It is often difficult to diagnose Sjögren syndrome (SS) with neurologic manifestations as frequently only the nervous system is affected and anti-Ro (SSA) and anti-La (SSB) antibodies are found in fewer than 50% of cases.1,2⇓ In a recent study, we demonstrated that primary progressive multiple sclerosis (PPMS) should be the principal differential diagnosis for SS with CNS manifestations.2 However, the question remains as to whether SS is secondary to MS or whether the two are separate entities.3,4⇓ It was recently reported that antibodies against α-fodrin are both a sensitive and a specific marker for SS.5,6⇓ α-Fodrin is a cytoskeletal protein that binds to the cytoplasmic domains of a variety of molecules expressed on the cell surface. It is abundantly expressed in salivary glands but also other tissues including synapses and is probably involved in exocytosis. α-Fodrin is cleaved by caspase 3 upon apoptosis into a 120-kd product, which can be a target for autoantibodies.5
We investigated whether testing for autoantibodies against α-fodrin is an effective means of differentiating between patients with SS and those with MS and, in particular, those with PPMS.
Patients and methods.
Patients. We investigated 20 patients with neurologic manifestations of SS (table). Ten patients had peripheral manifestations (sensory neuropathy) and 10 patients had CNS manifestations (acute myelopathy in 6 cases and brain-restricted involvement in 4 cases). All 20 patients had definite SS according to the new diagnostic criteria for SS.7 Details of 10 of the patients, who fulfilled the criteria for both SS and PPMS, have already been published.2
Table 1Demographic data and results of SSA/SSB and anti-α-fodrin antibody evaluation
We also included 60 MS patients, none of whom met the criteria for SS, as a control group. Of these 60 patients, 20 had PPMS, 20 had a secondary progressive form of the disease, and 20 had a relapsing–remitting form. The Declaration of Helsinki principles were followed, and all patients gave their written consent for the study.
All the results regarding α-fodrin and SSA/SSB autoantibodies were analyzed blind to the clinical data.
α-Fodrin ELISA.
This method has been described elsewhere.6 For this ELISA, intra-assay variations are between 2.5 and 8.8% and interassay variations between 2.9 and 6.5%. The specificity of α-fodrin in blood donors and in autoimmune diseases such as systemic lupus erythematosus is higher than 95%.6
Detection of SSA and SSB antibodies.
To increase the sensitivity of autoantibody detection, we assessed three different tests for anti-SSA/anti-SSB detection: immunofluorescence (Bioadvance, Emerainville, France), double immunodiffusion (Biomedical Diagnostics, Marne-la-Vallée, France), and western blotting (standard in-house procedure). The western blotting method has been described elsewhere.2
Statistical analysis.
We performed χ2 tests for qualitative comparisons and Mann–Whitney U tests for quantitative comparisons.
Results.
We observed α-fodrin autoantibodies in 6 of the 10 (60%) patients with both PPMS and SS criteria and in 8 of the 60 MS patients without SS (13.3%), irrespective of the clinical form of MS (p < 0.01) (see the table). Of the 20 SS patients with neurologic manifestations, 14 (70%) had α-fodrin autoantibodies, 7 of whom had CNS manifestations. The presence of α-fodrin antibodies was not correlated with clinical measures. When we considered the results of the two tests (α-fodrin and SSA or SSB) together, 8 of the 10 (80%) patients with both SS and PPMS criteria had autoantibodies compared with 12 of the 60 (20%) MS patients without SS criteria (p < 0.01). Eighteen of the 20 (90%) SS patients with neurologic manifestations were positive for autoantibodies. The sensitivity of the α-fodrin antibody test for SS with neurologic manifestations was 70% for patients with SS and neurologic manifestations and the specificity was 86.7%. The positive predictive value was 63.6% and the negative predictive value 89.6%.
Discussion.
We found that autoantibodies against α-fodrin may help in differentiating between SS and MS, and more especially PPMS, showing an acceptable level of sensitivity and a good specificity for this test. Although the question remains open,3,4⇓ our results tend to support the notion that SS with neurologic involvement and PPMS are different diseases. The α-fodrin antibody test is a potential additional diagnostic tool for SS, and especially for SS with neurologic manifestations, where anti-SSA/SSB antibodies are less frequently found.1,2⇓ The specific role of α-fodrin autoantibodies remains undetermined, but previous studies have suggested that in SS, it may be an organ-specific autoantigen.5,6⇓ It would be interesting to evaluate in situ α-fodrin reactivity to both peripheral nerve and brain samples. However, α-fodrin and SSA/SSB are probably not the only target, and they may be immunologic markers of a more complex dysfunction.
- Received September 16, 2002.
- Accepted December 19, 2002.
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