Workshop Report:
Outcomes Measures for Sjögren’s Syndrome

Date
Location
Why a workshop on outcome measures?
Why a core set of outcome measures?
Goal
Summary
Chairs
Participants
Sponsors
Additional Bibliography

Date: April 10-11, 2003

Location: Bethesda, Maryland

Why a workshop on outcome measures?
Outcome measures in clinical trials are extremely important, since they are used to determine whether the outcome of a treatment is successful or not. For example, good outcomes in Sjögren’s syndrome after exposure to a new treatment may include improvement in symptoms of dry eyes and dry mouth. increased production of tears and saliva, and evidence of decreased inflammation in blood tests. Although a number of small and few large clinical trials have been performed to test potential treatments for Sjögren’s syndrome, the outcome measures used have differed from trial to trial. This results in difficulties in designing new clinical trials, interpreting the results of individual trials, and comparing the results of trials with one another.

Why a core set of outcome measures?
Agreement on collecting data on a fixed set of outcome measures, which are collected in the same manner in every Sjögren’s syndrome clinical trial, is important. Other measures can be used in addition to a core set of measures, but a core set would allow for comparisons across trials. The data from such trials can be used to develop response criteria. Such criteria spell out the rules by which data on outcome measures are to be used to decide whether or not a patient has responded to treatment.

Workshop Goal
Develop consensus on a core set of outcome measures for clinical trials in Sjögren’s syndrome (SS).

Summary
The workshop was aimed at developing an internationally acceptable core set of outcome measures for Sjögren’s syndrome, and represented a continuation of previous international efforts.

On the first day, overviews of approaches to the development of outcome measures as well as the frequency of the features of SS were given. Then the participants presented reviews of data on outcome measures relevant to clinical trials in SS in three main areas: 1) subjective measures, 2) objective measures and 3) additional measures. After each presentation, voting machines recorded participant responses to questions about the data and outcome measures, and graphs of the voting results shown immediately thereafter on a large screen. The results were then discussed further.

Over 50% of the participants voted in favor of the following, which were designated as core outcome measures:

• Sicca symptoms (oral, ocular)
• Sicca objective oral (unstimulated whole salivary flow)
• Sicca objective ocular (dye score; Schirmer: with or without anesthetic)
• Health Related Quality of Life
• Laboratory measures (Total IgG level)
• Fatigue

Over 6% up to 50% of the participants voted in support of the following, which were designated as secondary outcome measures:

• Composite activity
• C4
• Stimulated salivary flow
• Anti-La antibody
• Tear film break up time
• C3
• Scintigraphy
• Sialochemistry

The following were designated as "Additional data required" and were voted for by 6% or fewer of the participants:

• Sleep disturbance
• Labial salivary gland biopsy
• Individual gland salivary fluid
• Corneal Sensitivity
• Impression cytology
• Tear chemistry
• Lower urinary tract symptoms

More than 90% of the participants voted in favor of the listed items as a whole for each of the three categories.

During the deliberations, the participants strongly emphasized that the outcome measures selected should serve to enhance further data collection on relevant outcomes in clinical trials of SS. It was clear that a great deal of information existed in some areas relevant to SS outcomes, for example many studies on outcome measures pertaining to dry eyes, which could not adequately be presented during the time available at the workshop. In other areas, there was not enough information available to determine whether certain outcomes could be useful or should be excluded.

The participants were diverse and included ophthalmologists, dentists, rheumatologists, statisticians, basic scientists and clinicians. They expressed concerns that voting in specialized areas beyond their own expertise might be invalid. Therefore, the participants recommended that working groups in ophthalmology, dentistry, rheumatology and other areas be set up to advise which would be the most valid and useful measures in those fields. Also, they recommended that the measures chosen should, as far as possible, be used in all future clinical trials in SS to allow further the development of outcome measures for Sjögren’s syndrome.

