Re: 류마티스 관절염 간헐적 단식으로 염증 호전!! RCT논문 2025 nature

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류마티스 관절염 환자.. 간헐적 단식 8주만에.. 

류마티스 염증 호전결과!!

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The effects of intermittent fasting on antioxidant and inflammatory markers and liver enzymes in postmenopausal, overweight and obese women with rheumatoid arthritis: a randomized controlled trial

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• Published: 18 January 2025

The effects of intermittent fasting on antioxidant and inflammatory markers and liver enzymes in postmenopausal, overweight and obese women with rheumatoid arthritis: a randomized controlled trial

• Aryan Tavakoli, 
• Camellia Akhgarjand, 
• Hastimansooreh Ansar, 
• Hirad Houjaghani, 
• Amirhossein Khormani, 
• Kurosh Djafarian, 
• Abdolrahman Rostamian, 
• Mahsa Ranjbar & 
• Gholamreza Mohammadi Farsani 

Scientific Reports volume 15, Article number: 2357 (2025) Cite this article

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Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting postmenopausal women. This study investigated the effects of intermittent fasting (IF) on antioxidant and inflammatory markers and liver enzymes in postmenopausal, overweight and obese women with RA. This 8-week randomized controlled trial included 44 postmenopausal women with RA divided into an intervention group following a 16:8 IF diet and a control group maintaining their usual diet and received recommendations for healthy eating. Inflammatory indices, oxidative stress markers, and liver enzymes were measured at baseline and post intervention. The IF group showed significant decreases in serum malondialdehyde (MDA) levels (P = 0.02) and neutrophil-to-lymphocyte ratio (P = 0.018) and increased catalase levels (P = 0.004) compared to the control group. Liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) also decreased significantly in the IF group (P = 0.02 and P = 0.03, respectively). No significant differences were observed in the other measured parameters between groups. In conclusion, the 16:8 IF diet demonstrated beneficial effects on some oxidative stress markers, inflammatory indices, and liver enzymes in postmenopausal, overweight, and obese women with RA. These findings suggest that IF may be an effective non-pharmacological intervention for managing RA in this population, potentially addressing both primary disease symptoms and associated metabolic complications. Further research is needed to elucidate the long-term effects and mechanisms of IF in the management of RA.

초록

류마티스 관절염(RA)은

폐경 후 여성에게 영향을 미치는 만성 염증성 질환입니다.

본 연구는

폐경 후 과체중 및 비만 여성 RA 환자를 대상으로

간헐적 단식(IF)이 항산화 및 염증 지표 및 간 효소에 미치는 영향을 조사했습니다.

이 8주간의 무작위 대조 시험에는

RA를 앓고 있는 폐경 후 여성 44명이 참여했으며,

이들은 16:8 IF 식단을 따르는 개입 그룹과

평소 식단을 유지하며 건강한 식습관 권장 사항을 받은 대조 그룹으로 나누어졌습니다.

염증 지표, 산화 스트레스 지표 및 간 효소는

기저치와 개입 후 측정되었습니다.

IF 그룹은 대조군에 비해

혈청 말론디알데히드(MDA) 수치(P = 0.02)와 중성구-림프구 비율(P = 0.018)이 유의미하게 감소했으며,

카탈라아제 수치(P = 0.004)는 유의미하게 증가했습니다.

간 효소인

아스파르테이트 트랜스아미나제(AST)와 알라닌 트랜스아미나제(ALT)도

IF 그룹에서

유의미하게 감소했습니다(P = 0.02 및 P = 0.03 각각).

다른 측정 지표에서는 두 그룹 간 유의미한 차이는 관찰되지 않았습니다.

결론적으로, 16:8 IF 식단은

폐경 후 과체중 및 비만 여성 RA 환자에서

일부 산화 스트레스 지표, 염증 지표, 간 효소에 유익한 효과를 보여주었습니다.

이 결과는

IF가 이 인구 집단에서 RA 관리에 효과적인 비약물적 개입 방법이 될 수 있음을 시사하며,

주요 질환 증상 및 관련 대사 합병증을 동시에 개선할 수 있음을 보여줍니다.

RA 관리에서

IF의 장기적 효과와 기전을 규명하기 위해

추가 연구가 필요합니다.

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Introduction

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory condition that primarily affects synovial joints, causing pain, inflammation, stiffness, and eventually joint damage and disability1. It affects approximately 0.5–1% of the global population and is more common in females, especially those over the age of 502. Postmenopausal women, in particular, experience a higher incidence of RA, which is often compounded by overweight and obesity, conditions that exacerbate disease severity3. The complications arising from RA include increased cardiovascular disease risk, osteoporosis, and the development of malignancies4. The disease not only imposes significant physical and emotional burdens on patients but also results in substantial socioeconomic costs. In the United States alone, the annual direct medical costs associated with RA are estimated to exceed $19 billion, with indirect costs such as lost productivity further amplifying the economic impact5. Given the chronic nature of RA and its associated comorbidities, there is a critical need to explore and establish effective management strategies to alleviate symptoms and improve patients’ quality of life.

