Research Question: Does Vitamin D reduce the symptoms of rheumatoid arthritis in pre-menopausal women?

 

Hypotheses:

  • H0 (null hypothesis): Vitamin D supplementation reduces rheumatoid arthritis symptoms in individuals with hypovitaminosis D.
  • H1 (alternate hypothesis): Vitamin D does not reduce the symptoms of rheumatoid arthritis.

 

Introduction

Rheumatoid arthritis is an autoimmune condition in which joints, particularly small joints, become inflamed impacting mobility and causing a frequent amount of pain in those individuals who experience this condition.1 Typically, RA is diagnosed between the ages of 35 and 60, but can be seen in young adults as young as 16 or even earlier as juvenile arthritis.2 As this autoimmune condition impacts many, there is statistical evidence to show that middle aged women experience rheumatoid arthritis at a higher rate compared to their male counterparts.1,2Many interventions are used to combat the pain and inflammation that those with RA experience. Some of these interventions include dietary changes and supplements added to support healthful joints and hopeful pain relief that can be physically as well as emotionally debilitating. Many individuals who experience symptoms of RA often reach for any sign of relief. One of the supplements that has been under the research scope within the RA community is vitamin D. The influence of vitamin D serum levels on rheumatoid arthritis susceptibility and severity is being examined for the complexities of treatment and relief options.3 This objective is to determine correlations between vitamin D serum levels and the association of susceptibility and severity of rheumatoid arthritis symptoms

 

 

Nutrient of Interest

Vitamin D is a vital vitamin that greatly impacts health and wellness in human beings. However, at least50% of the population worldwide is vitamin D insufficient or deficient including all age groups, ethnicities, and genders.4 Vitamin D is two-fold as it can equally be consumed by supplementation and food products but is also absorbed via sunlight, often referred to as the “sunshine” vitamin.4 The Endocrine Society recommends a vitamin D range of 40 to 60 ng/mL and recommends an intake of at least 1500 to 2000 IU’s for adults to maintain this range and likely a higher dosage for those experiencing medical complexities.4Vitamin D deficiencies has been correlated with the prevalence and severity of many different autoimmune diseases, including rheumatoid arthritis.5 RA is an inflammatory condition that includes flares, remissions, and a continuous lifecycle of evolving joint complications that has recently been researched to determine the diffusion of this joint pain that occurs in these individuals who have been diagnosed with RA.1 Women are at a higher risk of developing RA throughout their lives.2

 

Goals and Objectives

This research study aims to explore the autoimmune condition, rheumatoid arthritis, in pre-menopausal women and the impact of vitamin D in symptoms on rheumatoid arthritis. The objective of this research will determine the role that vitamin D plays in the symptoms of rheumatoid arthritis in the population of premenopausal women with rheumatoid arthritis.

 

Literature Review

Rheumatoid Arthritis

 

Rheumatoid arthritis (RA) is an autoimmune condition that involves inflammation of the synovial joints with likely causes for complication in the future such as permanent joint damage and vasculitis that could be present if the condition remains untreated.1 The autoimmune nature of this disease is caused by an immune system that attacks the lining of the membranes that surround the joints, though it is not fully understood why the immune system does this.3 Symptoms of RA typically include, but are not limited to, warm, swollen joints, stiff joints, weakness, exhaustion, and rheumatoid nodules.3 There is currently not cure for RA and only varying treatment options at this time for those experiencing this autoimmune condition. Because of this, treatment modalities are aimed at providing relief, achieving low disease activity state (LDAS), and attempting to expedite the diagnoses of RA.2

There are a few scales used to determine the disease activity such as the Disease Activity Score using 28 joints (DAS-28), Simplified Disease Activity Assessment Index (SDAI), and Clinical Disease Assessment Index (CDAI).2 These tests are routinely used by rheumatologists to monitor the activity of RA and use these scales as a means of treatment and dosing markers. Additional laboratory tests are used to look at features of RA. They include erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) provide the best information about the acute phase response. The level of CRP was shown to be significantly correlated with the severity of disease as well as radiographic changes.4

