Therapeutic Response to Tumor Necrosis Factor-alpha (TNF-alpha) Antagonists in Rheumatoid Arthritis. (TNF-alpha)

Evaluation of the Therapeutic Response to TNF-alpha Antagonist (Etanercept, Infliximab, Adalimumab) in Patients With Rheumatoid Arthritis; Using Plasma TNF-alpha as a Competent Biomarker. Single Center Study in Sulaymaniyah/ Iraq

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disease and TNF-alpha has been recognized as a triggering cytokine in the induction of joints inflammation and is involved in the pathogenesis of RA.

Treatment for RA aims to reduce disease activity, prevent or manage joint deterioration and lower the risk of major comorbidities such as heart disease and stroke.

The strategy of targeting cytokines has significantly increased RA patient outcomes. Therefore management with biological disease-modifying antirheumatic drugs "bDMARD" (Etanercept, Infliximab, Adalimumab) should be considered, If the treatment goal is not met with the first conventional synthetic drug modifying antirheumatic drugs (csDMARD) strategy, or if there are poor prognostic factors.

The multi-biomarker disease activity test could be used to help standardise individual treatment decisions, especially in patients who failed to respond well to the traditional treatment.

Iraq does not currently have specific guidelines, which might pose a risk to patients' safety. More data about the choice of bDMARD is needed in terms of tracking therapeutic response, or whether TNF or other pro-inflammatory cytokines like interleukin-6 (IL-6) is the main factor for the development and severity of RA.

These data are important to improve the overall status of the patient, better choice of treatment and biomarkers to detect.

There is limited information on the treatment patterns of rheumatoid arthritis (RA) across Iraq including the Kurdistan Region. Therefore, the aim of this research is to evaluate the efficacy, and clinical responses of RA patients who have been treated with different anti-TNF, as well as on answering the research hypothesis, Can plasma TNF-alpha and IL-6 be used as markers of therapeutic response to TNF alpha antagonist in patients with RA?

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis; Inflammatory Arthritis; Ankylosing Spondylitis
• Intervention / Treatment: Biological: Infliximab: Adalimumab; Etanercept

Detailed Description

Rheumatologists in Iraq, including those in the Kurdistan Region, rely on the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) guidelines and publications due to a lack of evidence-based national guidelines.

Several studies found that targeting TNF-alpha in the early stages of RA and evaluating serum TNF- levels, in combination with DAS28's assessment of disease clinical activity to track disease progression could result be advantageous for patients on anti-TNF medication in the future.

Objectives: The current research focuses on identifying the efficacy of three TNF-alpha antagonists (Etanercept, Infliximab, and Adalimumab) used currently in Sulaymaniyah Hospitals.

Methodology, an observational open-label study of ~60-80 adult patients with active RA from both genders that are registered at Rehabilitation and Rheumatology Center in Sulaymaniyah City who have been treated with biological agents (Etanercept, Infliximab, Adalimumab), regardless of disease activity and concomitant treatments.

Baseline data will be collected during the first visit and patients will be followed up during the study at regular intervals.

The study includes data of patients after filling the patient consent form, and are willingly giving their demographic data such as; Age, Sex, and Race (ethnic group). and answer the questions of multidimensional health assessment. Also measuring patients' weight at each visit, The clinical assessment of the patients is based on DAS28 (Disease Activity Score) by using ESR(Erythrocyte Sedimentation Rate), and VAS (Visual analogue score).

The laboratory data or the biomarkers at each visit include; CBC (complete blood count), C-reactive protein and ESR as inflammatory biomarkers, and detecting TNF-alpha and IL-6 to indicate the efficacy of the treatment and better choice of the treatment.

As for the statistical analysis plan, the Software SPSS (version 27) will be used.

Demographic and nominal results will be reported in percentages and frequencies.

Numerical results will be reported as the mean and standard deviation in cases of normal distribution, and as the median and interquartile range (IQR) in cases of skewed distribution.

