Introduction patients with Rheumatoid Arthritis, affecting visual acuity,

Introduction 

Rheumatoid Arthritis (RA) is an autoimmune disease that causes joint damage as well as extra-articular complications1. It affects nearly 1%2 of the adult population globally, with its incidence peaking in the fourth and fifth decades of life3. The prevalence in India ranges from 0.28-0.7%4, affecting nearly seven million people.

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Symptoms of dry eyes/dry mouth often coexist with RA and it is the most common connective tissue disorder to be associated with Sjögren’s Syndrome (SS)5,6. SS is a chronic systemic autoimmune disease that is best characterised by lymphocytic infiltration of the exocrine glands and epithelia resulting in classic sicca symptoms of dry eyes and dry mouth, and objective evidence of keratoconjunctivitis sicca and xerostomia6. It can occur by itself, called Primary SS (pSS) or in association with other autoimmune diseases (i.e. polyautoimmunity), the most frequent being RA, autoimmune thyroid disease, and systemic lupus erythematosus7, wherein it is called Secondary SS (sSS). Studies have shown that the prevalence of sSS among patients with RA ranges from 4-40%8,9,10,11. There are a limited number of studies that have been published on the epidemiology of SS in India, a recent study conducted in North India reports a prevalence of around 5%17.

Symptoms related to SS, like dry eyes, hypo salivation and difficulty in swallowing, can significantly worsen the quality of life in patients with Rheumatoid Arthritis, affecting visual acuity, ability to work, and increase the risk of ocular and oral infections12,13. It is also known to cause dental cavities, oral thrush and corneal damage. Vision threatening complications, including corneal ulcers, can occur in upto 13% of patients diagnosed with SS, while systemic complications like peripheral neuropathy, interstitial nephritis and vasculitis are also more common in these patients14 . It is also estimated that people with SS are around 5 times more likely to develop non-Hodgkin’s lymphoma than people without SS24. 
Despite availability of treatment options, such patients continue to suffer due to under diagnosis and lack of awareness22.

Studies indicate some significant clinical correlations of sSS among RA patients, with disease duration17, extra-articular manifestations1, disability15, disease activity and anti-CCP antibody titres16, while some studies remain inconclusive23.
This study aims to estimate the prevalence of sSS among patients with RA, and evaluate any significant clinical correlations, to allow early diagnosis and management of this condition, thereby improving the quality of life of patients suffering from this lifelong disease.

Objectives

This study aims to:

Assess the prevalence of Secondary Sjögren’s Syndrome (sSS) among patients with Rheumatoid Arthritis presenting to a tertiary care setting hospital in New Delhi.
Evaluate any significant association of sSS in such patients with clinical parameters, autoantibody status, disability and disease activity scores.