Treatment of RA is aimed at reaching full remission or reaching a significantly lower disease activity within the span of 6 months in order to prevent joint damage, disability, and systemic manifestations of RA.5Varying therapies are used to treat RA, but also to provide relief and extended functionality to the patient with RA. Pharmacology therapies include drugs within the categories of delayed DMARDs, anti-body based, T-cell targeted, Interleukin targeted, etc. and common NSAIDs to reduce joint inflammation.4,5

For many, RA can be a debilitating and painful barrier to everyday living. There are many research studies that have been or are currently aimed at interpreting the impact that RA has on everyday life due to the increase levels of pain occurring throughout the joints impacted as well as disease activity reducing physical function.6 One of the most common symptoms in patients with RA is the stiffness that occurs particularly in the morning time, or after a long period of rest.7 Morning stiffness is so prevalent that is listed as a classification criteria for RA.7

Women in particular have higher rates of RA than their male counterparts at a 3:1 ratio.2,8 The age range that is most impacted by RA is middle aged women, however, lower rates of RA still do occur in younger and older women.2 There are many theories within the research that have been developed regarding the etiology as well as the development of the disease discrepancy between men and women. Many of these research studies, though conflicting, primarily focus on the hormonal elements that occur within women as opposed to men.8 There is particular concern with estrogen as pregnancy and breastfeeding, for example, have been associated with a decreased risk of developing RA and concomitantly, the post-partum and post-menopausal periods, and in particular, early-onset menopause (less than 44 years old) have been associated with an increased risk.8 A research study examined women with RA and their widespread pain levels as determined by DAS28 and determined that these women with pain display severe muscle function deficiency in clinical examinations, general activity limitations, low psychological levels, and low health compared to other women with RA and no reported widespread pain.9 The results of this study brought up an important question for researchers involved in rheumatoid arthritis as the treatment aim for this research is to reduce inflammation and achieve remission in order to prevent deformities and further health consequences. However, though this is an important goal, this treatment may not be the enough to address myriad of ways that those experiencing the symptoms of RA are drastically impacted in day-to-day living.9

With the discomfort levels that correspond to RA, many patients will seek relief from other sources such as diet and supplementations along with their prescribed medication. Research examining the impact of diet and RA symptoms as well as disease markers is relatively new and sparse, beginning the field of diet and RA treatment. A study type called ADIRA has examined to determine efficacy of whether treatment of RA can reduce disease activity and improve quality of life as well as reduce individual and societal costs in addition to pharmacological treatment.10 Varying supplemental products have also increased in use among those with RA as the fight for relief continues. However, this is typically against the practitioners recommendations as supplements can be unregulated and lack supportive research.  Given the apparent communication gap between patients and providers regarding supplement use and higher potential risks associated with this usage in RA, ongoing surveillance of population-based practices may help facilitate RA management and direct future NDS research.18

Vitamin D

 

Vitamin D is among the largest deficiencyin humankind throughout the world. Vitamin D insufficiency impacts at least 50% of the population worldwide and is estimated to be deficient in at least 1 billion people worldwide, across all ethnicities and age groups likely due to lifestyle and environmental factors.11,14 Because very few foods contain vitamin D and is recommended to be supplemented at tolerable UL levels.11

Vitamin D plays a great role in immunity as it is a powerful nuclear receptor-activating hormone, especially to the immune system.12,14 The proposed doses would probably suffice to maintain vitamin D levels around or over 75-100 nmol/L, with practically zero risk of toxicity. Undeniably, further studies are needed to clarify the optimal supplementation of vitamin D, although it is uncertain whether a universal recommended dietary allowance is feasible.12

Bone health is greatly impacted by vitamin D and is thus suffering with the worldwide pandemic of vitamin D deficiency or insufficiency.10 Rickets has been the disease of concern with vitamin D deficiency, and newer research has shown that it is impactful to many other health implications such as osteomalacia, osteoporosis, and preventing fractures.13

Vitamin D and Rheumatoid Arthritis

Vitamin D deficiency has been shown to play a large role in human immune health. Reduced vitamin D intake has been linked to increased susceptibility to the development of rheumatoid arthritis (RA) and vitamin D deficiency has been found to be associated with disease activity in patients with RA.16  Because of the recent nature of this field of research, much of the literature is determining associations and baselines for the future of vitamin D and rheumatoid arthritis.17 Recent research has determined that vitamin D plays a large role in autoimmune conditions, especially bone conditions such as rheumatoid arthritis. There is some research to support that low levels of vitamin D have been associated with RA, though that is not always consistent.15

