Acta Neurol Scand 2015: 131: 140–143 DOI: 10.1111/ane.12357
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome Signoriello E, Sagliocchi A, Fratta M, Lus G. Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome. Acta Neurol Scand 2015: 131: 140–143. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands with neurological involvement in about 20% of patients. The neurological manifestations in the central nervous system CNS may vary and include a multiple sclerosis (MS)-like disease, and the treatments with immunosuppressive drugs have been undertaken. Case presentation – We describe a case of 40-year-old woman with clinical and instrumental evidence of an MS characterized by numerous relapses and demyelinating lesions prevailing in the infratentorial and spinal cord. Immunological analysis showed biological data that were consistent with an SS. The treatment with fingolimod showed not only an optimal response to the demyelinating events but also biological parameters. Conclusion – These data allow us to hypothesize possible combined efficacy of treatment with fingolimod in SS associated with definite MS.
Introduction
Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands (1) and may occur alone (primary Sjogren syndrome pSS) or in association with other connective tissue diseases (associated Sjogren syndrome aSS). pSS has neurological involvement in about 20% of patients (2). It can involve the peripheral (PNS) or central (CNS) nervous system. The neurological manifestations in the CNS may vary and include a multiple sclerosis (MS) (a chronic demyelinating CNS inflammatory pathology)-like disease. On this basis, SS might be taken into account in a differential diagnosis with MS. Therefore, hematological screening for SS should be considered for patients with an atypical onset of MS and poor systemic symptoms, as neurological manifestations may precede the more common sicca syndrome in 40–96% of SS patients (3). Despite extensive research in the field, the scientific community has not clearly delineated the 140
E. Signoriello, A. Sagliocchi, M. Fratta, G. Lus Multiple Sclerosis Center, II Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy
Key words: Sjogren syndrome; multiple sclerosis; fingolimod G. Lus, Second University of Naples, Naples 80131, Italy Tel.: +390815666788 Fax: +390815666788 e-mail: [email protected] Accepted for publication October 31, 2014
neurological involvement in SS pathogenesis. To this regard, there are three different theories. The first hypothesis is a direct infiltration of the CNS by mononuclear cells (4). The second is vascular injury perhaps related to the presence of antineuronal antibodies and anti-Ro antibodies; the latter may bind to brain endothelial cells and take part in the inflammatory process that leads to vascular damage (5). Alexander et al. (5) also proved the negative prognostic role played by the anti-Ro antibodies, correlated with the severity of CNS disease. The last hypothesis is ischemia secondary to small vessel vasculitis (1). The similarities between MS and pSS can be found also in the pathophysiology: both are immunologically mediated diseases with a B- and T-cell contribution. For this reason, treatments with immunosuppressive drugs have been undertaken. Azathioprine, methotrexate, and cyclophosphamide have been tested with different efficacy (6). Recently, the trials involving biological molecules such as rituximab, whose rationale is B-cell depletion, are showing
Fingolimod in MS associated with Sjogren syndrome poor results in controlling the neurological symptoms (7, 8). In this report, we present a 40-year-old woman with a MS definite presentation of pSS and a complete clinical response and an almost complete normalization of the biological parameters with fingolimod treatment. Case report
