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1. SJÖGREN’S SYNDROME RESEARCH STUDIES AND
CLINICAL RESEARCH IN SOUTHEAST ASIA
1.1 Sjögren’s Syndrome Research Studies.
1.1.1 The Sjögren’s Clinic at UCSF
J.P. Whitcher, A. Wu, T. Daniels
The weekly Sjögren’s Clinic provides the basis for a long-term study with joint collaboration between the Department of Oral Medicine, the Department of Rheumatology, and the Proctor Foundation. Clinical and laboratory information is collected, as well as labial and salivary gland biopsy specimens on patients with the clinical diagnosis of Sjögren’s syndrome. The Sjögren’s Study Group has found that Sjögren’s syndrome is clearly associated with focal sialoadenitis in the labial salivary glands while other causes of keratitis sicca are associated with diffuse sialoadenitis. More than 650 patients with positive labial salivary gland biopsies, who have had complete ocular, oral, and rheumatologic work-ups, have been evaluated over the past 31 years. This study comprises the largest group of patients in the United States with pathological confirmation of the diagnosis of Sjögren’s syndrome.
Because this database includes both ocular and oral findings, Dr. Whitcher has published several papers on the correlation between the ocular and oral clinical findings with a detailed statistical analysis of the data. He is continuing his analysis of this large database to sort out the specific clinical features of Sjögren’s syndrome that are associated with the primary and secondary manifestations of the disease as well as the differences in association with gender and age. He is also looking into the diagnostic sensitivity and specificity of the different tests used to diagnose keratoconjunctivitis sicca in patients suspected of having Sjögren’s syndrome. In addition, he is looking at the ocular component of Sjögren’s syndrome separately in a 31-year retrospective clinical study.
In addition to analyzing this large database, Dr. Whitcher and colleagues are considering clinical studies such as follow-up of Sjögren’s syndrome patients, to determine whether or not they stabilize or continue to worsen with time. Because of the large number of patients who can be reached for follow-up, this study promises to answer some basic questions about the progression of the disease over several decades. There also exist several possibilities for clinical studies of various medications for the treatment of Sjögren’s syndrome, both symptomatic therapy and treatment of the underlying inflammatory component of the disease.
1.1.2 The Sjögren’s International Collaborative Clinical Alliance (SICCA)
J. Whitcher, E. Strauss, N. McNamara, A. Wu,
J. Greenspan, T. Daniels
In 2003 the Sjögren’s Study Group was awarded a $12 million five-year NIH grant to establish an international collaborative research center at UCSF to participate with four other international satellite Sjögren’s syndrome centers in Kanazawa, Japan; Beijing, China; Copenhagen, Denmark; and Buenos Aires, Argentina examining patients with primary Sjögren’s Syndrome, as well as related and non-related controls. This year a sixth center was added in London, England and a seventh center at Aravind Eye Hospital in Madurai, India is awaiting confirmation by the Indian Government. The coordinating center at UCSF is collecting all information pertaining to the examinations and a database of Sjögren’s syndrome patients is being created that includes tissue samples, serum, and bucal mucosal smears are collected from the patients and banked for future research. The criteria for the ocular diagnosis of primary Sjögren’s have been standardized and the scoring system has been validated by data from a cohort of 736 patients. These ocular diagnostic criteria that are quantitative and validated by data are the first ocular scoring system for Sjögren’s patients that is data based. The scoring system has also been designed to be simple and user friendly so that it will be universally accepted.
Tissue samples collected from labial salivary gland (LSG) biopsies, bucal mucosal smears, serum samples, tear samples, and conjunctival impression for RNA will be made available to researchers on a competitive basis to investigate the genetic characteristics of Sjögren’s syndrome. It is anticipated that six thousand patients and controls will be recruited for the study during the five-year period. The Sjögren’s Study Group makes site visits to all of the international sites annually to standardize examination procedures, data collection and transmission procedures, methods for doing surgical procedures on LSGs, and methods for collection of other materials for genetic analysis. We anticipate that the data collected in the SICCA Study will provide the impetus for many secondary research projects investigating the diagnosis, immunology, genetics, and treatment of Sjögren’s syndrome, with the ultimate goal of finding a cure.
1.2 Clinical Research Studies in Southeast Asia
1.2.1 Corneal Ulceration in Southeast Asia.
The Incidence of Corneal Ulceration In Southeast Asia.