Research examining serum vitamin D levels and the correlations between RA patients and healthy controls. A particular study resulted in that RA patients having lower vitamin D serum values than healthy controls, and that among RA patients there is a negative relationship between vitamin D serum values and RA disease activity.19

As RA continues to be more prevalent among middle-aged women, the health of women and treatment concentration of this population is imperative. Seldom research has narrowed this population as a focus for research. However, research examining older women and vit D levels associated with RA symptoms did determine an inverse reaction between greater intake of Vitamin D and RA risk.20

Significance of Study:

While vitamin D and rheumatoid arthritis are frequently researched as individual and comparative associations, in depth research is needed for particular population needs. Premenopausal women are continually counted as the population with the highest rates of rheumatoid arthritis. The correlation of vitamin D supplementation and rheumatoid arthritis is a newer explored field with new and upcoming numbers of research papers. Research further narrowing the population to premenopausal women will determine if vitamin D supplementation will assist this population and their symptoms of RA.

Contribution to Field:

Existing research on rheumatoid arthritis and vitamin D supplementation has limited reporting in reference to the particular population of premenopausal women with rheumatoid arthritis. It is often seen as more generalized research. This research will be among new literature within the field to examine if vitamin D supplementation in this population relieves the symptoms of rheumatoid arthritis.

Discoveries/Interventions

Premenopausal women with rheumatoid arthritis will be the subjects of this study. Vitamin D supplementation will be given at varying doses to these women and examine premenopausal women with varying supplementation and those without. It is theorized that symptomatic events are reduced by such supplementation.

Subject Recruitment:

For this research study, the population will be pre-menopausal women with rheumatoid arthritis and vitamin D serum levels at <30 ng/mL.1 Participants must include biological women. Self-identifying women having experienced a sexuality transition and are biologically male will not be included for this particular study. Pre-menopausal women diagnosed with RA who have normal or high serum values for vitamin D between 30 ng/mL and 50 ng/mL will be excluded.1 Women who are experiencing menopausal symptoms and are suspected to be undergoing menopause by their practitioner do not meet the criteria for this research study and will be excluded.

This female cohort will be gathered in the Salt Lake City, Utah valley by reaching out to local rheumatology clinics and practitioners. This will be done by surveying a 30 miles radius of Salt Lake City within the state of Utah and personally visiting or calling the offices and meeting with the doctors or the other practitioners of the offices. During these conversations, they will receive information regarding the nature of the research study, and the need for this type of research. They will then be invited to include their clinic’s patients in participation. If the clinic agrees to help facilitate this study for us, they will be given material and handouts designed by the research team that details the study for the participant. The nursing staff and medical assistants will be tasked with introducing and discussing this research study with their patients. They will be well versed and trained on the inclusion and exclusion criteria for whom to offer participation to and how to get in contact with the research team for any future questions.

The goal is to recruit as many clinics and offices as possible to deliver this opportunity to participate in the research study to as many participants that are eligible. When eligible patients come into the office, they will be briefed by the medical assistant and/or nurse regarding the opportunity to participate in this research study and the compensation of a $50 gift card for doing so. They will give the patient our information as well as a pamphlet. The patient then will have the opportunity to learn about it from the brochure as well as a website listed. If they choose to participate, they will fill out a form online that includes the requirements, risk/benefits, and timeframe commitments. Once that is complete, the online form will be sent to the research team and from there, the research team will reach out and get this participant enrolled.

The estimated number of subjects was calculated using a Qualitrics calculator and determined to be around 278 having discussed research information with at least 1000 qualified patients.2 This number would be with a 95% confidence level and 5% margin of error. The research study will be beginning in March and going through November. The gathering of participants will begin in January.