A 40-year-old woman presented in January 2012 with right hemiparesis with sensory and bladder disturbances and an inflammatory C2–C3 spinal cord lesion. A complete clinical recovery was achieved with steroid treatment. A CSF analysis at that time showed an overall increase in the barrier indexes, without oligoclonal bands. After 2 months, a new MRI showed an increase in the spinal cord lesions, in particular at the C5–C6 level. However, a new inflammatory lesion developed in the spinal cord at the C4–C5 level a few months later (June 2012). This did not completely remit after steroid therapy. In the hypothesis of an inflammatory demyelinating disease, not fully meet McDonald criteria, the patient started alike immunomodulatory treatment with interferon beta 1b. Within another 2 months (August 2012) the patient had developed a new lesion in the brainstem, at the pontine level, causing diplopia with nystagmus, right-side hearing loss and continuous vomiting, which decreased with steroid pulse therapy. The patient was hospitalized at our department in September 2012. She had no sign of a systemic disease; the neurological examination showed a spastic paresis and hypopallesthesia of the lower limbs and urinary urgency (EDSS 5.0). She underwent a cranial MRI scan showing the absence of encephalic lesions. Moreover, the A
serum and CSF analyses for infectious diseases, oligoclonal bands, and AQP4ab were negative. After 1 month (October 2012), due to another bulbar lesion with left paresis of the tongue, dysphagia and hiccups, in agreement with McDonald criteria for defined MS, it was decided to begin second-line treatment with fingolimod (that the patient started in January 2013), Fig. 3 shows clinical history. During the next year of therapy, there were no new relapses and a complete disappearance of some lesions previously evident on MRI (Figs 1 and 2). Further immunological analysis showed HLA-DQ2, anti-La Ab, anti-Ro Ab, anti-sy Ab, ASMA positivity, and ANA and ANCA negativity. In a retrospective evaluation, the anti-Ro Abs were reduced from a value >240 U/ml (before fingolimod) to 175 U/ml (during treatment with fingolimod). Table 1 shows the biological progress of the disease. To confirm the diagnosis of SS, additional tests were performed. The oculistic evaluation showed positivity of the Schirmer test. The lip biopsy confirmed a morphological histopathology compatible with a diagnosis of SS. Moreover, after 1 year from the first symptoms, the patient developed sicca syndrome with the need for artificial tears. The last neurological examination showed slight nystagmus, brisk reflexes and bilateral Babinski sign (EDSS 1.5). The patient underwent a new MRI, which confirmed a stationary situation compared to the previous one; a general checkup was negative for lymphadenopathy, lung involvement, arthritis and for any systemic issues. Fig. 3 summarizes the clinical evolution of the patient. Discussion and conclusions
SS can be considered in a differential diagnosis with MS. Hematological screening for this disease B
Figure 1. Images show the cervical cord lesion before (A) and its reduction after 6 months of treatment (B).
141
Signoriello et al. B
A
Figure 2. Cranial MRI before starting treatment (A) and after 6 months of Fingolimod treatment (B).
Table 1 Biological progress of the disease at different periods of Fingolimod treatment
Antibodies
Before treatment
After 1 month of treatment
After 6 months of treatment
Anti-Ro Anti-La Anti-sy ANA AMA ASMA
>240 U/ml 11 U/ml >36 U/ml Negative Negative 1:160
215 U/ml 25 U/ml 43 U/ml Negative Negative 1:80
172 U/ml 19 U/ml 36 U/ml Negative Negative 1:80
(ANA, anti-SSA, anti-SSB) in patients with an atypical onset of MS and poor systemic symptoms should be considered. Our patient had a neurological presentation of pSS, a relatively rare disease with a prevalence ranging from 2.5 to 6% (9). In particular, the neurological presentation of this patient was an MS-like syndrome, with spinal cord and infratentorial expression as occurs in the majority of neurological pSS involvements (10). Subsequently, the emergence of new relapses and an increase in lesion load in
Figure 3. Clinical history.
