established for p < 0.05.
Clinical, laboratory, and MRI findings of patients with primary progressive MS (PPMS)
Results.
The results of each criterion for SS are shown in table 1. Twenty-one of the 60 patients (35%) had symptoms of xerophthalmia. Schirmer test was abnormal in 24 patients (40%). Twenty-one patients (35%) had xerostomia. The salivary scintigraphy was considered positive in 28.3% of patients, 13 of whom (21.7%) were grade III and 4 (6.7%) were grade IV. The minor accessory gland biopsy was positive in 30% of patients, 16 of whom (26.7%) were grade III for and 2 (3.3%) were grade IV. Systemic manifestations were found in 10 patients (16.5%) including inflammatory arthritis (9.8%) and Raynaud phenomenon (6.7%). We did not find other symptoms of the sicca complex. Latex rheumatoid factor was positive in only one patient (with SS) and antinuclear antibodies were positive (titer higher or equal to1:80) in nine cases (15%). Anti-Ro (SSa) antibodies were positive in eight patients (13.3%) and anti-La (SSb) antibodies were positive in one patient (1.7%). Finally, 10 patients (16.7%) had definite SS (at least four criteria), including two patients with six criteria, two patients with five criteria, and six patients with four criteria. Furthermore, 14 patients (23.3%) met three criteria. The most sensitive criteria for SS were xerophthalmia (90%) and Schirmer test (100%), and the most specific criteria was anti SS-A and anti SS-B autoantibodies (92%). Table 2 summarizes clinical, laboratory, and MRI data for the 10 patients with PPMS and SS. A comparison of PPMS with (Group 1) and without SS (Group 2) is given in table 1. We did not find statistical differences between these two subgroups in terms of clinical patterns. We found a higher mean age and ratio of women in Group 1, but the difference was not significant (table 1). Although this group of patients was small, we found significant differences concerning the criteria for PPMS. The number of patients with definite PPMS was higher in Group 2 (p < 0.01). Conversely, the number of patients with possible or probable PPMS was higher in Group 1. The frequency of CSF, MRI, or VEP abnormalities was not different between the two subgroups except that brain MRI was more frequently equivocal or normal in Group 1 (patients with SS) (p < 0.01). In Group 1, brain and spinal cord MRI were normal in two patients.
Clinical, laboratory, and MRI findings in patients with primary progressive MS (PPMS) with Sjögren syndrome
Discussion.
Our study shows that out of 60 consecutive patients with PPMS, 10 patients (16.7%) had a diagnosis of SS (based on the presence of four or more criteria). This rate is clearly higher than the usually accepted prevalence of SS in the general population (1 to 5%).6 The recently published criteria for PPMS did not consider in detail the differential diagnosis of SS.8 However, the likelihood of confusion between PPMS and SS may be greater than with other differential diagnoses, such as adrenoleukodystrophy or Lyme disease. We suggest that screening for SS should be considered in all patients presenting with PPMS. Our results are not entirely in agreement with those of previous studies showing no association between MS and SS.2,3⇓ However, whereas those studies included PPMS, they did not focus on this particular subgroup of patients. This was notably the case in a previous study, which included only 12 patients with PPMS.3 In this small subgroup, these authors found one patient with SS, suggesting that SS may be overrepresented in PPMS (8.3%).3 In contrast, another study did not find any patients with SS in a larger cohort of 56 patients with PPMS.2 However, the authors did not systematically screen for SS criteria.5 Some of their patients had dry eyes, dry mouth, or laboratory test abnormalities but, as these findings were poorly concordant, the authors did not perform salivary gland scintigraphy or minor salivary gland biopsy.2 This is likely to have resulted in a loss of sensitivity, as shown by the recently revised European criteria of Vitali and colleagues.5 Previous studies showed that only 35 to 50% of the patients with SS with CNS involvement were positive for autoantibodies.2,16⇓ Previous studies also highlighted the fact that SS-A and SS-B autoantibodies are not sensitive enough to exclude a diagnosis of SS in patients with peripheral neuropathy (positive in 10 to 30%).17,18⇓ Using a sensitive method, we confirmed these data, with only 50% of the patients in our study with SS having autoantibodies. We demonstrated that salivary gland scintigraphy and biopsy are useful for the diagnosis especially when clinical signs are absent, as was the case in one of our patients. Recent evidence suggests that an autoantibody to peripheral muscarinic receptors may be important in the pathogenesis of SS and a potential marker of SS.19,20⇓ As this autoantibody is not yet included in routine tests we did not look for it, but