Considerable research has been devoted to understanding the pathophysiology and management of RA. Traditional treatments include disease-modifying antirheumatic drugs (DMARDs) and biological agents that aim to reduce inflammation and prevent disease progression6. Nevertheless, these therapies frequently have unfavorable impacts and fail to effectively address the metabolic issues linked to RA, such as oxidative stress and dyslipidemia7.

While traditional treatments have focused on inflammation control, growing evidence suggests that lifestyle modifications, particularly dietary interventions, may play a complementary role in managing RA. Among these, intermittent fasting (IF) has emerged as a promising approach to reducing inflammation, enhancing antioxidant defenses, and improving metabolic markers8. Several studies have shown that IF can modulate oxidative stress and inflammatory pathways, but much of this research has focused on the general population or individuals with metabolic syndrome9,10. There is a notable gap in the literature regarding the specific effects of IF in postmenopausal women with RA, a demographic in which both inflammation and oxidative stress are heightened due to hormonal changes and excess adiposity9,11.

Despite these promising findings, significant gaps in the literature remain. Most studies on IF have focused on the general population or individuals with metabolic syndrome, with limited research specifically targeting postmenopausal women with RA11. Additionally, the effects of IF on specific biomarkers of inflammation and oxidative stress in this demographic remain underexplored12.

The rationale for this study extends beyond merely filling a gap in the literature. Postmenopausal women with RA face unique clinical challenges due to the combined influences of hormonal shifts, chronic inflammation, and metabolic dysregulation. These factors can exacerbate disease severity, leading to increased morbidity and a reduced quality of life13. Therefore, understanding whether IF can mitigate these factors by improving both inflammatory and oxidative stress markers, as well as liver enzyme profiles, could offer a novel, non-pharmacological strategy for managing RA and its associated metabolic complications in this vulnerable population.

The current study aimed to address these gaps by investigating the effects of intermittent fasting on antioxidant and inflammatory markers, as well as liver enzymes, in postmenopausal, overweight, and obese women with RA. This study is significant for several reasons. First, postmenopausal women represent a unique population in which hormonal changes exacerbate both RA symptoms and metabolic dysfunction14. Understanding how IF affects this group can inform tailored dietary interventions that improve clinical outcomes. Second, the dual focus on inflammation and oxidative stress markers, along with liver enzymes, provides a comprehensive assessment of the potential benefits of IF. This approach could offer novel insights into the mechanisms by which IF exerts its effects, potentially leading to new therapeutic strategies for managing RA.

소개

류마티스 관절염(RA)은

주로 관절막 관절을 공격하는 만성적인 전신성 염증성 질환으로,

통증, 염증, 경직을 유발하며 결국 관절 손상과 장애를 초래합니다1.

전 세계 인구의 약 0.5–1%가 이 질환을 앓고 있으며,

특히 50세 이상의 여성에서 더 흔히 발생합니다2.

특히 폐경 후 여성은

RA 발병률이 높으며,

비만과 같은 요인이 질환의 중증도를 악화시켜

이 문제를 더욱 복잡하게 만듭니다3.

RA로 인한 합병증에는

심혈관 질환 위험 증가, 골다공증, 악성 종양의 발생 등이 포함됩니다4.

류마티스 관절염(RA) 환자는 일반 인구와 비교해 사망 위험이 높습니다. 연구 결과, 이 증가된 사망 위험은 주로 심혈관(CV) 사망의 증가에 기인하는 것으로 나타났습니다. 미네소타주 로체스터에서 RA 환자를 대상으로 한 초기 코호트 연구에서, RA 환자는 연령과 성별이 일치하는 지역 사회 대조군과 비교해 CV 사망, 허혈성 심장 질환, 심부전 위험이 높다는 사실을 확인했습니다. 또한, 사망 후 심장 조직을 분석한 결과, RA 환자의 심장 조직에서 염증의 증가와 불안정 플라크의 비율이 높게 관찰되었습니다. 우리는 전통적인 심혈관 질환 위험 요인과 RA 특이적 위험 요인이 이 증가된 심혈관 질환 발생률 및 사망률에 미치는 영향을 조사했습니다. 전통적인 심혈관 질환 위험 요인이 RA 환자의 사망 위험 증가에 기여하는 것으로 나타났지만, 이는 RA에서 관찰된 심혈관 사망률 증가를 완전히 설명하지 못했습니다. 대신 RA와 관련된 염증의 증가가 심혈관 사망률 증가에 크게 기여하는 것으로 보입니다. 다른 연구에서도 RA와 심혈관 사망률 간의 유사한 연관성이 입증된 점을 고려할 때, 이러한 데이터는 RA 환자의 예후 개선을 위해 염증 관리에 더 적극적인 접근이 필요함을 시사합니다.