Methods and Procedures:

            Once chosen, participants in this research study will initially fill out a consent form. Once this is filled out, the research team will reach out to the participant for them to come to the University of Utah where the study will be held. At their initial appointment with us, they will receive a questionnaire where the participants will answer basic questions that pertain to the research study including their current RA signs and symptoms, medications being taken to manage their RA as well as other medications, sunlight exposure, all supplement information and dosage, SPF in sunscreen and makeup, types of exercise, remedies used to manage RA symptoms, and any additional information the participant feels necessary to disclose. After this information is taken, the patient will receive a body composition test with BodPod machine at the university to determine body composition. A phlebotomist will be on site during appointment slots with participants to take vitamin D labs. At the end of this initial meeting, the participants will be given a vitamin D supplement of 1000 IUs to begin. They are required to take this supplement everyday at a consistent time each day. The participant will then set up the next appointment for lab work every two weeks for the period of 6 months.  Every two weeks these participants will also receive a survey to report symptoms of RA. Vitamin D lab work will be assessed by the research team and adjusted as needed. The research team will update the participant via email throughout the study and if no adjustments are needed. If the team feels an adjustment necessary, they will be updated via phone call and instructed on new dosage and mailed additional supplements if needed.

At the end of the 6-month trial, a final vitamin D level will be drawn and assessed on the patients as well as a final survey reporting the symptoms of RA being experienced by each participant. Research team will evaluate correlations among the reported symptom severity and the vitamin D level occurring within the participant.

All questionnaires will be completed on an iPad and retained as research content. Patient lab work will be recorded on a secure website that only the research team has access. All information will be used for the purpose of data collection.

Provisions to Maintain Confidentiality of Data:

            The collection of data during this research study will be gathered and input by the research team members. An IT team will have previously created a secure website that will house all the content for the research team including the individuals participating, their information, and all of their results and adjustments. This will only be accessed by team members that are directly reporting and analyzing the data.  During the appointments the participants attend, they will be notified that their results will be available to them via email within a week from their lab draw.

Due to the eligibility requirements for the research study, no identifiable information will be retained. The use of identifiers was deemed unnecessary for the study due to the narrowing nature of the requirements for participation.

Research Setting:

The research setting will be within the walls of the health science building on the university of Utah campus. This will be a collaborating institution as the research will be done for UNE, but also assisted and provided by the University of Utah and many of its staff, machinery, and technology.

Participants will be required to come to the facility to complete their lab draws. No other travel requirements will be necessary. Phone calls and email will also be utilized as a transmission of information from the research team to the participants.

 

 

Consent/Assent Process

            Consent will be obtained at the initial appointment so as to ensure participant understands all elements of the research study and have the opportunity to ask questions. The research team and phlebotomists are obtaining consent from participants to complete the lab draws, analyze the data they provide, and report on findings.

Privacy will be maintained for the participant as no access will be provided to anyone besides the research team regarding their surveys, questionnaires, and lab work. This information will be retained on a private web-based location and can be sent to the participant via email at any time they request. Lab work values will be routinely sent out as soon as values are available to the research team.

Appointment visits for participants will be no longer than 1hr every two weeks and time will be respected. Schedulers from the research team will ensure a time slot is given to one participant at a time.   

Risks/Benefits to Participants

            Possible risks involved in this research study are unlikely. Physical risks involved with lab draws could include infection, hematoma, painful draws, bruising, and physical discomfort.  Trained personnel will be on site performing lab draws to ensure properly done with minimal risk. Psychological risks could include negative mental states such as anxiety and stress. Legal risk may be present if participant engages in conduct contrary to laws to which the participant will be liable criminally or civilly. Confidentiality risk is included due to human subjects of research study and a possible breach of information. Participants are awarded the right to protection of their privacy, identify, and all other personal data to remain confidential.

Benefits in participation include possible relief of symptoms with supplemental experimentation throughout trial. Additionally, data collected by participants will be used to directly benefit the population involved with the research study.

Data Analysis:

Based on the nature of the study, the data being looked at, and the data that is being recorded from the participants, the team will include variations of data collection. This study will be analyzed primarily via a qualitative method. However, there will be quantitative elements of this research that will be included to maximize the results needed to gather research that will maximize the outcomes for those expected to benefit from the results of the study.