WHO SEAR Study Group, New Delhi, India
Dr. Whitcher was designated a World Health Organization Consultant in November 1999 and spent two weeks in New Delhi, India at the WHO headquarters of the Southeast Asia Region (WHO SEAR) chairing a study group on corneal ulceration in Southeast Asia. The region comprises a population of 1.6 billion, and there were representatives from India, Nepal, Bhutan, Bangladesh, and Myanmar. Dr. Madan Upadhyay and Dr. Whitcher developed a questionnaire six months prior to the meeting and circulated it among five collaborating ophthalmologists in the respective countries. Data were collected on the epidemiology, risk factors, and incidence of ocular trauma and corneal ulceration in the area. This was a first step in a concerted effort to define the problem of corneal ulceration in this area that is home to a quarter of the world’s population. One of the outcomes of this work was the publication of World Health Organization monograph, “Guidelines for the Management of Corneal Ulcer at Primary, Secondary, & Tertiary Care Health Facilities in the Southeast Asia Region”. This monograph was distributed by the WHO to all the health care facilities in the region in an effort to standardize the diagnosis and treatment of corneal ulcers. The Corneal Ulcer Study Group has now completed the manuscript of an extended version of this document in book form that concentrates on the epidemiology and prevention of corneal ulcers.
Front Row: S. Osaki, Dr. J. Whitcher, V. Cevallos
Back Row: M. Bodeker, E. Yi, student, Dr. B. Gaynor, Dr. D. Lee
1.2.2 Prevention of Corneal Ulceration in Southeast Asia:
Studies in Bhutan, Myanmar, and South India.
M. Upadhyay, M. Srinivasan, T. Kyaw, K. Ketshen, J. Whitcher
The three studies began in the fall of 2002, funded by the W.H.O. Southeast Asia Regional Office. These sites included villages in Madurai District, India, three large townships in Bago, Myanmar, and scattered small villages in the Punakha and Paro Districts, Bhutan. All three studies were completed at the end of 2004 except for the Myanmar study that was completed in the spring of 2005. To summarize the Bhutan data: during the 18 month period 135 individuals in this defined population of 10,139 in 55 villages in Paro and Punakha Districts reported to the Village Health Workers (VHW) with an ocular injury of which 115 were found to have a corneal abrasion. All 115 were treated with 1% Chloramphenicol ointment and all healed without sequelae. There were no corneal ulcers in the study population, although we calculated based on the previously reported incidence of 339/100,000 for the country that there should have been 52 ulcers. During the same time the remainder of the population of the two districts not in the study area (32,001) were documented to have an incidence of 306/100,000 corneal ulcers per year. The message appears to be that corneal ulcers can be effectively prevented in a developing country, where corneal trauma is the main risk factor and bacterial pathogens are the main cause of ulceration.
In the Myanmar study 15 VHWs followed 16,987 individuals in three villages for 12 months and treated all the corneal abrasions with 1% Chloramphenicol and 1% Clotrimazole ointment. There were 273 individuals with ocular injuries and 126 were found to have corneal abrasions. All healed without complications, and there were no corneal ulcers in this defined population where the corneal ulcer incidence is 710/1000,000 and we expected to see 120 ulcers, 80 of them caused by fungal pathogens in the 12 month period.
In South India two panchayaths in Madurai District comprising a population of 48,039 were followed prospectively for 18 months by 15 VHWs who were trained to identify post-traumatic corneal abrasions. Patients were randomized into two groups and treated with either 1% Chloramphenicol and a placebo ointment or with 1% Chloramphenicol and 1% Clotrimazole ointment three times a day for three days. Patients, physicians, and VHWs were masked to treatment. During the 18-month period 13365 individuals reported to VHWs with ocular injuries, and 374 with corneal abrasions were eligible for treatment. Of these, 368 (98.5%) healed without complications. Two patients had mild localized allergic reactions to the ointment, two dropped out, and two patients in the placebo group developed microscopic culture-negative corneal stromal infiltrates that healed in one week with Natamycin drops. Because we knew the incidence of fungal ulceration in this population from previous studies (113 per 100,000) we expected at least 20 fungal ulcers to occur in the placebo arm. In fact there were no fungal or bacterial ulcers in either arm.
The findings of this last study imply that both fungal and bacterial ulcers that occur following traumatic corneal abrasions appear to be effectively prevented in a village setting by using only antibiotic prophylaxis. The antifungal effects off antibiotics have been described in several studies recently. If these findings are confirmed by other studies, prevention of both bacterial and fungal ulcers in the developing world may be achieved by the simple grass roots public health strategy of antibiotic prophylaxis in all patients who suffer a corneal abrasion. The three studies were published separately in the British Journal of Ophthalmology this academic year.
1.2.3 Future Studies Defining the Epidemiology, Prevention and Treatment of Corneal Ulcers in Southeast Asia
J. Whitcher, V. Cevallos, M. Srinivasan, M. Upadhyay
Since prophylactic antibiotic treatment of corneal abrasions with 1% chloramphenicol ointment alone appears to drastically reduce the incidence of fungal ulceration in the population at risk, a study at Aravind Eye Hospital, with input from the Proctor Foundation and WHO, is currently being conducted involving over 100,000 villagers in Tamil Nadu to confirm this premise. Our colleagues in Bhutan have also requested that we design a prospective laboratory-based prevalence study in Thimpu to determine conclusively which pathogens are responsible for corneal ulceration in Bhutan. The paucity of fungal ulcers in that country raises some interesting epidemiologic questions that can be addressed only after we have determined with certainty the prevalence of pathogens causing ulceration.
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