이 질환은 환자에게 심각한 신체적 및 정서적 부담을 가하는 동시에

상당한 사회경제적 비용을 초래합니다.

미국 alone에서 RA와 관련된 연간 직접 의료 비용은 $190억을 초과하는 것으로 추산되며, 생산성 손실 등 간접 비용은 경제적 영향을 더욱 확대합니다5. RA의 만성적 특성 및 동반 질환을 고려할 때, 증상 완화와 환자의 삶의 질 개선을 위한 효과적인 관리 전략을 탐구하고 확립하는 것이 시급합니다.

RA의 병리생리학과 관리에 대한 연구가 활발히 진행되어 왔습니다. 전통적인 치료법에는 염증을 줄이고 질병 진행을 예방하는 것을 목표로 하는 질병 수정 항류마티스 약물(DMARDs)과 생물학적 제제가 포함됩니다6. 그러나 이러한 치료법은 종종 부작용을 동반하며, RA와 관련된 대사 문제(예: 산화 스트레스와 이상지질혈증)를 효과적으로 해결하지 못합니다7.

전통적인 치료법이 염증 조절에 초점을 맞춘 반면, 생활 방식 변경,

특히 식이 개입이 RA 관리에 보완적인 역할을 할 수 있다는 증거가 증가하고 있습니다.

이 중 간헐적 단식(IF)은

염증을 감소시키고 항산화 방어력을 강화하며

대사 지표를 개선하는 데 유망한 접근법으로 부상했습니다8.

여러 연구에서 IF가 산화 스트레스와 염증 경로를 조절할 수 있음을 보여주었지만, 대부분의 연구는 일반 인구나 대사 증후군을 가진 개인에 초점을 맞췄습니다9,10. 폐경 후 RA를 가진 여성에서 IF의 특정 효과에 대한 문헌에는 주목할 만한 공백이 존재합니다. 이 인구 집단은 호르몬 변화와 과도한 체지방으로 인해 염증과 산화 스트레스가 증가하기 때문입니다9,11.

이러한 유망한 결과에도 불구하고 문헌에는 여전히 중요한 공백이 존재합니다. 대부분의 IF 연구는 일반 인구나 대사증후군 환자를 대상으로 진행되었으며, 폐경 후 RA를 가진 여성에 대한 특정 연구는 제한적입니다11. 또한 이 인구 집단에서 IF가 염증 및 산화 스트레스의 특정 생물학적 지표에 미치는 영향은 여전히 충분히 탐구되지 않았습니다12.

이 연구의 목적은 단순히 문헌의 공백을 메우는 것을 넘어섭니다. 폐경 후 RA를 앓는 여성은 호르몬 변화, 만성 염증, 대사 장애의 복합적 영향으로 인해 독특한 임상적 도전 과제에 직면합니다. 이러한 요인은 질병의 중증도를 악화시켜 사망률 증가와 삶의 질 저하를 초래할 수 있습니다13. 따라서 IF가 염증 및 산화 스트레스 지표와 간 효소 프로필을 개선함으로써 이러한 요인을 완화할 수 있는지 이해하는 것은 이 취약한 인구 집단에서 RA 및 관련 대사 합병증을 관리하기 위한 새로운 비약물적 전략을 제시할 수 있습니다.

본 연구는 폐경 후 과체중 및 비만 여성 RA 환자를 대상으로 간헐적 단식이 항산화 및 염증 지표, 간 효소 수치에 미치는 영향을 조사함으로써 이러한 연구 공백을 메우기 위해 수행되었습니다. 이 연구는 여러 측면에서 중요합니다.

첫째, 폐경 후 여성은 호르몬 변화가 RA 증상 및 대사 장애를 악화시키는 독특한 인구 집단입니다14. 이 그룹에 대한 간헐적 단식의 영향을 이해하는 것은 임상 결과를 개선하기 위한 맞춤형 식이 개입을 개발하는 데 기여할 수 있습니다.

둘째, 염증 및 산화 스트레스 지표와 간 효소를 동시에 평가하는 이중 초점은 간헐적 단식의 잠재적 이점을 포괄적으로 평가합니다. 이 접근 방식은 간헐적 단식이 효과를 발휘하는 메커니즘에 대한 새로운 통찰을 제공할 수 있으며, 이는 RA 관리 위한 새로운 치료 전략 개발로 이어질 수 있습니다.

