Summary
Aims
Fingolimod, an orally active immunomodulatory drug for relapsing‐remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the ...sphingosine‐1‐phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune‐monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod.
Methods
Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow‐up in 40 RRMS patients starting fingolimod therapy.
Results
Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in Treg (memory Treg: 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated Treg: 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed.
Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively P < 0.001).
Conclusion
The results support that immune‐monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.
Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in ...peripheral blood samples from 66 RRMS patients under DMF (n=22) or fingolimod (n=44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60±4.17%vs. nonrelapsed: 9.25±3.17%, p<0.05) and Th1Th17CM cells (relapsed: 15.65±6.15%vs. nonrelapsed: 10.14±4.05%, p<0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA-CCR6+CXCR3+) cells>11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells<11.48% whose relapse-free survival was 88% (p=0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02±5.87%vs. no MRI activity: 9.82±4.06%, p<0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.
Neuromyelitis optica (NMO), or Devic's disease, is an autoimmune, inflammatory and demyelinating disease of the central nervous system which mainly and characteristically involves the optic nerve and ...the spinal cord. Anti-aquaporin-4 (AQ-4) antibodies are a specific biomarker of the entity and, since their discovery, both the number of symptoms and the radiological data about the disease have progressively increased, and the concept of clinical spectrum of NMO has been defined.
A 66-year-old female diagnosed with NMO after suffering attacks of optic neuritis and recurrent myelitis, and showing positive for AQ-4 antibodies. The patient presented a diminished level of consciousness, and magnetic resonance imaging of the head revealed a number of lesions in the white matter, without contrast enhancement, which resolved without treatment. One month later, her general state had declined and was accompanied by symptoms of confusion and blindness. A magnetic resonance imaging scan showed new lesions in the white matter and an increase in the size of those already present. The patient was diagnosed as suffering from encephalopathy within the context of NMO and she was treated with intravenous immunoglobulins and corticoids, which resulted in a clinical and radiological improvement.
Since the discovery of AQ-4 antibodies, there has been an increase in the number of clinical and radiological manifestations of NMO beyond involvement of the optic nerve and the spinal cord, including manifestations in the brain. It is important to recognise them in order to make an early diagnosis, to avoid unnecessary complementary tests and to establish the most suitable treatment.
Cowden syndrome is a rare autosomal dominant disease. It is characterized by multiple noncancerous tumorlike growths called hamartomas, which typically are found in the skin, oral mucosa, thyroid, ...breast, and gastrointestinal tract. It carries with it a potential risk of malignant transformation, especially of the breast and thyroid. In 80% of the cases, the human tumor suppressor gene, phosphatase and tensin homolog ( PTEN ), is mutated in the germ line. We report a patient with Cowden syndrome who presented with generalized seizure and left anterior temporal hemorrhage and a nontraumatic subarachnoid hemorrhage due to multiple intracranial arteriovenous fistulas (AVFs). We discuss previous reports about vascular malformations in patients with Cowden syndrome and PTEN mutations. Importantly, we hypothesize that the production of multiple AVFs in our patient was associated with PTEN mutation.
Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in ...peripheral blood samples from 66 RRMS patients under DMF (
n
=
22
) or fingolimod (
n
=
44
) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1
CM
cells (relapsed:
11.60
±
4.17
%
vs
. nonrelapsed:
9.25
±
3.17
%
,
p
<
0.05
) and Th1Th17
CM
cells (relapsed:
15.65
±
6.15
%
vs
. nonrelapsed:
10.14
±
4.05
%
,
p
<
0.01
) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17
CM
(CD4
+
CCR7
+
CD45RA
-
CCR6
+
CXCR3
+
)
cells
>
11.48
%
had a 50% relapse-free survival compared to patients with Th1Th17
CM
cells
<
11.48
%
whose relapse-free survival was 88% (
p
=
0.013
, log-rank test). Additionally, a high percentage of Th1Th17
CM
cells was also found in patients with MRI activity (MRI activity:
14.02
±
5.87
%
vs
. no MRI activity:
9.82
±
4.06
%
,
p
<
0.01
). Our results suggest that the percentage of Th1Th17
CM
lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.
Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in ...peripheral blood samples from 66 RRMS patients under DMF (
= 22) or fingolimod (
= 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1
cells (relapsed: 11.60 ± 4.17%
. nonrelapsed: 9.25 ± 3.17%,
< 0.05) and Th1Th17
cells (relapsed: 15.65 ± 6.15%
. nonrelapsed: 10.14 ± 4.05%,
< 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17
(CD4
CCR7
CD45RA
CCR6
CXCR3
) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17
cells < 11.48% whose relapse-free survival was 88% (
= 0.013, log-rank test). Additionally, a high percentage of Th1Th17
cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%
. no MRI activity: 9.82 ± 4.06%,
< 0.01). Our results suggest that the percentage of Th1Th17
lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.
Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory disease characterized by painful recurrent episodes of optic neuritis with clear response to steroids and relapses with ...treatment withdrawal.
To performed a systematic review of the literature about CRION, since 2003 to present in medical database. We excluded pediatric or animal research articles. Search terms: CRION, chronic relapsing inflammatory optic neuropathy, recurrent optic neuritis, steroid dependent optic neuritis, and immunosuppression dependent optic neuritis.
CRION is a relapsing optic neuritis of unknown aetiology. The strong response to corticosteroids to avoid recurrence suggests that it might be an immune-mediated disease. CRION typically presents as a subacute and recurrent optic neuropathy with severe visual loss. The principal differential diagnoses are the demyelinating (multiple sclerosis, neuromyelitis optica spectrum disorders and anti-MOG), systemic (mostly sarcoidosis) and infectious diseases. CRION has a dramatic and dependent corticoids response; to avoid adverse events, we use immunosuppressive treatment in long-term.
CRION is a rare, recurrent and cortico-dependent disease of optic nerve. An early diagnosis and accuracy treatment will improve the prognosis.
Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in ...peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1.sub.CM cells (relapsed: 11.60 + or - 4.17% vs. nonrelapsed: 9.25 + or -3.17%, p <0.05) and Th1Th17.sub.CM cells (relapsed: 15.65 + or - 6.15% vs. nonrelapsed: 10.14 + or -4.05%, p <0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17.sub.CM (CD4.sup.+CCR7.sup.+CD45RA.sup.-CCR6.sup.+CXCR3.sup.+) cells >11.48% had a 50% relapse-free survival compared to patients with Th1Th17.sub.CM cells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17.sub.CM cells was also found in patients with MRI activity (MRI activity: 14.02 + or - 5.87% vs. no MRI activity: 9.82 + or -4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17.sub.CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.
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