An observational study in Rheumatoid Arthritis (RA and Chronic Pain, sponsored by 4th Military Clinical Hospital with Polyclinic, Poland. Recruiting at 1 site in Poland. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-18.
Sponsored by 4th Military Clinical Hospital with Polyclinic, Poland · Observational
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease in which pain remains the most prominent and burdensome symptom from the patient's perspective. Although the introduction of biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) has significantly improved the control of inflammatory activity, an estimated 20-30% of patients continues to experience persistent moderate-to-severe pain despite achieving clinical remission. This discordance between objective inflammatory markers and subjective pain perception reflects an important unmet clinical need and suggests that chronic pain in RA may become partially or fully independent of peripheral inflammation, driven instead by central sensitization and nociplastic mechanisms. The RA-PAIN-AI study is a prospective, observational, case-control study integrating clinical assessment, patient-reported outcome measures, neurophysiological evaluation, and multiomic profiling, analyzed using artificial intelligence (AI)-based methods. Two groups of adult patients with RA are enrolled: a study group of patients with active disease qualifying for biological therapy under the Polish national drug program B.33, and a control group of patients in sustained clinical remission (at least 1.5 years) under biological therapy, without clinically significant chronic pain. All participants undergo clinical assessment, standardized questionnaires, peripheral blood collection at the baseline (Visit 1) and follow-up (Visit 2) visits. Electroencephalography (EEG) is offered as an optional procedure, at the discretion of the investigator. Biological samples are analyzed using advanced multiomic technologies, including whole genome sequencing (genomics), mRNA expression profiling (transcriptomics), and measurement of circulating proteins (secretomics). All clinical, biological, and neurophysiological data are then integrated using AI methods, including dimensionality reduction, clustering, and supervised machine learning, to identify distinct pain-related patient subtypes (endotypes). The primary objective of the study is to identify and characterize clinical, neurophysiological, and multiomic signatures associated with chronic pain in RA. Expected outcomes include identification of biomarkers predictive of chronic pain persistence despite effective anti-inflammatory treatment, improved differentiation between inflammation-driven pain and pain mediated by central nervous system changes, and support for the development of more personalized, mechanism-based treatment strategies in rheumatology. The study is non-interventional: no experimental therapeutic interventions are administered, and all participants continue to receive standard clinical care. All biological analyses are performed ex vivo.
Background and rationale. Chronic pain in rheumatoid arthritis (RA) represents a complex, multidimensional clinical phenomenon extending beyond the traditional paradigm of inflammation-driven nociception. Despite significant therapeutic advances enabling effective control of peripheral inflammation with biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs), an estimated 20-30% of patients continues to experience persistent moderate-to-severe pain, even after achieving clinical remission. This therapeutic gap highlights the evolution of pain mechanisms from peripheral nociception toward central sensitization and nociplastic pain. Evidence from quantitative sensory testing (QST) studies demonstrates widespread pressure pain threshold reduction at sites remote from inflamed joints, indicating generalized central sensitization. Conditioned pain modulation (CPM) protocols reveal impaired descending inhibitory pathways. Functional magnetic resonance imaging (fMRI) studies show pathological hyperconnectivity between the default mode network and the insula, correlating with pain centralization independently of inflammatory markers. At the molecular level, transcriptomic analyses of human dorsal root ganglia have revealed pathological remodeling of primary sensory neurons, including ectopic immunoglobulin signaling and neurogenesis. Metabolomic and lipidomic profiling demonstrates hypoxia-driven glycolytic reprogramming, lactate accumulation acting as an independent algogen through acid-sensing ion channels, and glycerophospholipid metabolism disruption impairing production of specialized pro-resolving mediators. Integrative multi-omic studies have further identified distinct immunometabolic signatures between ACPA-positive and ACPA-negative RA, suggesting serotype-dependent pain mechanisms.
Study design. The RA-PAIN-AI study is designed as a prospective, observational, case-control study integrating clinical, laboratory, neurophysiological, and multiomic data. Two main groups are enrolled: a study group of patients with confirmed RA in an active phase of the disease, qualified for biological therapy according to the Polish national drug program B.33, and a control group of patients with RA in long-term remission (≥1.5 years) under biological therapy, without clinically significant chronic pain.