Methods and materials

Study design and population

This was an 8-week parallel-randomized controlled study involving 44 overweight or obese postmenopausal women with rheumatoid arthritis, conducted from May 2022 to March 2023, to eval‎uate inflammatory and oxidative stress markers, as well as liver enzymes. The study protocol received approval from the Ethics Committee at Tehran University of Medical Sciences (IR.IUMS.TMU.REC.1400.015) and was registered with the Iranian Clinical Trials Registry (IRCT20220929056058N1) (15/01/2024). The research adhered to the ethical principles outlined in the Declaration of Helsinki, with all participants providing informed consent15. RA was diagnosed based on the American College of Rheumatology (ACR) guidelines and the severity of rheumatoid arthritis (RA) was assessed according to the Disease Activity Score 28 (DAS 28). The DAS28 score ranges from 0 to 9.4, with higher scores indicating greater disease activity. The disease activity levels based on the DAS28 score were: Remission: <2.6, Low disease activity: ≥2.6 and ≤ 3.2, Moderate disease activity: >3.2 and ≤ 5.1, High disease activity: >5.1. The criteria and recommendations for identifying and confirm‎ing of menopause were based on the North American Menopause Society (NAMS) and the American College of Obstetricians and Gynecologists (ACOG).

Individuals were invited to take part in the study through online platforms, social media channels, and web-based resources. Subsequently, they presented themselves at rheumatology clinic at Shariati Hospital, located in Tehran, Iran, for further eval‎uation and monitoring. The inclusion criteria included: a BMI of 25–35 kg/m², age between 50 and 70 years, postmenopausal status, a rheumatoid arthritis diagnosis over 6 months, moderate to low disease activity (DAS28 < 5.1), adjusted type, dose, or frequency of disease-modifying anti-rheumatic drugs (DMARDs such as methotrexate, hydroxychloroquine, or sulfasalazine for 3 months before the study, no use of NSAIDs, and willingness to participate. Patients were excluded if they took non-steroidal anti-inflammatory drugs (NSAIDs), any change in the dose, type, or frequency of DMARDs, consumed alcohol, had other autoimmune diseases, kidney disorders, pancreatitis, gallstones, or cancer, followed special diets in the past three months, or had recent medication changes.

During our study, all participants followed their RA medications.

방법 및 재료

연구 설계 및 대상 집단

이 연구는 2022년 5월부터 2023년 3월까지 진행된 8주간의 병렬 무작위 대조 연구로, 류마티스 관절염을 동반한 과체중 또는 비만 여성 44명을 대상으로 염증 및 산화 스트레스 지표 및 간 효소 수치를 평가하기 위해 실시되었습니다. 본 연구 프로토콜은 테헤란 의과대학 윤리위원회(IR.IUMS.TMU.REC.1400.015)의 승인을 받았으며, 이란 임상시험 등록처(IRCT20220929056058N1)에 등록되었습니다(2024년 1월 15일). 연구는 헬싱키 선언에 명시된 윤리적 원칙을 준수했으며, 모든 참가자는 서면 동의서를 제출했습니다15.

RA는 미국 류마티스 학회(ACR) 지침에 따라 진단되었으며, 류마티스 관절염(RA)의 중증도는 질병 활동도 점수 28(DAS 28)에 따라 평가되었습니다. DAS28 점수는 0에서 9.4까지 범위로, 점수가 높을수록 질병 활동도가 높음을 의미합니다. DAS28 점수에 따른 질병 활동도 수준은 다음과 같습니다: 완화: <2.6, 낮은 질병 활동성: ≥2.6 및 ≤3.2, 중간 질병 활동성: >3.2 및 ≤5.1, 높은 질병 활동성: >5.1. 폐경의 진단 및 확인을 위한 기준과 권장 사항은 북미 폐경학회(NAMS)와 미국 산부인과 학회(ACOG)를 기반으로 했습니다.

참가자들은 온라인 플랫폼, 소셜 미디어 채널, 웹 기반 자원을 통해 연구에 참여하도록 초대되었습니다. 이후 그들은 이란 테헤란에 위치한 샤리아티 병원 류마티스 클리닉에서 추가 평가 및 모니터링을 위해 방문했습니다. 포함 기준은 다음과 같습니다: 체질량 지수(BMI) 25–35 kg/m², 연령 50–70세, 폐경 상태, 류마티스 관절염 진단 후 6개월 이상 경과, 중등도에서 경도의 질병 활동도(DAS28 < 5.1), 연구 시작 3개월 전 질병 수정 항류마티스 약물(DMARDs, 예를 들어 메토트렉세이트, 하이드록시클로로퀸, 설파살라진)의 용량, 유형, 또는 투여 빈도의 조정, 비스테로이드성 항염증제(NSAIDs) 사용 없음, 연구 참여 동의였습니다. 다음 조건에 해당하는 환자는 제외되었습니다: 비스테로이드성 항염증제(NSAIDs) 복용, DMARDs의 용량, 유형, 또는 투여 빈도 변경, 알코올 섭취, 다른 자가면역 질환, 신장 질환, 췌장염, 담석, 암, 최근 3개월 내 특수 식이요법 준수, 또는 최근 약물 변경.