Workshop Chairs
Dr. Stanley Pillemer, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, Maryland
Dr. Simon Bowman, University of Birmingham, Birmingham, United Kingdom

Participants

• Elaine Alexander, MD, PhD
  Consultant, Arena Pharmaceuticals, Inc
  San Diego, California
• Karsten Asmussen, MD, PhD
  Department of Rheumatology, Rikshospitalet
  Copenhagen, Denmark
• Jane Atkinson, DDS
  Dean of Clinical Affairs, University of Maryland
  Baltimore, Maryland
• Bruce J. Baum, Chief, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH
  Bethesda, Maryland
• Arthur Bookman, MD, FRCP(C)
  Division of Rheumatology, Western Hospital
  Toronto, Canada
• Steven Carsons, MD, Division of Rheumatology, Winthrop University Hospital
  Mineola, New York
• Troy Daniels, MS, DDS
  Dean for Academic Affairs, School of Dentistry
  San Francisco, California
• Gary Foulks, MD
  University of Pittsburgh School of Medicine, Department of Ophthalmology
  Pittsburgh, Pennsylvania
• Philip C. Fox, DDS
  Visiting Scientist, Carolinas Medical Center, President-elect Sjögren's Syndrome Foundation
  Cabin John, Maryland
• Arthur Grayzel, MD, MACR
  Mamaroneck, New York
• John Harley, MD, PhD
  Arthritis and Immunology Laboratory, Oklahoma Medical Research Foundation
  Oklahoma City, Oklahoma
• Lennart Jacobsson, MD, PhD
  Rheumatology, Lund University, Malmö University Hospital, Malmö
  Sweden
• Roland Jonsson, DMD, PhD
  Professor, Broegelmann Research Laboratory, University of Bergen
  Bergen, Norway
• Stuart Kassan, MD
  Clinical Professor of Medicine, University of Colorado Health Sciences Center
  Denver, Colorado
• Albert Kingman, PhD
  Division of Population and Health Promotion Sciences, NIDCR, NIH
  Bethesda, Maryland
• Haralampos Moutsopoulos, MD, FACP
  Dept of Pathophysiology, National University Medical School
  Athens, Greece
• Ann L. Parke, MB
  Department of Rheumatology, University of CT Health Center
  Farmington, Connecticut
• Maureen Rischmueller, MD
  Staff Consultant Rheumatologist, Rheumatology Department, The Queen Elizabeth Hospital
  Woodville Sth, Australia
• Oliver D. Schein, MD, MPH
  Wilmer Opthalmological Institute, Johns Hopkins Hospital
  Baltimore, Maryland
• Janine Smith, MD
  National Eye Institute, NIH
  Bethesda, Maryland
• Nehad Solomon, MD
  Division of Rheumatology, Winthrop University Hospital
  Mineola, New York
• Elke Theander, MD
  Rheumatology, Lund University, Malmö University Hospital
  Malmö, Sweden
• Susan Vitale, PhD
  National Eye Institute
  Bethesda, Maryland
• Claudio Vitali, MD
  Chief, Dept of Internal Medicine and Rheumatology, Ospedale 'Villamarina' — Piombino
  Livorno, Italy
• Frederick Vivino, MD
  The Penn Center for Primary Care, Presbyterian Medical Center
  Philadelphia, Pennsylvania

Workshop Sponsors

• The Sjögren's Syndrome Foundation
• the National Institute of Dental and Craniofacial Research
• the National Eye Institute
• the Office of Research on Women’s Health
• Allergan, Inc.
• Daiichi Pharmaceutical Corporation
• MGI Pharma, Inc.

Additional Bibliography
The full Outcomes Measures Workshop article can be found through The Journal of Rheumatology.

Simon Bowman, Anthony Bron & Angus Warwick Turner

Overview
Vitali C (editor). Proceedings from the Workshop on Diagnostic Criteria for Sjögren's Syndrome. Clin Exp Rheumatol 1989;7 Suppl:111-218.

Asmussen K, Anderson V, Bendixen G, Bendtzen K, Prause JU, Thorn J, Wiik, Oxholm P. Quantitative assessment of clinical disease status in primary Sjögren's syndrome. Scand J Rheumatol 1997;26:197-205.

Additional dry eye questionnaires
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McMonnies CW. Key questions in a dry eye history. J Am Optom Assoc 1986; 57:512-7.

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Schein OD, Tielsch JM, Munoz B, Bandeen-Roche K, West S. Relation between signs and symptoms of dry eye in the elderly. A population-based perspective. Ophthalmology 1997;104:1395-401.