142
MRI allowed to diagnose a definite MS. SS and MS are T-cell-mediated autoimmune diseases, and the involvement of Th1 cells in their pathogenesis has been established. Therefore, a crucial role in the activation of the BAFF pathway overproducing B- and T-cell activation has been recognized (11). Also, recent studies proved that T cells, producing IL-17, are actively involved in the pathogenic mechanisms leading to glandular dysfunction and damage in pSS and may play a role in ectopic lymphoneogenesis occurring during the disease (12). Our patient was treated with interferon 1b, with no remission of the disease. This treatment is, in fact, reported to be ineffective in neuro-Sjogren (13) because of its positive effect on the activity of Th2-mediated autoimmune disease. In this case, fingolimod acts as a non-selective functional antagonist of the sphingosine-1-phosphate receptor family (S1P1/3/4/5), trapping B and T lymphocytes in secondary lymphoid tissues (14, 15). The treatment showed considerable control of the inflammatory activity, not only clinically or visible on the MRI scan,
Fingolimod in MS associated with Sjogren syndrome but probably also biologically, as the typical biological markers for pSS decreased throughout the treatment. No effective treatments for pSS and in particular for its neurological involvement exist. Experimental evidence validating the use of molecules inducing the suppression of B lymphocytes, such as rituximab, is still not significant: two small double-blind randomized studies demonstrated the efficacy on fatigue and sicca syndrome in an early disease, but no efficacy on the neurological manifestations (16). The biological efficacy of the treatment is also demonstrated by the significant influence on the reduction of AbRo that plays a key role in the pathogenic mechanism of CNS involvement in Sjogren’s disease (5). In this case, it is difficult to define the combination of two diseases dysimmune (MS and pSS) or how these are related between them. Both diseases are clinical, instrumental, and biological defined; good response to treatment with fingolimod for both the MS and for pSS leads us to hypothesize a common pathogenetic mechanism with a double clinical expression. These data allow us to speculate possible treatment with fingolimod in SS with involvement of the central nervous system as in MS. Acknowledgements
No acknowledgment to declare. Conflict of interest
The authors have no conflict of interest to declare that is directly relevant to the contents of this manuscript. References 1. TOBON GJ, PERS JO, DEVAUCHELLE-PENSEC V, YOUINOU P. Neurological disorders in primary Sjogren syndrome. Autoimmun Dis 2012. 2012: 645967 doi: 10.1155/2012/ 645967. Epub 2012 Mar 5. 2. ALEXANDER EL, PROVEOST TT, STEVENS MB, ALEXANDER GE. Neurologic complications of primary Sjogren syndrome. Medicine 1982;61:247–57.
3. ALEXANDER EL. Neurologic disease in Sjogren’s syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral nervous system and muscle. A clinical review and update of immunopathogenesis. Rheum Dis Clin North Am 1993;19:869–908. 4. BAKCHIN S, DUYCKAERTS C, HASSINE L. Central and peripheral neurologic lesions in primary Sjogren’s Syndrome. Clinico-pathological study of a case. Rev Neurol (Paris) 1991;147:368–75. 5. ALEXANDER EL, RANZENBACH MR, KUMAR AJ. Anti-Ro autoantibodies in central nervous system disease associated with Sjogren Syndrome: clinical neuroimaging and angiographic correlates. Neurology 1994;44:899–908. 6. SARAUX A. The point on the ongoing B-cell depleting trials currently in progress over the world in primary Sjogren syndrome. Autoimmun Rev 2010;9:609–14. 7. GOTTEMBERG JE. Primary Sjogren’s syndrome: pathophysiological, clinical and therapeutic advances. Joint Bone Spine 2009;76:591–4. 8. MEKINIAN A, RAVAUD P, LARROCHE C et al. Rituximab in central nervous system manifestations of patients with primary Sj€ ogren’s syndrome: results from the AIR registry; Club Rhumatismes et Inflammation. Curr Pharm Des 2008;14:1270–3. 9. MORREALE M, MARCHIONE P, GIACOMINI P et al. Neurological involvement in primary Sjogren syndrome: a focus on central nervous system. PLoS One. 2014;9:e84605. 10. MASSARA A, BONAZZA S, CASTELLINO G et al. Central nervous system involvement in Sjogren’s syndrome: unusual, but not unremarkable-clinical, serological characteristics and outcomes in a large cohort of Italian patients. Rheumatology 2010;49:1540–9. 11. ALUNNO A, CARUBBI F, BISTONI O et al. CD4-CD8- Tcells in primary Sj€ ogren’s syndrome: association with the extent of glandular involvement. J Autoimmun 2014;51: 38–43. 12. ALUNNO A, CARUBBI F, BISTONI O et al. Pathogenic role of IL-17 producing double negative (DN) T cells in primary sjogren’s syndrome. Ann Rheum Dis 2014;1:73. 13. TSAI KY, TSAI CP, LIAO N. Sjogren’s Syndrome with central nervous system involvement presenting as multiple sclerosis with failure response to beta-interferon. Eur Neurol 2001;45:59–60. 14. COHEN JA, CHUN J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 2011;69:759–77. 15. SEMPERE AP, MARTIN-MEDINA P, BERENGUER-RUIZ L et al. Switching from natalizumab to fingolimod: an observational study. Acta Neurol Scand 2013;128:e6–10. 16. MEIJER JM, MEINERS PM et al. Effectiveness of rituximab treatment in primary Sjo¨gren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:960–8.
