Shorter Time to MS Disease Progression Linked With Intrathecal Immunoglobulin Synthesis


The investigators suggested that this may be indicative of intrathecal IgG synthesis as a useful marker of disability worsening in patients with MS, as well as in making early treatment decisions.

Dr Bernhard Hemmer

Bernhard Hemmer, MD, head, Department of Neurology, vice dean, Technische Universitat Munchen

Bernhard Hemmer, MD

New study results have proposed that patients with intrathecal immunoglobulin (IgG) synthesis and a new diagnosis of relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome (CIS) have a higher risk of disease progression, as well as a shorter time to increased disease progression.1

These findings, the investigators suggested, may be indicative of intrathecal IgG synthesis as a useful marker of disability worsening in patients with MS, and that it could be of use in making early treatment decisions. This is notable as an important unmet need in MS is the utility of a reliable biomarker of disability worsening.

“The disease course in patients with MS is highly variable, and reliable biomarkers for prognostication of disability worsening are lacking,” study author Bernhard Hemmer, MD, head, Department of Neurology, and vice dean, Technische Universität München, and colleagues wrote. “Because in many countries CSF analysis is a standard diagnostic procedure in patients presenting with symptoms suggestive of MS, a prognosis of the disease course based on CSF parameters could be a valuable tool to guide treatment decisions.”

"The course of MS is still highly unpredictable and biomarkers are missing that would allow stratification of patients according to their risk of early disease progression," Hemmer told NeurologyLive®. "Thus we cannot reliably predict at disease onset which patient should go on highly active drugs very early (even after the first relapse) and which patients might be fine with a less active drug or even no treatment. Our aim was to contribute to the identification of such markers that hopefully allow stratifying patients in the future."

The study cohort included 673 patients with a new diagnosis—defined as ≤6 months for CIS and ≤2 years with MS prior to inclusion—of either CIS or MS. At the point of study inclusion, 319 patients (47.4%) had been diagnosed with CIS and 354 patients (52.6%) had been diagnosed with MS, per the 2005 revised McDonald criteria. The median time from manifestation to inclusion was 3 months. In total, 327 (88.6%) patients were treated with disease-modifying therapies during the first 4 years from baseline.

Ultimately, the results showed that those with intrathecal IgG synthesis (n = 352; 58.2%) had a greater risk of reaching an Expanded Disability Status Scale (EDSS) score of 2.5 (odds ratio [OR], 3.31; 95% CI, 1.37 to 7.98; P = .009). Additionally, these patients had a higher risk of reaching an EDSS score of 3 (OR, 2.29; 95%CI, 1.02 to 5.14; P = .04).

“Similar findings were obtained in the Kaplan-Meier analyses on time to reach EDSS scores of 2.5 and 3, although the analysis regarding a score of 3 did not reach significance,” Hemmer and colleagues wrote.

Four years after inclusion, the percentage of patients in whom EDSS worsened and intrathecal IgG synthesis was present was 28.4% (95% CI, 22.7 to 34.1), while for those without intrathecal IgG synthesis, it was 18.1% (95% CI, 12.4 to 23.9). Hemmer et al. noted that within that 4-year period, only 28%of all patients had an increase of the EDSS score—in line with what the literature has described.

Notably, and as described by the investigators, previous small studied have suggested that there may be prognosticative value of intrathecal IgG synthesis in MS.2,3 Additionally, oligoclonal bands being present in the cerebrospinal fluid (CSF)—which is a signal of localized production of IgG in the central nervous system—has also been associated with a higher risk of disability worsening in MS. This study, however, found no association between their presence and EDSS worsening, nor was a link displayed between EDSS worsening and elevated CSF-to-serum albumin ratio or leukocyte count.

“This could be owing to the low number of patients with negative OCB status (12.2%) in this cohort, which differs from the prevalence of patients who were OCB negative in aforementioned studies (16%-43%),” the authors wrote. They recognized that a much bigger sample size would be needed to observe this outcome.

Hemmer and colleagues acknowledged some limitations, most importantly the lack of long-term data to show this association over a period longer than 4 years. Additionally, as CSF analyses were performed by each participating center independently, differences in sample handling or analysis could potentially impact the results.

"We believe that a spinal tap should be part of the diagnostic workup in MS," Hemmer said. "According to our findings, the presence of intrathecal IgG synthesis would double the risk of early disease worsening within the next 4 weeks. This finding in combination with other parameters can help to guide early treatment decisions."


1. Gasperi C, Salmen A, Gisela A, et al. Association of intrathecal immunoglobulin G synthesis with disability worsening in multiple sclerosis. JAMA Neurol. Published online April 29, 2019. doi:10.1001/jamaneurol.2019.0905.

27. Izquierdo G, Angulo S, Garcia-Moreno JM, et al. Intrathecal IgG synthesis: marker of progression in multiple sclerosis patients. Acta Neurol Scand. 2002;105(3):158-163. doi: 10.1034/j.1600-0404.2002.1o009.x.

3. Stendahl-Brodin L, Link H. Relation between benign course of multiple sclerosis and low-grade humoral immune response in cerebrospinal fluid. J Neurol Neurosurg Psychiatry. 1980;43(2):102-105. doi: 10.1136/jnnp.43.2.102.

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