연구 기간 동안 모든 참가자는 류마티스 관절염 치료제를 계속 복용했습니다.

Sample size

With an α error probability of 0.05 and a statistical power of 80%, the largest sample size requirement was determined based on serum ALT concentrations as the dependent variable16. Employing the following formula prescribed for parallel trials and accounting for a 10% attrition rate in each group, the calculations indicated a need for 22 participants in each group to adequately address the research objectives.

n=2×(z1−α2+z1−β)2Δ2S2

n = sample size in each group. a = first type error = 0.05. b = 0.80 power. S2 = standard deviation of the studied result (SD). Δ2 = minimal clinically important difference.

Randomization

Upon eval‎uating 100 prospective participants for eligibility, 56 individuals were rendered ineligible due to their failure to meet the predetermined exclusion criteria. The remaining 44 participants, who satisfied the inclusion requirements, were randomly assigned to one of two distinct groups, with each group comprising 22 members. This randomization process was facilitated through a stratified block design approach, employing a fixed block size of four, and was executed via an online platform (www.sealedenvelope.com). The allocation of participants to either the intervention or the control group was contingent upon stratification based on age and BMI. For this trial, the personnel responsible for conducting laboratory analyses were kept blind of the assigned interventions to maintain impartiality.

Dietary interventions

The study implemented an IF regimen for the intervention group, allowing only non-caloric beverages during a 16-hour fasting period and unrestricted eating for 8 h. The diet was tailored to provide 55% carbohydrates, 30% fat, and 15% protein, with a 300-kilocalorie deficit based on individual energy requirements calculated using the Harris-Benedict formula17.

The control group, in contrast, followed a traditional diet with three meals (breakfast, supper, dinner) per day and two snacks. The rationale for the variation in diets between the groups lies in the nature of the intervention: the IF group focused on time-restricted eating, while the control group maintained a more conventional dietary pattern. This distinction was necessary to eval‎uate the specific effects of IF on the study outcomes. To assess adherence, participants submitted 24-hour dietary records every four weeks and completed physical activity questionnaires. The researchers maintained regular contact with participants through weekly phone calls and monthly meetings, providing support and monitoring compliance.

Adherence was measured by attendance at phone sessions, adherence to meal plans, and following diet guidelines. Participants who missed more than two consecutive phone sessions or deviated from the diet three times in two consecutive weeks were deemed non-compliant. The study utilized 3-day dietary recalls to track food consumption accurately, with researchers providing guidance on portion sizes and food item recording. Throughout the intervention, participants were instructed to maintain their usual physical activity levels and medication regimens. The study aimed to compare the effects of intermittent fasting with a traditional low-calorie diet on various health parameters, including liver health as assessed by fibro scan and biochemical eval‎uations.

식이 개입
연구에서는 개입 그룹에 간헐적 단식(IF) 프로그램을 적용했으며, 

16시간의 단식 기간 동안 칼로리가 없는 음료만 섭취하도록 허용하고, 

8시간 동안 제한 없이 식사를 할 수 있도록 했습니다. 

식단은 개인별 에너지 요구량(Harris-Benedict 공식을 사용하여 계산)을 기반으로

 55% 탄수화물, 30% 지방, 15% 단백질을 제공하도록 조정되었으며, 

300kcal의 칼로리 결핍을 유지하도록 설계되었습니다.

대조군은 하루 3끼(아침, 저녁, 밤)와 간식 2회를 포함한 전통적인 식단을 따랐습니다. 두 그룹 간의 식단 차이는 개입의 성격에 기인합니다: IF 그룹은 시간 제한 식사에 초점을 맞췄으며, 대조군은 더 전통적인 식사 패턴을 유지했습니다. 이 구분은 IF가 연구 결과에 미치는 특정 효과를 평가하기 위해 필요했습니다.

준수도를 평가하기 위해 참가자들은 4주마다 24시간 식이 기록을 제출하고 신체 활동 설문지를 작성했습니다. 연구진은 주간 전화 상담과 월간 회의 통해 참가자와 정기적으로 연락을 유지하며 지원과 준수 여부를 모니터링했습니다.

준수도는 전화 상담 참석률, 식사 계획 준수 여부, 식이 지침 준수 여부를 통해 측정되었습니다. 연속 2회 이상의 전화 상담을 결석하거나 2주 연속으로 식이 지침을 3회 이상 위반한 참가자는 준수하지 않은 것으로 간주되었습니다. 연구는 식이 섭취를 정확히 추적하기 위해 3일 식이 회상법을 사용했으며, 연구진은portion 크기 및 식품 항목 기록에 대한 지침을 제공했습니다. 개입 기간 동안 참가자들은 평소와 같은 신체 활동 수준과 약물 복용 계획을 유지하도록 지시받았습니다. 이 연구는 간 건강(피브로 스캔 및 생화학적 평가를 통해 평가)을 포함한 다양한 건강 지표에 대한 간헐적 단식과 전통적인 저칼로리 식이의 효과를 비교하는 것을 목표로 했습니다.