Non-interventional nature. The study is non-interventional. No experimental therapeutic interventions are administered as part of this study, and all biological analyses are performed ex vivo. All participants continue to receive standard clinical care according to routine rheumatology practice; study procedures are aligned with routine clinical visits whenever possible. Participation is associated with minimal risk. The primary procedures involving participants include venous blood collection, questionnaire assessments, and, optionally (at the discretion of the investigator), electroencephalography (EEG). The risks associated with these procedures are comparable to those encountered in routine clinical practice.
Study procedures - Visit 1 (Baseline, Day 0). All participants undergo: verification of eligibility criteria; collection of informed consent; clinical assessment and medical history; completion of standardized questionnaires (EQ-5D-5L, PHQ-9, VAS, DN4, painDETECT, HAQ, SF-36, FAS, ISI, HADS, GAD-7, CSQ, RS-25); peripheral blood collection (approximately 30 mL total). EEG assessment is performed in selected participants, at the discretion of the investigator.
Study procedures - Visit 2 (Follow-up, 3-6 months after baseline). Participants undergo repeat peripheral blood collection (approximately 10 mL), completion of standardized questionnaires (EQ-5D-5L, PHQ-9, VAS, DN4, painDETECT, HAQ, SF-36, FAS, ISI, HADS, GAD-7, CSQ, RS-25) and, in participants who underwent EEG at Visit 1, repeat EEG assessment, at the discretion of the investigator.
Key assessment tools. The study integrates three complementary assessment domains: (i) patient-reported outcome measures (PROMs) covering pain intensity and character (VAS, DN4, painDETECT), functional status (HAQ), health-related quality of life (EQ-5D-5L, SF-36), psychological status (PHQ-9, HADS, GAD-7, CSQ, RS-25), and sleep quality (ISI), and fatigue (FAS); (ii)optional neurophysiological assessment by EEG (in selected participants, at the discretion of the investigator); and (iii) biological samples (peripheral blood) analyzed for multiomic and laboratory profiles, including whole genome sequencing (genomics), mRNA expression profiling (transcriptomics), and circulating protein measurement (secretomics).
Study setting. The study is conducted at the 4th Military Clinical Hospital with Polyclinic (4WSzKzP SPZOZ) in Wrocław, Poland, a tertiary referral center. Laboratory and multiomic analyses are conducted in collaboration with the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (IITD PAN; responsible for genomic and transcriptomic analyses) and the Biobank and Research Group at Łukasiewicz - PORT Polish Center for Technology Development (blood processing for genomic analysis and long-term biobanking). All procedures are conducted in accordance with Good Clinical Practice (GCP) guidelines and applicable national regulations.
Analysis framework. All clinical, biological, and neurophysiological data will be analyzed using both conventional statistical methods and artificial intelligence (AI)-based approaches. Statistical analyses will include descriptive statistics, between-group comparisons, correlation analyses, and multivariable analyses, as appropriate. In addition, AI methods, including dimensionality reduction, clustering, and supervised machine learning, will be used to identify distinct pain-related endotypes, develop predictive models for chronic pain persistence and treatment response, and support the transition from inflammation-centered management toward mechanism-based, personalized pain treatment in RA. The study also aims to create a structured, high-quality dataset and biobank resource to support future research in precision medicine and chronic pain in RA.
3,332 studies on the registry are indexed under Arthritis, Rheumatoid; 443 are open to participants now.
This study's planned enrollment of 100 is below the median of 176 across 1,016 observational studies indexed under Arthritis, Rheumatoid.
Browse Arthritis, Rheumatoid studies →4th Military Clinical Hospital with Polyclinic, Poland is the lead sponsor of 10 studies on the registry; 8 are open to participants now.
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Adults with confirmed rheumatoid arthritis recruited during routine clinical care visits at a tertiary rheumatology referral center (4th Military Clinical Hospital with Polyclinic, Wrocław, Poland). The study population includes patients with active RA qualifying for biological therapy and patients in sustained clinical remission under biological therapy.
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Exclusion Criteria - Study Group
Inclusion Criteria - Control Group (RA in Remission)
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Group 1 - Active RA With Chronic Pain (Study Group) Description: Adult patients with confirmed rheumatoid arthritis in the active phase of disease, qualified for initiation of biological therapy under the Polish national drug program B.33 (Treatment of rheumatoid arthritis and juvenile idiopathic arthritis with aggressive course; ICD-10: M05, M06, M08). Participants undergo clinical assessment, biological sample collection (peripheral blood approximately 30 mL), standardized questionnaire evaluation, and, optionally (at the discretion of the investigator), EEG assessment. Intervention(s): No therapeutic intervention. Study procedures: blood collection, PROM assessment, optional EEG (at the discretion of the investigator), multiomic profiling (ex vivo).