The continuous variables CRP, TNF, IL-6 and the change over time, will be analyzed using linear mixed models for repeated measures. The chi-squared test will be used for dichotomous variables.

• Study Type: Observational
• Enrollment (Anticipated): 80

Contacts and Locations

• Study Contact: Name: Hiwa K Saaed, PhD; Phone Number: +9647701530462; Email: hiwa.saaed@univsul.edu.iq
• Study Contact Backup: Name: Sana M Mohammed, BSc; Phone Number: +9647702105174; Email: sana.mohammed@univsul.edu.iq

Study Locations

• Iraq
  • Kurdistan Region
    • Sulaymaniyah, Kurdistan Region, Iraq, 46001
      • Recruiting
      • Hiwa Khidhir Saaed
      • Contact: Sana M Mohammed, BSc; Phone Number: +9647702105174; Email: sana.mohammed@univsul.edu.iq
      • Contact: Hiwa Saaed, PhD; Phone Number: 07701530462; Email: hiwa.saaed@univsul.edu.iq

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

~60-80 adult patients [≥18 years] with Rheumatoid Arthritis from both genders registered at Rehabilitation and Rheumatology Center in Sulaymaniyah City, who are not responding to conventional DMARDs regardless of disease activity and concomitant treatments.

Description

Inclusion Criteria:

• Meeting the ACR/EULAR 2010 criteria for rheumatoid arthritis (RA).
• Patients (or Legal Guardian, if applicable) who are willing to give informed consent for the study period-time follow up.
• Concomitant DMARDs
• Duration of treatment with TNF-alpha antagonists <1 year, 1-5 years, >5 years

Exclusion Criteria:

• Tubercle Bacillus (TB)
• Hepatitis B, Hepatitis C
• Pregnancy and lactation
• Patients with heart failure.
• Previous or concurrent malignancies

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Plasma Tumor Necrosis Factor alpha (TNF-α) among different TNF alpha antagonist Therapy in Patients with Rheumatoid Arthritis.	Tumor Necrosis Factor alpha (TNF-α) is a pro-inflammatory cytokine produced by activating macrophages and T-cells that play a key role in the production of other cytokines and the induction of chronic inflammation.	Up to 12 Weeks
Comparison of Plasma Interleukin-6 (IL-6) among different TNF alpha antagonist Therapy in Patients with Rheumatoid Arthritis.	Interleukin-6 (IL-6) is a major pro-inflammatory cytokine, triggers the vicious circle of escalating RA disease activity via inducing immune activation and inflammation in RA.	Up to 12 Weeks
Mean change of C-reactive Protein (CRP) among different TNF alpha antagonist Therapy in Patients with Rheumatoid Arthritis.	C-reactive protein (CRP) a potential marker of systemic inflammation and is elevated in patients with rheumatoid arthritis (RA).	Up to 12 Weeks
Mean change of Erythrocyte Sedimentation Rate (ESR) among different TNF alpha antagonist Therapy in Patients with Rheumatoid Arthritis.	Erythrocyte sedimentation rate (ESR) is a popular hematology test that may detect and track an increase in inflammatory activity in the body, which can be caused by autoimmune illness, infections, or malignancies.	Up to 12 Weeks
Complete blood count (CBC)	A complete blood count (CBC) is a blood test used to evaluate overall health and detect a wide range of hematological disorders, including anemia.	Up to 12 Weeks
Assessment of Disease Activity Score (DAS)	Disease Activity Score (DAS) is a continuous measure of RA disease activity that combines information from swollen joints, tender joints, acute phase response and general health.	Up to 12 weeks
Assessment of Visual Activity Score (VAS)	Visual Activity Score (VAS) A psychometric pain rating scale for parameters that range across a continuum of values, such as pain. The VAS pain scale ranges from "no pain" to "worst pain," and patients mark a line to indicate how they are feeling.	Up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A correlation between plasma Tumor Necrosis Factor alpha (TNF-α) and disease activity and severity.	To determine how different Tumor Necrosis Factor-alpha (TNF-α) antagonist medications affected plasma (TNF-α) levels and the Disease Activity Score (DAS) in rheumatoid arthritis (RA) patients.	Up to 12 weeks
A correlation between plasma Interleukin-6 (IL-6) and disease activity and severity.	To determine how different Tumor Necrosis Factor-alpha (TNF-α) antagonist medications affected plasma Interleukin-6 (IL-6) levels and the Disease Activity Score (DAS) in rheumatoid arthritis (RA) patients.	Up to 12 weeks