Anthropometric assessment

Participants’ body measurements were taken using standardized methods and equipment. A digital scale (Seca, Hamburg, Germany) with 100 g precision was used to measure weight, with subjects wearing light clothing and no footwear. Height measurements were obtained using a measuring tape fixed to a wall, with participants standing barefoot and maintaining a natural shoulder position. The height was recorded to the nearest centimeter. Body Mass Index (BMI) was computed by dividing the weight in kilograms by the square of the height in meters. For waist and hip measurements, a non-elastic measuring tape was employed, taking care not to apply pressure to the skin. Waist circumference was measured at the navel level, while hip circumference was taken at the widest part of the hips. Both measurements were recorded to the nearest 0.5 cm. The waist-to-hip ratio was calculated by dividing the waist measurement by the hip measurement.

All these anthropometric measurements were conducted with participants wearing minimal clothing to ensure accuracy. The combination of these measurements provided a comprehensive assessment of the participants’ body composition and proportions.

Biochemical assessments

Blood samples were collected from the participants at the beginning of the study and after the intervention period, following a 12–14 h fasting period. Ten milliliter of blood was transferred into tubes containing the anticoagulant EDTA to separate red blood cells; 10 mL of blood without any anticoagulant was used to obtain serum. The serum was then centrifuged in the laboratory at 3500 rpm for 10 min to separate it from whole blood. The separated serum from each individual was transferred into sterile micro tubes and stored at −80 °C until further analysis. The levels of antioxidant indicators, including superoxide dismutase, catalase, glutathione reductase, and nitric oxide, as well as peroxidation indicators such as myeloperoxidase and malondialdehyde, were measured using Enzyme-Linked Immunosorbent Assay (ELISA). To ensure the accuracy and sensitivity of the biochemical assessments, all ELISA kits were sourced from reputable manufacturers (Bio-Rad Laboratories, USA; R&D Systems, USA). These kits have been validated for their high precision and sensitivity in detecting the biomarkers of interest. The intra- and inter-assay coefficients of variation were kept below 10% for all assays, ensuring reliability and reproducibility of the results.

Statistical analysis

The normality of variables was eval‎uated using the Kolmogorov-Smirnov test and visual tools like Q-Q plots. Non-normally distributed data underwent logarithmic transformation to achieve normality. The analysis followed the intention-to-treat principle, utilizing linear regression to impute missing data from participants who dropped out during the study. Descriptive statistics were presented as means with standard deviations for quantitative variables and as frequencies with percentages for qualitative variables. Comparisons between the intervention and control groups for quantitative variables were conducted using independent-sample t-tests, while chi-squared tests were employed for qualitative variables. To eval‎uate the impact of the intermittent fasting diet on various health parameters, including anthropometric measures, liver enzymes, and inflammatory and oxidative stress markers, repeated-measures ANOVA was utilized. Furthermore, one-way ANCOVA was performed to examine changes in dependent variables between groups, with adjustments made for baseline values. All statistical analyses were executed using SPSS version 25 (SPSS Inc. Chicago, Illinois USA). The threshold for statistical significance was set at a P-value of less than 0.05.

Results

The study involved 44 postmenopausal women with rheumatoid arthritis, split into two groups of intervention (n = 22) and control (n = 22). The intervention group followed a 16:8 intermittent fasting diet, whereas the control group received standard dietary advice. By the end of study, 38 participants had remained, resulting in an 88% adherence rate. In the intervention group, three participants were excluded: one voluntarily withdrew and two failed to adhere to the fasting diet based on the food record assessments. The control group also lost three participants: one due to surgery and two who chose to discontinue (Fig. 1). To enhance statistical power of the study, researchers employed the intention-to-treat (ITT) method for data analysis.

Fig. 1

Flow diagram of the study participants.

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Table 1 presents the general characteristics of the participants. No significant differences were observed between the 16:8 IF group and the control group in terms of age, body mass index, marital status, education, physical activity, or smoking habits.

Table 1 Baseline characteristics of the study participants*.

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Table 2 outlines participants’ food intake during the study period. Both groups had similar intake levels of energy, carbohydrates, and proteins. However, the IF group demonstrated higher consumption of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), vitamin D, vitamin B2, magnesium, and calcium than the control group. Conversely, the control group had a higher intake of fiber, vitamin C, vitamin B1, iron, caffeine, and potassium. No significant differences were found between the groups in the intake of vitamin B3, vitamin B6, folic acid, vitamin B12, zinc, and sodium.