Description: Adult patients with confirmed rheumatoid arthritis in sustained clinical remission for at least 1.5 years under biological therapy, with good treatment tolerance and not reporting current chronic pain in clinical interview. Participants undergo the same assessment procedures as the study group. Intervention(s): No therapeutic intervention. Same study procedures as Group 1.
Multiomic Profiles Associated With Chronic Pain in Rheumatoid Arthritis
Genomic, transcriptomic, and secretomic profiles associated with chronic pain in rheumatoid arthritis.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Integrated Differentiation Between Study Groups
Integrated clinical, biological, and neurophysiological features differentiating participants with active rheumatoid arthritis and chronic pain from participants with rheumatoid arthritis in sustained remission without clinically significant chronic pain.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
AI-Based Classification of Pain-Related Endotypes
Development of integrative artificial intelligence-based models for classification of pain-related endotypes using clinical, multiomic, and neurophysiological data.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Pain Intensity Assessed Using the Visual Analogue Scale.
Self-reported pain intensity will be assessed using the Visual Analogue Scale. Scores range from 0 to 100 mm, where 0 mm indicates no pain and 100 mm indicates the worst imaginable pain. Higher scores indicate greater pain intensity.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Functional Status Assessed Using the Health Assessment Questionnaire.
Functional status will be assessed using the Health Assessment Questionnaire. Scores range from 0 to 3, where 0 indicates no disability and 3 indicates severe disability. Higher scores indicate worse functional status.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Health-Related Quality of Life Assessed Using the EuroQol 5 Dimensions 5 Levels Index Value.
Health-related quality of life will be assessed using the EuroQol 5 Dimensions 5 Levels instrument. The EQ-5D-5L index value will be calculated according to the applicable value set. Index values generally range from values below 0 to 1, where 1 indicates full health, 0 indicates a health state equivalent to death, and values below 0 indicate health states valued as worse than death. Higher scores indicate better health-related quality of life.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Health-Related Quality of Life Assessed Using the Short Form Health Survey.
Health-related quality of life will be assessed using the Short Form Health Survey. Domain scores are transformed to a 0 to 100 scale. Higher scores indicate better health status / better health-related quality of life.
Time frame: Time Frame: Baseline, Day 0, and Visit 2, 3-6 months after baseline.
Depressive Symptoms Assessed Using the Patient Health Questionnaire-9.
Depressive symptoms will be assessed using the Patient Health Questionnaire-9. Total scores range from 0 to 27. Higher scores indicate greater depressive symptom severity.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Sleep Quality Assessed Using the Insomnia Severity Index.
Sleep quality / insomnia severity will be assessed using the Insomnia Severity Index. Total scores range from 0 to 28. Higher scores indicate greater insomnia severity and worse sleep quality.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Between-Group Comparison of Genomic Profiles.
Genomic profiles will be compared between participants with active rheumatoid arthritis and chronic pain and participants with rheumatoid arthritis in sustained remission without clinically significant chronic pain using whole genome sequencing. Results will be reported as genomic variants or genomic signatures associated with chronic pain status according to the Statistical Analysis Plan.
Time frame: Time Frame: Baseline, Day 0.
Electroencephalography-Derived Markers of Altered Pain Processing.
In participants who undergo optional exploratory electroencephalography, predefined electroencephalography-derived markers of altered pain processing will be assessed according to the Statistical Analysis Plan. Associations between each predefined electroencephalography-derived parameter and pain intensity and neuropathic pain features will be explored. Results will be reported separately for each predefined electroencephalography parameter.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Predictive Performance of an Integrative Biomarker Model for Chronic Pain Persistence.
Predictive performance of an integrative biomarker model for chronic pain persistence at Visit 2 will be assessed using model performance metrics specified in the Statistical Analysis Plan, such as discrimination metrics for classification models. Higher discrimination values indicate better predictive performance.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Number of Participants Assigned to Each Multidimensional Pain Phenotype Cluster.
