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Published on: December 9, 2015
Comorbidities for Predicting Progression Independent of Relapse Activity in Multiple Sclerosis Treated With B-Cell
Peter Alping1, Anton Öberg Sysojev1, Fredrik Piehl2
1Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
Background:
Progression independent of relapse activity (PIRA) has been shown to account for a majority of the disability accumulation in relapsing-remitting multiple sclerosis (RRMS) patients treated with disease-modifying therapies. While comorbidities are common in MS and linked to disability progression, their role in PIRA remains unclear. We investigated whether comorbidities at treatment initiation could predict PIRA in RRMS patients receiving B-cell depleting therapy.
Methods:
This population-based cohort study included RRMS patients initiating rituximab between August 2010 and April 2019, without relapses during six-year follow-up. PIRA was defined as confirmed disability worsening (Expanded Disability Status Scale). We performed hypothesis-driven analysis of pre-specified comorbidities and data-driven analysis of all ICD-10 codes from secondary care. Comorbidity-PIRA associations were assessed using adjusted logistic regression. Predictive performance for elastic net, random forest, XGBoost, and neural networks was evaluated as the area under the curve (AUC) and Brier score through nested cross-validation.
Results:
Among 2837 patients, 563 (20%) experienced PIRA within 6 years. The most prevalent comorbidities were depression/anxiety (36%), hypertension (15%), and headache (8%). No pre-specified comorbidities were statistically significant predictors of PIRA. Among all diagnosis codes, only neuromuscular bladder dysfunction reached significance after multiple comparison correction. Predictive models demonstrated modest performance (AUC 0.563-0.652) and adding comorbidities did not improve prediction.
Conclusions:
In this rituximab-treated RRMS cohort, comorbidities at therapy start were not associated with higher PIRA risk when accounting for MS-associated disability. The association with bladder dysfunction likely reflects spinal tract engagement rather than an independent comorbidity effect.
Insights
Comorbidities at treatment initiation did not predict progression independent of relapse activity (PIRA) in relapsing-remitting multiple sclerosis (RRMS) patients. Bladder dysfunction was linked to PIRA, likely due to spinal cord involvement.
Area of Science:
- Neurology
- Immunology
- Clinical Research
Background:
- Progression independent of relapse activity (PIRA) significantly contributes to disability in relapsing-remitting multiple sclerosis (RRMS) patients on disease-modifying therapies.
- The influence of comorbidities on PIRA development in RRMS patients remains poorly understood.
- This study examines the predictive role of comorbidities at treatment initiation for PIRA in RRMS patients receiving B-cell depleting therapy.
Purpose of the Study:
- To determine if comorbidities present at the start of B-cell depleting therapy predict progression independent of relapse activity (PIRA) in relapsing-remitting multiple sclerosis (RRMS) patients.
- To investigate the association between various comorbidities and PIRA development.
- To assess the predictive performance of machine learning models incorporating comorbidities for PIRA.
Main Methods:
- A population-based cohort study of RRMS patients initiating rituximab (2010-2019) with a six-year follow-up was conducted.
- Progression independent of relapse activity (PIRA) was defined as confirmed disability worsening (EDSS).
- Comorbidity data (pre-specified and all ICD-10 codes) were analyzed using logistic regression and machine learning models (elastic net, random forest, XGBoost, neural networks) with cross-validation.
Main Results:
- Of 2837 RRMS patients, 20% experienced PIRA within six years. Most common comorbidities included depression/anxiety (36%), hypertension (15%), and headache (8%).
- No pre-specified comorbidities significantly predicted PIRA. Neuromuscular bladder dysfunction was the only diagnosis code to reach statistical significance after multiple comparison correction.
- Machine learning models showed modest predictive performance (AUC 0.563-0.652), and adding comorbidities did not enhance prediction accuracy.
Conclusions:
- Comorbidities at rituximab initiation were not associated with an increased risk of PIRA in RRMS patients, independent of MS-related disability.
- The observed association between bladder dysfunction and PIRA likely reflects spinal cord involvement rather than an independent comorbidity effect.
- Current comorbidity assessments may not be sufficient to predict PIRA in RRMS patients treated with B-cell depleting therapies.
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