Table 2 Mean (SD) dietary intakes of participants throughout the study based on dietary food record.

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Table 3 displays the mean and standard deviation of the inflammatory indices and oxidative stress markers at the start and end of study for both the intervention and control groups.

Table 3 Mean (SD) findings of inflammation and oxidative stress markers among postmenopausal, overweight and obese women with rheumatoid arthritis.

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Compared with control group, serum levels of malondialdehyde and neutrophil to lymphocyte ration (NLR) significantly decreased in the intervention group. After adjusting for baseline values, they experienced a significant mean (SD) reduction in MDA (−0.01 [0.01] vs. −0.002 [0.09]) and NLR (−0.11 [0.21] vs. 0.008 [0.83]). Conversely, serum catalase levels were increased in both groups, with a more pronounced increase in the intermittent fasting group. Mean (SD) serum catalase changed by 0.02 (0.03) µM for IF group and − 0.008 (0.01) µM for control group after adjusting for baseline levels. No significant differences were found between the intervention and control groups at the end of study in serum myeloperoxidase, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, total oxidant capacity, or total oxidant capacity (Table 4).

Table 4 Adjusted changes in inflammation and oxidative stress markers among postmenopausal, overweight and obese women with rheumatoid arthritis.

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Table 5 presents the mean and standard deviation of liver enzymes and creatinine levels at the beginning and end of the study for both groups. In the intervention group, serum levels of AST and ALT decreased significantly at the end of study. After adjusting for baseline values, a significant mean (SD) reduction in ALT − 2.34 (0.29) vs. −0.75 (0.30) and AST − 4.82 (0.24) vs. −1.02 (0.24) was observed. However, no significant difference was found in the serum creatinine levels between the intervention and control groups (Table 6).

Table 5 Mean (SD) findings of liver enzymes and creatinine among postmenopausal, overweight and obese women with rheumatoid arthritis.

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Table 6 Adjusted changes in liver enzymes and creatinine among postmenopausal, overweight and obese women with rheumatoid arthritis.

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Discussion

This study provides compelling evidence for the beneficial effects of intermittent fasting in postmenopausal, overweight, and obese women with rheumatoid arthritis. The key findings demonstrate that an 8:16 intermittent fasting regimen, when compared to standard dietary recommendations, led to significant improvements in several markers of oxidative stress and inflammation. Specifically, the intervention group showed a marked decrease in serum malondialdehyde levels, reduction in the neutrophil-to-lymphocyte ratio, and increase in catalase levels. Furthermore, thise study revealed significant reductions in liver enzymes (AST and ALT) in the intermittent fasting group, indicating potential hepatoprotective effects.

One of the key findings of our study was the significant decrease in serum MDAlevels in the IF group. MDA is a well-established marker of lipid peroxidation and oxidative stress18,19. This reduction aligns with previous research by Harvie et al. (2011), who reported that intermittent energy restriction led to improvements in oxidative stress markers in overweight women8. Similarly, Longo and Matson (2014) have highlighted the potential of fasting regimens to enhance cellular stress resistance mechanisms9,11. Our results extend these findings to a specific population of postmenopausal women with RA, suggesting that IF may be particularly effective in mitigating oxidative stress20.

Another notable outcome was the increase in catalase levels observed in the IF group. Catalase is a crucial antioxidant enzyme that plays a vital role in protecting cells against oxidative damage21,22. This finding is consistent with that of De Cabo and Mattson (2019), who reported that IF can enhance antioxidant defense mechanisms12. The upregulation of catalase in our study suggests that IF may bolster the body’s intrinsic antioxidant systems, potentially offering protection against oxidative stress associated with RA23.

Our study also revealed a significant reduction in the neutrophil-to-lymphocyte ratio (NLR) in the IF group. The NLR is an emerging marker of systemic inflammation that has been associated with disease activity in RA24,25. This reduction indicates that IF may have broad anti-inflammatory effects beyond traditional markers. While previous studies have primarily focused on standard inflammatory markers, our findings suggest that IF may modulate the immune response at the cellular level, potentially offering a novel mechanism for managing inflammation in RA26.

With regard to liver function, our study demonstrated significant reductions in AST and ALT levels in the IF group. These findings are particularly relevant given the increased risk of non-alcoholic fatty liver disease (NAFLD) in overweight and obese individuals with RA27,28. Our results are in line with those of Trepanowski et al. (2018), who reported improvements in liver function markers with alternate-day fasting29. The hepatoprotective effects observed in our study suggest that IF may offer additional benefits beyond inflammation control in patients with RA, potentially addressing comorbidities associated with metabolic dysfunction16.