Collaborators and Investigators

• Sponsor: University of Sulaimani
• Investigators: Principal Investigator: Hiwa Saaed, PhD, University of Sulaimani College of Pharmacy; Principal Investigator: Sana M Mohammed, BSc, Directorate of Health, Sulaymaniyah

Publications and helpful links

General Publications

• Inam Illahi M, Amjad S, Alam SM, Ahmed ST, Fatima M, Shahid MA. Serum Tumor Necrosis Factor-Alpha as a Competent Biomarker for Evaluation of Disease Activity in Early Rheumatoid Arthritis. Cureus. 2021 May 29;13(5):e15314. doi: 10.7759/cureus.15314.
• Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, van Vollenhoven RF, de Wit M, Aletaha D, Aringer M, Askling J, Balsa A, Boers M, den Broeder AA, Buch MH, Buttgereit F, Caporali R, Cardiel MH, De Cock D, Codreanu C, Cutolo M, Edwards CJ, van Eijk-Hustings Y, Emery P, Finckh A, Gossec L, Gottenberg JE, Hetland ML, Huizinga TWJ, Koloumas M, Li Z, Mariette X, Muller-Ladner U, Mysler EF, da Silva JAP, Poor G, Pope JE, Rubbert-Roth A, Ruyssen-Witrand A, Saag KG, Strangfeld A, Takeuchi T, Voshaar M, Westhovens R, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020 Jun;79(6):685-699. doi: 10.1136/annrheumdis-2019-216655. Epub 2020 Jan 22.
• Oderda GM, Lawless GD, Wright GC, Nussbaum SR, Elder R, Kim K, Brixner DI. The potential impact of monitoring disease activity biomarkers on rheumatoid arthritis outcomes and costs. Per Med. 2018 Jul 1;15(4):291-301. doi: 10.2217/pme-2018-0001. Epub 2018 Apr 25.
• Abbasi M, Mousavi MJ, Jamalzehi S, Alimohammadi R, Bezvan MH, Mohammadi H, Aslani S. Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol. 2019 Jul;234(7):10018-10031. doi: 10.1002/jcp.27860. Epub 2018 Dec 7.
• Xiao Q, Li X, Li Y, Wu Z, Xu C, Chen Z, He W. Biological drug and drug delivery-mediated immunotherapy. Acta Pharm Sin B. 2021 Apr;11(4):941-960. doi: 10.1016/j.apsb.2020.12.018. Epub 2020 Dec 31.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Anticipated): August 31, 2022
• Study Completion (Anticipated): October 1, 2022

Study Registration Dates

• First Submitted: May 7, 2022
• First Submitted That Met QC Criteria: May 12, 2022
• First Posted (Actual): May 18, 2022

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 12, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis, Cytokines
• Additional Relevant MeSH Terms: Infections; Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Spinal Diseases; Bone Diseases; Spondylarthropathies; Spondylarthritis; Bone Diseases, Infectious; Ankylosis; Arthritis; Arthritis, Rheumatoid; Spondylitis; Spondylitis, Ankylosing; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Etanercept; Adalimumab; Infliximab
• Other Study ID Numbers: UoS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The data will be presented as a Mean of the sample population.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes