Biomarkers of response to ocrelizumab in relapsing-remitting multiple sclerosis.
To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response.
Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity.
After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients.
Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA.
Rodríguez-Jorge F
，Fernández-Velasco JI
，Villarrubia N
，Gracia-Gil J
，Fernández E
，Meca-Lallana V
，Díaz-Pérez C
，Sainz de la Maza S
，Pacheco EM
，Quiroga A
，Ramió-Torrentà L
，Martínez-Yélamos S
，Bau L
，Monreal E
，López-Real A
，Rodero-Romero A
，Borrega L
，Díaz S
，Eguía P
，Espiño M
，Chico-García JL
，Barrero FJ
，Martínez-Ginés ML
，García-Domínguez JM
，De la Fuente S
，Moreno I
，Sainz-Amo R
，Mañé-Martínez MA
，Caminero A
，Castellanos F
，Gómez López A
，Labiano-Fontcuberta A
，Ayuso L
，Abreu R
，Hernández MÁ
，Meca-Lallana J
，Martín-Aguilar L
，Muriel García A
，Masjuan J
，Costa-Frossard L
，Villar LM
... -
《Frontiers in Immunology》
Azathioprine for people with multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated, chronic, inflammatory demyelinating disease of the central nervous system, impacting around 2.8 million people worldwide. Characterised by recurrent relapses or progression, or both, it represents a substantial global health burden, affecting people, predominantly women, at a young age (the mean age of diagnosis is 32 years). Azathioprine is used to treat chronic inflammatory and autoimmune diseases, and it is used in clinical practice as an off-label intervention for MS, especially where access to on-label disease-modifying treatments (DMTs) for MS is limited. Given this, a review of azathioprine's benefits and harms would be timely and valuable to inform shared healthcare decisions.
To evaluate the benefits and harms of azathioprine (AZA) for relapsing and progressive multiple sclerosis (MS), compared to other disease-modifying treatments (DMTs), placebo or no treatment. Specifically, we will assess the following comparisons. AZA compared with other DMTs or placebo as first-choice treatment for relapsing forms of multiple sclerosis AZA compared with other DMTs or placebo for relapsing forms of MS when switching from another DMT AZA compared with other DMTs or placebo as first-choice treatment for progressive forms of MS AZA compared with other DMTs or placebo for progressive forms of MS when switching from another DMT SEARCH METHODS: We conducted an extensive search for relevant literature using standard Cochrane search methods. The most recent search date was 9 August 2023.
We included randomised controlled trials (RCTs) lasting 12 months or more that compared azathioprine versus DMTs, placebo or no intervention in adults with MS. We considered evidence from non-randomised studies of interventions (NRSIs) as these studies may provide additional evidence not available from RCTS. We excluded cluster-randomised trials, cross-over trials, interrupted time series, case reports and studies of within-group design with no control group.
We followed standard Cochrane methodology. There were three outcomes we considered to be critical: disability, relapse and serious adverse events (SAEs, as defined in the studies). We were also interested in other important outcomes: quality-of-life (QoL) impairment (mental score), short-term adverse events (gastrointestinal disorders), long-term adverse events (neoplasms) and mortality.
We included 14 studies: eight RCTs (1076 participants included in meta-analyses) and six NRSIs (1029 participants). These studies involved people with relapsing and progressive MS. Most studies included more women (57 to 83%) than men, with participants' average age at the onset of MS being between 29.4 and 33.4 years. Five RCTs and all six NRSIs were conducted in Europe (1793 participants); two RCTs were conducted in the USA (126 participants) and one in Iran (94 participants). The RCTs lasted two to three years, while NRSIs looked back up to 10 years. Four studies received some funding or support from commercial interests and five were funded by government or philanthropy; the other five provided no information about funding. There are three ongoing studies. Comparison groups included other DMTs (interferon beta and cyclosporine A), placebo or no treatment. Below, we report on azathioprine as a 'first choice' treatment compared to interferon beta for people with relapsing MS. None of the studies reported on any critical or important outcome for this comparison for progressive MS. No study was retrieved comparing azathioprine to placebo or other DMTs for either relapsing or progressive MS. Furthermore, the NRSIs did not provide information not already covered in the RCTs. Azathioprine as a first-choice treatment compared to other DMTs (specifically, interferon beta) for relapsing MS - The evidence is very uncertain about the effect of azathioprine on the number of people with disability progression over two years compared to interferon beta (risk ratio (RR) 0.19, 95% confidence interval (CI) 0.02 to 1.58; 1 RCT, 148 participants; very low certainty evidence). - Azathioprine may decrease the number of people with relapses over a one- to two-year follow-up compared to interferon beta (RR 0.61, 95% CI 0.43 to 0.86; 2 RCTs, 242 participants; low-certainty evidence). - Azathioprine may result in a possible increase in the number of people with SAEs over two years in comparison with interferon beta (RR 6.64, 95% CI 0.35 to 126.27; 1 RCT, 148 participants; low-certainty evidence). - The evidence is very uncertain about the effect of azathioprine on the number of people with the short-term adverse event of gastrointestinal disorders over two years compared to interferon beta (RR 5.30, 95% CI 0.15 to 185.57; 2 RCTs, 242 participants; very low certainty evidence). We found no evidence comparing azathioprine to other DMTs for QoL impairment (mental score), long-term adverse events (neoplasms) or mortality.
Azathioprine has been proposed as an alternative treatment for MS when access to approved, on-label DMTs is limited, especially in resource-limited settings. The limited evidence available suggests that azathioprine may result in a modest benefit in terms of relapse frequency, with a possible increase in SAEs, when compared to interferon beta-1b, for people with relapsing-remitting multiple sclerosis. The evidence for the effect on disability progression and short-term adverse events is very uncertain. Caution is required in interpreting the conclusions of this review since our certainty in the available evidence on the benefits and harms of azathioprine in multiple sclerosis is low to very low, implying that further evidence is likely to change our conclusions. An important limitation we noted in the available evidence is the lack of long-term comparison with other treatments and the failure of most studies to measure outcomes that are important to people with multiple sclerosis, such as quality of life and cognitive decline. This is especially the case in the evidence relevant to people with progressive forms of multiple sclerosis.
Ridley B
，Nonino F
，Baldin E
，Casetta I
，Iuliano G
，Filippini G
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
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