It is worth noting that while we observed significant improvements in several markers, we did not find significant differences in total oxidant capacity or total antioxidant capacity between the groups. This contrasts with previous studies that have reported broader changes in oxidative stress parameters with IF30,31. This discrepancy may be due to the specific characteristics of the study population or duration of the intervention. Further research is needed to elucidate the full spectrum of oxidative stress changes induced by IF in RA patients32.

Our findings support this notion and suggest that metabolic reprogramming induced by IF may have direct effects on inflammatory and oxidative stress pathways, independent of weight loss9,11. The results of our study are particularly significant, given the unique challenges faced by postmenopausal women with RA. As highlighted by Shah et al. (2020), menopause and aging can significantly affect the progression of RA33. Our findings suggest that IF may offer a promising non-pharmacological intervention for managing RA in this population, potentially addressing both primary disease symptoms and associated metabolic complications34.

Certainly, the exact mechanisms by which IF exerts its beneficial effects in postmenopausal, overweight, and obese women with rheumatoid arthritis (RA) are complex and multifaceted. Based on the results presented and the current understanding in the field, we can delve deeper into these mechanisms.

Modulation of Oxidative Stress:

The significant decrease in malondialdehyde (MDA) levels observed in the IF group indicated a reduction in lipid peroxidation35. This effect is likely to be mediated through several pathways:

a) Upregulation of antioxidant enzymes: The significant increase in catalase levels observed in the IF group suggests that IF enhances endogenous antioxidant defenses, as catalase is a key enzyme in detoxifying hydrogen peroxide and mitigating oxidative stress. This finding aligns with prior research showing that fasting interventions can upregulate antioxidant enzymes and reduce markers of oxidative stress21,36. In contrast, other potential mechanisms, such as mitochondrial hemostasis and reduced ROS production, remain theoretical. Previous studies have suggested that IF may induce mild mitochondrial stress, leading to improved mitochondrial function and reduced ROS generation over time37. However, our study did not directly assess mitochondrial function or ROS levels, and thus, this mechanism remains speculative. Similarly, while the activation of Nrf2 pathways may explain the upregulation of antioxidant defenses observed in other fasting studies38; this was not measured in our trial and represents a potential area for future research.

Modulation of Inflammation:

A reduction in the neutrophil-to-lymphocyte ratio indicates a shift in the inflammatory profile. This can be attributed to the following reasons:

1. a.

   NLRP3 inflammasome suppression: IF inhibits the NLRP3 inflammasome, a key mediator of inflammation in RA39.

2. b.

   Altered gut microbiome: IF can modify gut microbiota composition, potentially reducing the production of pro-inflammatory metabolites40.

Metabolic Reprogramming:

Improvements in liver enzymes (AST and ALT) suggest broader metabolic benefits:

1. a.

   Enhanced insulin sensitivity: IF can improve insulin signaling and reduce hepatic steatosis and inflammation41.

2. b.

   Activation of sirtuins: Particularly SIRT1 and SIRT3, which are NAD+-dependent deacetylases involved in metabolic regulation and stress resistance42.

Autophagy Induction:

IF is a potent inducer of autophagy, a cellular recycling process that can remove damaged cellular components and reduce inflammation43.

Circadian Rhythm Synchronization:

IF may help synchronize circadian rhythms, which are often disrupted in RA and obesity, leading to improved metabolic function and reduced inflammation44.

Ketone Body Production:

During fasting, the body produces ketone bodies, particularly β-hydroxybutyrate, which has been shown to have anti-inflammatory properties and may contribute to the observed effects45.

This study had several notable strengths. First, it focused on a specific and understudied population of postmenopausal, overweight, and obese women with rheumatoid arthritis providing valuable insights into the effects of intermittent fasting in this group. A randomized controlled design enhanced the reliability of the findings. The comprehensive assessment of multiple biomarkers, including inflammatory indices, oxidative stress markers, and liver enzymes, offers a holistic view of physiological changes induced by intermittent fasting. Additionally, the high retention rate (88%) and use of intention-to-treat analysis strengthened the validity of the results. However, this study had some limitations. The relatively small sample size (44 participants) may have limited the generalizability of the findings. The short duration of the intervention (eight weeks) may not capture the long-term effects or sustainability of the intermittent fasting regimen. Furthermore, while the study controlled for several confounding factors, unmeasured variables could have influenced the results. Finally, the study relied on self-reported dietary intake, which can be subject to recall bias, although efforts were made to minimize this through regular monitoring and food records.

In conclusion, these findings indicate that IF may offer a valuable non-pharmacological approach to managing rheumatoid arthritis in this specific population, addressing both the primary disease symptoms and associated metabolic complications. While further research is needed to fully elucidate the mechanisms and long-term effects, this study provides strong evidence for the potential of intermittent fasting as an adjunct therapy in the management of rheumatoid arthritis, particularly in postmenopausal women who are overweight and obese.

Data availability

All the data produced or examined during the research are included in this article. For additional information, please contact the corresponding author.

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