143
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome Signoriello E, Sagliocchi A, Fratta M, Lus G. Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome. Acta Neurol Scand 2015: 131: 140–143. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands with neurological involvement in about 20% of patients. The neurological manifestations in the central nervous system CNS may vary and include a multiple sclerosis (MS)-like disease, and the treatments with immunosuppressive drugs have been undertaken. Case presentation – We describe a case of 40-year-old woman with clinical and instrumental evidence of an MS characterized by numerous relapses and demyelinating lesions prevailing in the infratentorial and spinal cord. Immunological analysis showed biological data that were consistent with an SS. The treatment with fingolimod showed not only an optimal response to the demyelinating events but also biological parameters. Conclusion – These data allow us to hypothesize possible combined efficacy of treatment with fingolimod in SS associated with definite MS.
Introduction
Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands (1) and may occur alone (primary Sjogren syndrome pSS) or in association with other connective tissue diseases (associated Sjogren syndrome aSS). pSS has neurological involvement in about 20% of patients (2). It can involve the peripheral (PNS) or central (CNS) nervous system. The neurological manifestations in the CNS may vary and include a multiple sclerosis (MS) (a chronic demyelinating CNS inflammatory pathology)-like disease. On this basis, SS might be taken into account in a differential diagnosis with MS. Therefore, hematological screening for SS should be considered for patients with an atypical onset of MS and poor systemic symptoms, as neurological manifestations may precede the more common sicca syndrome in 40–96% of SS patients (3). Despite extensive research in the field, the scientific community has not clearly delineated the 140
E. Signoriello, A. Sagliocchi, M. Fratta, G. Lus Multiple Sclerosis Center, II Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy
Key words: Sjogren syndrome; multiple sclerosis; fingolimod G. Lus, Second University of Naples, Naples 80131, Italy Tel.: +390815666788 Fax: +390815666788 e-mail: [email protected] Accepted for publication October 31, 2014
neurological involvement in SS pathogenesis. To this regard, there are three different theories. The first hypothesis is a direct infiltration of the CNS by mononuclear cells (4). The second is vascular injury perhaps related to the presence of antineuronal antibodies and anti-Ro antibodies; the latter may bind to brain endothelial cells and take part in the inflammatory process that leads to vascular damage (5). Alexander et al. (5) also proved the negative prognostic role played by the anti-Ro antibodies, correlated with the severity of CNS disease. The last hypothesis is ischemia secondary to small vessel vasculitis (1). The similarities between MS and pSS can be found also in the pathophysiology: both are immunologically mediated diseases with a B- and T-cell contribution. For this reason, treatments with immunosuppressive drugs have been undertaken. Azathioprine, methotrexate, and cyclophosphamide have been tested with different efficacy (6). Recently, the trials involving biological molecules such as rituximab, whose rationale is B-cell depletion, are showing
Fingolimod in MS associated with Sjogren syndrome poor results in controlling the neurological symptoms (7, 8). In this report, we present a 40-year-old woman with a MS definite presentation of pSS and a complete clinical response and an almost complete normalization of the biological parameters with fingolimod treatment. Case report
A 40-year-old woman presented in January 2012 with right hemiparesis with sensory and bladder disturbances and an inflammatory C2–C3 spinal cord lesion. A complete clinical recovery was achieved with steroid treatment. A CSF analysis at that time showed an overall increase in the barrier indexes, without oligoclonal bands. After 2 months, a new MRI showed an increase in the spinal cord lesions, in particular at the C5–C6 level. However, a new inflammatory lesion developed in the spinal cord at the C4–C5 level a few months later (June 2012). This did not completely remit after steroid therapy. In the hypothesis of an inflammatory demyelinating disease, not fully meet McDonald criteria, the patient started alike immunomodulatory treatment with interferon beta 1b. Within another 2 months (August 2012) the patient had developed a new lesion in the brainstem, at the pontine level, causing diplopia with nystagmus, right-side hearing loss and continuous vomiting, which decreased with steroid pulse therapy. The patient was hospitalized at our department in September 2012. She had no sign of a systemic disease; the neurological examination showed a spastic paresis and hypopallesthesia of the lower limbs and urinary urgency (EDSS 5.0). She underwent a cranial MRI scan showing the absence of encephalic lesions. Moreover, the A
serum and CSF analyses for infectious diseases, oligoclonal bands, and AQP4ab were negative. After 1 month (October 2012), due to another bulbar lesion with left paresis of the tongue, dysphagia and hiccups, in agreement with McDonald criteria for defined MS, it was decided to begin second-line treatment with fingolimod (that the patient started in January 2013), Fig. 3 shows clinical history. During the next year of therapy, there were no new relapses and a complete disappearance of some lesions previously evident on MRI (Figs 1 and 2). Further immunological analysis showed HLA-DQ2, anti-La Ab, anti-Ro Ab, anti-sy Ab, ASMA positivity, and ANA and ANCA negativity. In a retrospective evaluation, the anti-Ro Abs were reduced from a value >240 U/ml (before fingolimod) to 175 U/ml (during treatment with fingolimod). Table 1 shows the biological progress of the disease. To confirm the diagnosis of SS, additional tests were performed. The oculistic evaluation showed positivity of the Schirmer test. The lip biopsy confirmed a morphological histopathology compatible with a diagnosis of SS. Moreover, after 1 year from the first symptoms, the patient developed sicca syndrome with the need for artificial tears. The last neurological examination showed slight nystagmus, brisk reflexes and bilateral Babinski sign (EDSS 1.5). The patient underwent a new MRI, which confirmed a stationary situation compared to the previous one; a general checkup was negative for lymphadenopathy, lung involvement, arthritis and for any systemic issues. Fig. 3 summarizes the clinical evolution of the patient. Discussion and conclusions
SS can be considered in a differential diagnosis with MS. Hematological screening for this disease B
Figure 1. Images show the cervical cord lesion before (A) and its reduction after 6 months of treatment (B).
141
Signoriello et al. B
A
Figure 2. Cranial MRI before starting treatment (A) and after 6 months of Fingolimod treatment (B).
Table 1 Biological progress of the disease at different periods of Fingolimod treatment
Antibodies
Before treatment
After 1 month of treatment
After 6 months of treatment
Anti-Ro Anti-La Anti-sy ANA AMA ASMA
>240 U/ml 11 U/ml >36 U/ml Negative Negative 1:160
215 U/ml 25 U/ml 43 U/ml Negative Negative 1:80
172 U/ml 19 U/ml 36 U/ml Negative Negative 1:80
(ANA, anti-SSA, anti-SSB) in patients with an atypical onset of MS and poor systemic symptoms should be considered. Our patient had a neurological presentation of pSS, a relatively rare disease with a prevalence ranging from 2.5 to 6% (9). In particular, the neurological presentation of this patient was an MS-like syndrome, with spinal cord and infratentorial expression as occurs in the majority of neurological pSS involvements (10). Subsequently, the emergence of new relapses and an increase in lesion load in
Figure 3. Clinical history.
142
MRI allowed to diagnose a definite MS. SS and MS are T-cell-mediated autoimmune diseases, and the involvement of Th1 cells in their pathogenesis has been established. Therefore, a crucial role in the activation of the BAFF pathway overproducing B- and T-cell activation has been recognized (11). Also, recent studies proved that T cells, producing IL-17, are actively involved in the pathogenic mechanisms leading to glandular dysfunction and damage in pSS and may play a role in ectopic lymphoneogenesis occurring during the disease (12). Our patient was treated with interferon 1b, with no remission of the disease. This treatment is, in fact, reported to be ineffective in neuro-Sjogren (13) because of its positive effect on the activity of Th2-mediated autoimmune disease. In this case, fingolimod acts as a non-selective functional antagonist of the sphingosine-1-phosphate receptor family (S1P1/3/4/5), trapping B and T lymphocytes in secondary lymphoid tissues (14, 15). The treatment showed considerable control of the inflammatory activity, not only clinically or visible on the MRI scan,