Methodology

Study Design
Cross Sectional Study 
Recruitment of participants 
Patients will be recruited from the Rheumatology Clinic, Lok Nayak Hospital, New Delhi. Patients will be invited to participate in the study during their regular outpatient clinic visit.
Study population 
Inclusion Criteria:
All adult patients with Rheumatoid Arthritis (RA), as defined by the 2010 ACR/EULAR classification criteria18, will be eligible for the study. The enrolment of patients in the study is defined by an Informed Consent for study participation. 
Exclusion Criteria:
Patients with a history of past head and neck radiation treatment, hepatitis C infection, diabetes, thyroid disease, HIV/AIDS, preexisting lymphoma, sarcoidosis, graft versus host disease and use of anti cholinergic/anti depressant drugs, will be excluded from the study. Also, those patients who do not give an informed consent will be excluded.
Study procedure 
Diagnosis of Secondary Sjögren’s syndrome (sSS)
Diagnosis of sSS among patients with RA, will be made on the basis of  the American-European Consensus Sjögren’s Classification Criteria19.
All patients who meet the inclusion criteria, will be recruited to participate in the study after obtaining informed consent. They will be screened using a questionnaire about disease characteristics and ocular/oral symptoms, based on the AECG Sjögren’s Classification Criteria. In addition, the questionnaire will include five questions based on symptoms, as measured by visual analogue scales, from 0 to 100, with 0 indicating no trouble at all, and 100 indicating the worst problems they could imagine. The five questions will assess oral and ocular dryness, joint pain, stiffness and level of tiredness. Patients who answer affirmatively at least 1 of 6 questions in the screening phase, will be followed up with an objective testing phase, comprising the Schirmer I test and the Unstimulated Whole Salivary Flow Rate (UWSFR) test.
Schirmer I test will be performed using standardised Whitman 41 filter paper tear strips, placed at the junction of the middle and outer thirds of the lower lids, without anaesthetic eye drops and removed after 5 min. The test will be  considered positive if the wetting is ? 5 mm in one or both eyes. The unstimulated whole salivary flow rate measurement will be done in the evening, at least one to two hours after the last food intake. The subjects will be advised to refrain from smoking and drinking, atleast two hours before the procedure.They will be asked to sit comfortably, relaxed and upright, swallow once, and not to speak, eat, drink or swallow for the next fifteen minutes, after which saliva will be collected in a test tube by passive spitting. Flow rates of less than 1.5 ml/15 minutes will be considered abnormal. Patients who test positive for either of the two objective tests, will be classified as having sSS.
Assessment of disease activity and disability
Patients will also be assessed for disability using the Indian version of the Health Assessment Questionnaire20. Also, the disease activity and remission status will be assessed using the Clinical Disease Activity Index(CDAI)21, with a score of less than 2.2 indicative of disease remission25.
 Statistical considerations and Data Analysis
 Sample size and Statistical power:
The sample size of 83 has been calculated using the formula n = (1.96)2 p (1?p)/d2 ? 4pq/ d2
where
p is the prevalence of sSS in patients with Rheumatoid Arthritis, taken as 5%, based on a recent study conducted in India17
q = 1-p and d is the allowable error, taken as 5%
We will take a sample size of 100, for our study.

Statistical Analysis 
All qualitative variables will be expressed as rates/percentage, and assessed by the Chi Square Test and Fischer’s exact test. All quantitative data will be expressed as mean ± standard error and assessed by the Students’ t test/non parametric inferential tests. All correlations will be checked using Pearson’s correlation coefficient/Spearman’s correlation coefficient. Results will be considered significant for p- values below 0.05.
Ethical Considerations
We will;

Respect the privacy of patients and keep their private information confidential. 
Respect the patients’ right to change their mind, to decide that the research does not match           their interests, and to withdraw without penalty. 
Inform them of new information that might emerge in the course of research, which might change their assessment of the risks and benefits of participating. 
Monitor their welfare and if they experience adverse reactions, untoward events, or changes in clinical status, ensure appropriate treatment and when necessary, removal from the study. 
Inform them about what was learned from the research.

Implications
For patients/practice:
The implication of this study is to estimate the prevalence of Secondary Sjögren’s Syndrome (sSS) among patients with Rheumatoid Arthritis(RA) , to provide a better understanding of the magnitude of this comorbidity. Early diagnosis and treatment of this condition can not only significantly improve the quality of life of these patients, but also prevent any associated complications, ranging from minor ocular/oral infections to blindness and cancer. 
For future research:
Our study, being of an exploratory and interpretive nature, raises a number of opportunities for future research. More research will in fact be necessary to refine and further elaborate our findings. This study will also evaluate significant correlations of sSS with disease characteristics, to predict disease specific risk factors, that can aid in identification and diagnosis.
For researcher:
This study will allow the Investigator to evaluate RA patients, develop communication skills, and learn clinical examination skills, including tests for the diagnosis of Sjögren’s Syndrome. It will also help the researcher gain knowledge and research experience, being introduced to the process of scientific discovery. It will encourage critical thinking and analytical skills necessary to stay up-to-date with rapidly evolving literature.
References
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