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Doughty MJ, Fonn D, Richter D, Simpson T, Caffery B, Gordon K. A patient questionnaire approach to estimating the prevalence of dry eye symptoms in patients presenting to optometric practices across Canada. Optom Vis Sci 1997; 74:624-31.

Oden NL. Lilienfeld DE, Lemp MA, Nelson JD, Ederer F. Sensitivity and specificity of a screening questionnaire for dry eye. Adv Exp Med Biol 1998; 438:807-20.

McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998;105:1114-9.

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Vitali C et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8.

Additional dry mouth questionnaires
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Henson BS, Inglehart MR, Eisbruch A, Ship JA. Preserved salivary output and xerostomia-related quality of life in head and neck cancer patients receiving parotid-sparing radiotherapy. Oral Oncol 2001;37:84-93.

Slade GD, Spencer AJ. Development and evaluation of the Oral Health Impact Profile. Community Dent Health 1994;11:3-11.

Allen PF, McMillan AS, Walshaw D, Locker D. A comparison of the validity of generic- and disease-specific measures in the assessment of oral health-related quality of life. Community Dent Oral Epidemiol 1999;27:344-52.

Allen PF, McMillan AS, Locker D. An assessment of sensitivity to change of the Oral Health Impact Profile in a clinical trial. Community Dent Oral Epidemiol 2001; 29:175-82.

Field EA, Rostron JL, Longman LP, Bowman SJ, Lowe D, Rogers SN. The development and initial validation of the Liverpool sicca index to assess symptoms and dysfunction in patients with primary Sjögren’s syndrome. Oral Pathol Med 2003;32:154-162.

Ocular staining scales
Van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol 1969 Jul;82(1):10-4.

Elke Theander & Lennart Jacobsson

Barendregt PJ, Tulen JHM, van den Meiracker AH, Markusse HM. Spectral analysis of heart rate and blood pressure variability in primary Sjögren's syndrome. Ann Rheum Dis 2002;61:232-6.

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Barendregt PJ, Visser MRM, Smets EMA, Tulen JHM, van den Meiracker AH, Boomsma F, et al. Fatigue in primary Sjögren´s syndrome. Ann Rheum Dis 1998;57:291-95.

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Strömbeck B, Ekdahl C, Manthorpe R, Wikström I, Jacobsson LT. Health-related quality of life in primary Sjögren's syndrome, rheumatoid arthritis and fibromyalgia compared to normal population data using SF-36. Scand J Rheumatol 2000;29:20-8.

Tensing EK, Solovieva SA, Tervahartiala T, Nordström TC, Laine M, Niissalo S, et al. Fatigue and health profile in sicca syndrome of Sjögren's and non-Sjögren's syndrome origin. Clin Exp Rheum 2001;19:313-6.

Steinfeld SD, Demols P, Salmon I, Kiss R, Appelboom T. Infliximab in patients with primary Sjogren's syndrome: a pilot study. Arthritis Rheum 2001;44:2371-5.

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Schwartz JE, Jandorf L, & Krupp L.B. The measurement of fatigue: a new instrument. J Psychosomatic Res 1993;37:753-762.

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Jane Atkinson & Janine Smith

Grisius MM, Bermudez DK, Fox PC. Salivary and serum interleukin 6 in primary Sjogren's syndrome. J Rheumatol 1997;24:1089-91.

Prause JU, Frost-Larsen K, Hoj L, Isager H, Manthorpe R. Lacrimal and salivary secretion in Sjogren's syndrome: the effect of systemic treatment with bromhexine. Acta Ophthalmol (Copenh) 1984;62:489-97.

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George Hermann & Frederick Vivino

Schall GL, Anderson LG, Wolf RO, et al. Xerostomia in Sjögren’s syndrome: Evaluation by sequential salivary scintigraphy. JAMA 1971;216:2109-2116.

Hermann GA, Vivino FB, Shnier D, et al. Variability of quantitative scintigraphic salivary indices in normal subjects. J Nucl Med 1998;39:1260-1263.

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Haralampos Moutsopoulos

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