Fingolimod in MS associated with Sjogren syndrome but probably also biologically, as the typical biological markers for pSS decreased throughout the treatment. No effective treatments for pSS and in particular for its neurological involvement exist. Experimental evidence validating the use of molecules inducing the suppression of B lymphocytes, such as rituximab, is still not significant: two small double-blind randomized studies demonstrated the efficacy on fatigue and sicca syndrome in an early disease, but no efficacy on the neurological manifestations (16). The biological efficacy of the treatment is also demonstrated by the significant influence on the reduction of AbRo that plays a key role in the pathogenic mechanism of CNS involvement in Sjogren’s disease (5). In this case, it is difficult to define the combination of two diseases dysimmune (MS and pSS) or how these are related between them. Both diseases are clinical, instrumental, and biological defined; good response to treatment with fingolimod for both the MS and for pSS leads us to hypothesize a common pathogenetic mechanism with a double clinical expression. These data allow us to speculate possible treatment with fingolimod in SS with involvement of the central nervous system as in MS. Acknowledgements
No acknowledgment to declare. Conflict of interest
The authors have no conflict of interest to declare that is directly relevant to the contents of this manuscript. References 1. TOBON GJ, PERS JO, DEVAUCHELLE-PENSEC V, YOUINOU P. Neurological disorders in primary Sjogren syndrome. Autoimmun Dis 2012. 2012: 645967 doi: 10.1155/2012/ 645967. Epub 2012 Mar 5. 2. ALEXANDER EL, PROVEOST TT, STEVENS MB, ALEXANDER GE. Neurologic complications of primary Sjogren syndrome. Medicine 1982;61:247–57.
3. ALEXANDER EL. Neurologic disease in Sjogren’s syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral nervous system and muscle. A clinical review and update of immunopathogenesis. Rheum Dis Clin North Am 1993;19:869–908. 4. BAKCHIN S, DUYCKAERTS C, HASSINE L. Central and peripheral neurologic lesions in primary Sjogren’s Syndrome. Clinico-pathological study of a case. Rev Neurol (Paris) 1991;147:368–75. 5. ALEXANDER EL, RANZENBACH MR, KUMAR AJ. Anti-Ro autoantibodies in central nervous system disease associated with Sjogren Syndrome: clinical neuroimaging and angiographic correlates. Neurology 1994;44:899–908. 6. SARAUX A. The point on the ongoing B-cell depleting trials currently in progress over the world in primary Sjogren syndrome. Autoimmun Rev 2010;9:609–14. 7. GOTTEMBERG JE. Primary Sjogren’s syndrome: pathophysiological, clinical and therapeutic advances. Joint Bone Spine 2009;76:591–4. 8. MEKINIAN A, RAVAUD P, LARROCHE C et al. Rituximab in central nervous system manifestations of patients with primary Sj€ ogren’s syndrome: results from the AIR registry; Club Rhumatismes et Inflammation. Curr Pharm Des 2008;14:1270–3. 9. MORREALE M, MARCHIONE P, GIACOMINI P et al. Neurological involvement in primary Sjogren syndrome: a focus on central nervous system. PLoS One. 2014;9:e84605. 10. MASSARA A, BONAZZA S, CASTELLINO G et al. Central nervous system involvement in Sjogren’s syndrome: unusual, but not unremarkable-clinical, serological characteristics and outcomes in a large cohort of Italian patients. Rheumatology 2010;49:1540–9. 11. ALUNNO A, CARUBBI F, BISTONI O et al. CD4-CD8- Tcells in primary Sj€ ogren’s syndrome: association with the extent of glandular involvement. J Autoimmun 2014;51: 38–43. 12. ALUNNO A, CARUBBI F, BISTONI O et al. Pathogenic role of IL-17 producing double negative (DN) T cells in primary sjogren’s syndrome. Ann Rheum Dis 2014;1:73. 13. TSAI KY, TSAI CP, LIAO N. Sjogren’s Syndrome with central nervous system involvement presenting as multiple sclerosis with failure response to beta-interferon. Eur Neurol 2001;45:59–60. 14. COHEN JA, CHUN J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 2011;69:759–77. 15. SEMPERE AP, MARTIN-MEDINA P, BERENGUER-RUIZ L et al. Switching from natalizumab to fingolimod: an observational study. Acta Neurol Scand 2013;128:e6–10. 16. MEIJER JM, MEINERS PM et al. Effectiveness of rituximab treatment in primary Sjo¨gren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:960–8.
143