it would be interesting to evaluate the frequency with which it occurs in SS with neurologic involvement. Studies concerning CNS involvement in SS are scarce but showed that many of the clinical and laboratory findings in SS may be similar to those found in MS.1,2,21,22⇓⇓⇓ Our results confirm these data, showing that only brain MRI patterns may differentiate the two populations. Only a few studies described brain and spinal cord MRI in SS.7,23,24⇓⇓ Brain MRI is found to be abnormal in 60 to 75% of patients with SS and may mimic demyelinating lesions.23,24⇓ However, this is lower than in PPMS, where hyperintense T2-weighted signal is found in about 93% of cases after a mean follow-up of 10 to 15 years.8,11,12⇓⇓ Our results are in accordance with these previous studies; namely, in that the frequency of equivocal or normal brain MRI was statistically higher in the group of patients with PPMS with SS. Spinal cord MRI abnormalities have not yet been studied in extensive cohorts of SS but, in a recent study, we found that MRI may be normal in patients with SS with progressive myelopathy.7 In the literature, the frequency of OCB in SS was evaluated at between 50 and 80% of cases, if only one band was required.2,23⇓ In these studies, if we were to consider as positive the presence of at least two bands in the CSF, the number of patients with OCB would fall to 5/18 (27.7%).2 Our recent study found similar results, with OCB in only 4 (36%) of the 11 patients with SS.7 This value is lower than in MS but the presence of OCB seems to be more frequent in patients with SS and progressive myelopathy than in patients with an acute course.7 Our current results are in line with these data, as the frequency of OCB was not different between patients with PPMS with SS and those without SS. However, this difference in CSF findings in acute and progressive forms of SS will have to be confirmed in a larger group of patients. VEP abnormalities were present in 80% of patients with PPMS with SS. In a previous study the frequency of VEP abnormalities in patients with SS with CNS involvement was evaluated at 59%.2 In our study, the frequency of VEP abnormalities was the same in patients with PPMS with SS and in those without SS and does not therefore appear to be discriminant. All these data underline the difficulty in discriminating between PPMS and SS with chronic myelopathy.7 However, we found some differences in clinical and laboratory profiles between patients with PPMS with SS and those without SS. First, many patients with possible and probable PPMS were positive for SS, suggesting that most of these cases probably do not have MS, especially if VEP deficits are the only abnormalities. Second, even though we did not find significant differences in terms of clinical parameters, probably due to the small size of the PPMS with SS subgroup, the rates of women and patients over 40 years old were higher in this group than in the PPMS without SS subgroup. All of the criteria should be investigated as they showed good sensitivity and specificity for SS detection.5 It would, however, be difficult to screen all patients with MS for SS. Thus, women, patients over 40 years old, patients with possible or probable PPMS, and patients with equivocal or normal brain MRI could be targeted for complete SS screening. For other patients with PPMS, we propose that a salivary gland biopsy and scintigraphy should be performed, but only if two or more SS criteria are met during the initial, noninvasive part of the screening (clinical xerostomia and xerophthalmia, Schirmer test, and level of autoantibodies). As the pathophysiology of SS is unclear, it is difficult to determine whether the two entities should be considered separately or if SS associated with PPMS could be defined as secondary SS.21 As we found different brain MRI features, we suggest that SS may mimic PPMS rather than there being an association between these two pathologies. However, there are insufficient data to determine which of these two hypotheses is correct. It would be interesting to evaluate patients with secondary progressive MS without relapse, as they share certain features with PPMS. This may be of importance for therapeutic strategies. At present there is no validated treatment for both SS and PPMS but several immunosuppressive drugs (cyclophosphamide, azathioprine, or corticosteroids) are currently used in an open label fashion.7,21,25⇓⇓ However, for PPMS, trials are in progress with interferon β or glatiramer acetate. If some of these treatments show efficacy in the next few years, the need for a differential diagnosis will become more acute.
Footnotes
-
See also page 1357
- Received May 9, 2001.
- Accepted July 26, 2001.
References
Letters: Rapid online correspondence
- Reply to Dr. Fox's Letter to the Editor
- The prevalence of Sjögren syndrome in patients with primary progressive multiple sclerosis
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