All surveys and questionnaires will be done electronically. The qualitative research will be gathered by an initial survey that will ask a few basic questions of the participant to ensure that they meet inclusion criteria for the research study. Informed consent will be completed prior to any data begins being collected. The survey will be gathered by the research team, evaluated, and then used to determine who is eligible for further exploration of this research study. After the invitation to be part of the research study, the participant will be given a questionnaire to complete that will be a variety of questions that include the participants experience of symptoms with rheumatoid arthritis, diet intake, daily activities including exercise frequency, sunlight exposure, and other supplements and medications that the participant is taking. This will also be analyzed and formulated into an Excel sheet that will be used to group the data together.

During the course of the research study trial, participants will be filling out an additional questionnaire to update their symptoms of rheumatoid arthritis as their individual vitamin D supplementation will be tailored and possibly changing throughout the trial period. These questionnaires will be simpler than the initial questionnaire and will have a symptom description to circle including the range of low, moderate, and high. These will describe symptoms such as weakness, stiffness, pain, function, and quality of life. These data results will be grouped together in an Excel format to watch trends overtime and determine symptomatic components of this research. This will allow to see how the supplementation is correlating with the reported symptoms of rheumatoid arthritis among the participants.

Part of the quantitative component of the questionnaire that will be included in data collection for this research will be using a Disease Activity Score (DAS), functionality score (HAQ), quality of life score (RAQoL), and pain score (VAS).

These questionnaires will be recorded anonymously but will be retained on a secure network so as to ensure that if participants want reference to their answers or their correlating scores, they will be able to be sent these results as agreed to within the initial paperwork and agreements. These scores will also coincide with the quantitative data that will additionally be included within this report.

Once all data has been uploaded for review, correlations will be drawn and reported via graphs, plots, and explanations. Statistics will be drawn to determine the correlations between symptoms and vitamin D supplementation and how much supplementation occurred. These results will be used to determine the effectiveness of the vitamin D supplementation in the symptoms of rheumatoid arthritis.

The preliminary report will be anonymously reported without any participant information, excluding result and reported data such as symptom reports as well as the qualitative data number that was agreed upon to disclose during the initial assessments prior to the beginning of the study. The patient information will be recorded securely to ensure the participant can request it up to 5 years following the trial. The participant will receive direct instructions on how to receive results from the study or their previous answers to questionnaires.

It is anticipated that the results will show a positive correlation between the tailored vitamin D 25(OH)D levels and the symptoms of rheumatoid arthritis in the participants. From previous research, vitamin D deficiency or insufficiency has been associated with higher rates of rheumatoid arthritis diagnosis.2 In other research studies, vitamin D supplementation improved overall rheumatoid arthritis symptoms of disease in patients.3 The newer nature of this literature also allows for more research as definitive conclusions cannot often be drawn by the limited research on the topic.

Discussion

This research will be an additional element in the fight for relief among those suffering from the effects of rheumatoid arthritis and the debilitating and painful symptoms that are associated with the condition. While the autoimmune nature of the condition cannot be reversed, additional means by which relief can be experienced by those diagnosed with the condition aims to be a very important feat. This research is aimed at doing just that, to determine the effectiveness of 25(OH)D levels and drawing conclusions among the symptoms that are being reported by the patient in their surveys and questionnaires.

The risks associated with this research study, while certainly present, are minimal and unlikely in terms of the outweighing factor of assisting and entire community of individuals living with rheumatoid arthritis across the globe. The work of this research study will, with hopeful intent, improve the lives of the participant, and reach other who, too, are looking for a means to find relief.

Conclusion

This research study will be a steppingstone the era of relief for those with rheumatoid arthritis. The test results and data collection will be analyzed and reported as it is made available to the team members via secure files within Excel.

Few limitations are present during this research study. A participant would be kindly excluded from participating in this research study if they did not have current diagnoses for condition, had extremely high Vit D levels.

This research will be a great future opportunity to bridge the gap between feeling good with rheumatoid arthrons and the difference the vitamin D supplementation will make in symptomatic levels. This will also be a great opportunity to set the stage for future research aimed at improving the symptoms of rheumatoid arthritis.

 

 

 

 

 

 

 

 

 

 

 

 

References

 

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Reflection