Participants will be assigned to multidimensional pain phenotype clusters using an integrative analytical approach based on clinical, laboratory, patient-reported, neurophysiological, and multiomic variables, according to the Statistical Analysis Plan. The outcome will be reported as the number of participants assigned to each derived phenotype cluster.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Neuropathic Pain Features Assessed Using the DN4 Neuropathic Pain Questionnaire.
Neuropathic pain features will be assessed using the DN4 Neuropathic Pain Questionnaire. Total scores range from 0 to 10. Higher scores indicate more neuropathic pain features / greater likelihood of neuropathic pain.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Fatigue Assessed Using the Fatigue Assessment Scale.
Fatigue will be assessed using the Fatigue Assessment Scale. Total scores range from 10 to 50. Higher scores indicate greater fatigue severity.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Pain Coping Strategies Assessed Using the Coping Strategies Questionnaire.
Pain coping strategies will be assessed using the Coping Strategies Questionnaire. Coping-strategy subscales will be reported separately according to the questionnaire scoring instructions. For each coping-strategy subscale, higher scores indicate greater use of the respective coping strategy.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Psychological Resilience Assessed Using the Resilience Scale-25.
Psychological resilience will be assessed using the Resilience Scale-25. Total scores range from 25 to 175. Higher scores indicate greater psychological resilience.
Time frame: Baseline (Day 0) and Visit 2 (3-6 months after baseline)
Anxiety Symptoms Assessed Using the Generalised Anxiety Disorder-7 Scale.
Anxiety symptoms will be assessed using the Generalised Anxiety Disorder-7 Scale. Total scores range from 0 to 21. Higher scores indicate greater anxiety symptom severity.
Time frame: Time Frame: Baseline, Day 0, and Visit 2, 3-6 months after baseline.
Anxiety and Depression Symptoms Assessed Using the Hospital Anxiety and Depression Scale.
Anxiety and depression symptoms will be assessed using the Hospital Anxiety and Depression Scale. The instrument includes two subscales: Hospital Anxiety and Depression Scale-Anxiety and Hospital Anxiety and Depression Scale-Depression. Each subscale ranges from 0 to 21. Higher scores indicate greater anxiety or depression symptom severity.
Time frame: Time Frame: Baseline, Day 0, and Visit 2, 3-6 months after baseline.
Between-Group Comparison of Transcriptomic Profiles.
Transcriptomic profiles will be compared between participants with active rheumatoid arthritis and chronic pain and participants with rheumatoid arthritis in sustained remission without clinically significant chronic pain using messenger RNA expression profiling. Results will be reported as differentially expressed transcripts or transcriptomic signatures associated with chronic pain status according to the Statistical Analysis Plan.
Time frame: Time Frame: Baseline, Day 0, and Visit 2, 3-6 months after baseline.
Between-Group Comparison of Secretomic Profiles.
Secretomic profiles will be compared between participants with active rheumatoid arthritis and chronic pain and participants with rheumatoid arthritis in sustained remission without clinically significant chronic pain using quantitative measurement of circulating proteins. Results will be reported as differentially abundant circulating proteins or secretomic signatures associated with chronic pain status according to the Statistical Analysis Plan.
Time frame: Time Frame: Baseline, Day 0, and Visit 2, 3-6 months after baseline.
Predictive Performance of an Integrative Biomarker Model for Response to Biological Therapy.
Predictive performance of an integrative biomarker model for response to biological therapy at Visit 2 will be assessed using model performance metrics specified in the Statistical Analysis Plan, such as discrimination metrics for classification models. Higher discrimination values indicate better predictive performance.
Time frame: Time Frame: Baseline predictors; treatment response assessed at Visit 2, 3-6 months after baseline.
Plan to share: Yes — De-identified individual participant data (IPD), including clinical, laboratory, and selected multiomic datasets, may be made available to qualified researchers upon reasonable request, subject to approval by the study investigators and relevant ethics committees. Data sharing will comply with applicable data protection regulations, including the General Data Protection Regulation (GDPR), as well as institutional policies. Access to data may require the conclusion of a data sharing agreement and will be limited to purposes consistent with the scope of the original informed consent and ethical approvals. Biological samples stored in the biobank may be used for future research projects only after obtaining appropriate ethical approvals.
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4th Military Clinical Hospital with Polyclinic, Poland