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Letters
Validity of the Scleroderma Functional Assessment Questionnaire To the Editor: The Scleroderma Functional Assessment Questionnaire (SFAQ) is a relatively new self-report of functional ability designed specifically for persons with scleroderma1. The authors state that the Health Assessment Questionnaire (HAQ)2, which has traditionally been used to measure function, includes items that are not considered major problems in persons with scleroderma. The 11 item assessment comprises 9 questions regarding upper extremity function and 2 questions regarding muscle weakness. Items are scored on a 4 point scale from 0 (able to perform in a normal matter) to 3 (impossible to perform) and are summed to get a total score ranging from 0 to 33. Kappa scores for test-retest reliability ranged from 0.69 to 0.94, indicating good agreement. Validity was established by comparing subjects' and therapists' scores, which yielded kappa scores from 0.19 to 0.60, which constitutes only fair agreement.1 However, the authors argue that there is no gold standard, as therapists' perceptions of disability are not more or less valid than subjects' self-reports. Thus, we compared the SFAQ with performance tests and other self-reports that have been shown to be reliable and valid in persons with scleroderma. Thirty-four women who fulfilled the American College of Rheumatology criteria for systemic sclerosis (scleroderma)3 were enlisted as a convenience sample. Ages of participants ranged from 26 to 74 years (mean 53.8 yrs). Disease duration ranged from 3 months to 33 years (mean 10.6 yrs). There were 18 participants with limited scleroderma (lSSc) and 16 with diffuse scleroderma (dSSc). Thirty participants were right handed, while 4 were left handed. Participants were administered these assessments in the following order: the SFAQ, the Hand Functional Disability Scale (HFDS)4, the Arthritis Hand Function Test (AHFT)5, the HAQ2, the Keitel Functional Test (KFT)6, the Hand Mobility Test in Scleroderma (HAMIS)7, and skin scores8. The HFDS is a self-report consisting of 18 items regarding hand ability in 5 categories: kitchen, dressing, hygiene, office, and other. Subjects rate their ability from 0 (no difficulty) to 5 (impossible to do)4. The AHFT is an 11 item performance-based test that measures grip and pinch strength, dexterity, applied strength and applied dexterity5. The HAQ is a self-report that consists of 8 categories of daily living (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and outside activity)2. Items are scored from 0 (can perform) to 3 (cannot manage). The HAMIS is a 9 item hand function test developed specifically for persons with scleroderma to measure range of motion movements7-11. The hand items from the KFT were used to measure joint motion6. The items are scored according to specific criteria, yielding a total score of 21 for each upper hand. Reliability and concurrent validity have been established for the HFDS (unpublished data), AHFT12, HAQ9,10, and the HAMIS7,11 and in persons with scleroderma. Skin thickness of the forearm, hand, and fingers was palpated and rated on a scale from 0 (normal) to 3 (severe skin thickness) to measure disease activity8. Table 1 shows descriptive data for the 34 subjects on the SFAQ, HFDS, AHFT, HAQ, KFT, HAMIS, and skin scores. There was no significant difference in scores for any of the variables between the subtypes of scleroderma. Spearman's rho correlation coefficients were calculated to estimate the concurrent validity of the SFAQ with scores on the HFDS, AHFT, HAQ, KFT, HAMIS, and skin scores. Table 2 shows the SFAQ correlated significantly with the HFDS, AHFT, HAQ, and the KFT.
Our results support the use of a self-report questionnaire, the SFAQ, with persons who have scleroderma. The study provides further support for the concurrent validity of the SFAQ. The SFAQ correlated strongly with the other 2 self-report instruments, as would be expected. As well, 3 of the items on the SFAQ are also on the HAQ and HFDS. Scores also correlated with the AHFT; however, the correlations were weaker. No correlation was found between the SFAQ and skin scores, in agreement with other studies9. Yet skin scores have been the traditional outcome used in clinical trials and intervention studies13. Interestingly, while the SFAQ correlated with the KFT, the SFAQ did not correlate with the HAMIS. While both of these assessments measure similar joint motions, the KFT consists of 4 items measuring finger flexion, while the HAMIS has only one. However, the HAMIS additionally measures finger extension, and thumb and finger abduction. Perhaps these latter motions are not as important for actual hand function as finger flexion. In conclusion, clinicians need reliable and valid measures to evaluate the effectiveness of interventions. The SFAQ is simple and quick to administer and has the potential to be useful as an outcome measure of hand function in clinical trials and other intervention studies. JANET L. POOLE, PhD, OTR/L; LISA BROWER, MOT Student, Occupational Therapy Graduate Program, Department of Orthopaedics and Rehabilitation, 1 University of New Mexico, MSC09, Albuquerque, New Mexico 87131-001, USA. REFERENCES 1. Silman A, Akesson A, Newman J, et al. Assessment of functional ability in patients with scleroderma: A proposed new disability assessment instrument. J Rheumatol 1988;25:79-83. 2. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcomes in arthritis. Arthritis Rheum 1980;23:137-45. 3. LeRoy EC, Black C, Fleishmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202-5. 4. Duruoz MT, Poiraudeau S, Fermanian J, et al. Development and validation of a rheumatoid hand functional disability scale that assesses functional handicap. J Rheumatol 1996;23:1167-72. 5. Backman C, Mackie H. Arthritis Hand Function Test manual. Vancouver: University of British Columbia; 1997. 6. Eberl DR, Fasching VV, Rahlfs V, Schleyer I, Wolf R. Repeatability and objectivity of various measurements in rheumatoid arthritis: A comparative study. Arthritis Rheum 1976;19:1278-86. 7. Sandqvist G, Eklund M. Hand Mobility in Scleroderma (HAMIS) Test: The reliability of a novel hand function test. Arthritis Care Res 2000;13:369-74. 8. Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P. Skin thickness score in systemic sclerosis: An assessment of interobserver variability in 3 independent studies. J Rheumatol 1996;20:1892-6. 9. Poole JL, Steen V. The use of the Health Assessment Questionnaire to determine physical disability in systemic sclerosis. Arthritis Care Res 1991;4:27-31. 10. Poole JL, Williams CA, Bloch DA, Hollack B, Spitz P. Concurrent validity of the Health Assessment Questionnaire in scleroderma. Arthritis Care Res 1995;8:189-93. 11. Sandqvist G, Eklund M. Validity of HAMIS: A test of hand mobility in scleroderma. Arthritis Care Res 2000;13:382-7. 12. Brower LM, Poole JL. Reliability and validity of the Hand Function Disability scale in persons with systemic sclerosis (scleroderma). Arthritis Care Res 13. Poole JL, Gallegos M, O'Linc S. Reliability and validity of the Arthritis Hand Function Test in adults with systemic sclerosis (scleroderma). Arthritis Care Res 2000;13:69-73. 14. Clements PJ, Furst DE, Seibold JR, Lachenbruch PA. Controlled trials: Trial design issues. In: Clements PJ, Furst DE, editors. Systemic sclerosis. Baltimore: Williams & Wilkins; 1995:515-33.
Lack of Association Between ICAM-1 Gene Polymorphisms and Biopsy-Proven Erythema Nodosum To the Editor: Erythema nodosum (EN) is a self-limiting hypersensitivity reaction characterized by multiple and bilateral inflammatory nodules. It may be idiopathic or associated with drugs, several infections, and systemic diseases1. The intercellular adhesion molecule (ICAM-1) is a member of the immunoglobulin superfamily and plays an important role in endothelial cell-leukocyte interactions during inflammation2. It contributes to the adhesion and transmigration of most leukocyte types including neutrophils, monocytes, lymphocytes, and natural killer cells through an interaction with ß2 integrins3. Expression of ICAM-1 on endothelium is induced by inflammatory mediators, which include lipopolysaccharide and cytokines. Two coding region polymorphisms have been identified for ICAM-1 -- Gly (G) or Arg (R) at codon 241 (exon 4) and Lys (K) or Glu (E) at codon 469 (exon 6)4. The functional significance of the 469 polymorphism is unknown, although it could potentially lead to alterations in binding and/or costimulatory activity of the ICAM-1 molecule. Similarly, the functional influence of the R/G polymorphism at codon 241 remains unclear, although this region (in exon 4) is in the functionally important domain III of ICAM-1 that contains the binding site for the leukocyte integrin, Mac-14. ICAM-1 gene polymorphisms have been reported to be important candidate susceptibility factors for multifactorial diseases with an inflammatory component. Given the inflammatory effect of EN, we assessed the implication of ICAM-1 polymorphisms in this condition. All patients (n = 101, ages 1578 yrs) in our study were diagnosed with biopsy-proven EN in close collaboration between the rheumatology and dermatology divisions of the Hospital Xeral-Calde in Lugo, Spain. Thirty-six were diagnosed as having idiopathic EN and the remaining 65 as secondary EN (31 of them had EN in the setting of sarcoidosis). Controls (n = 129) were also from Lugo. DNA from patients and controls was extracted from anticoagulated blood collected in EDTA using a commercial DNA extraction kit (BiolineTM, London, UK). Molecular analysis of ICAM-1: as reported5, amino acid polymorphisms, substitution of R for G at codon 241, and substitution of K for E at codon 469 were examined by polymerase chain reaction restriction fragment length polymorphism. Associations between patient groups and controls and alleles or genotypes of ICAM-1 polymorphisms were estimated using odds ratios (OR) and 95% confidence intervals (CI). Levels of significance were determined by either chi-square or Fisher exact analysis. Statistical significance was defined as p < 0.05. Power calculation was performed for an unmatched case-control study and estimated relative risk using EpiInfo 2000, v. 1.1.2 software. We found that in the control group, allele and genotype frequencies for ICAM-1 polymorphisms were in Hardy-Weinberg equilibrium; the chi-square data for the observed versus estimated expected genotype for ICAM-1 codon 241 and codon 469 in the control group were 1.9, p = 0.3, and 0.9, p = 0.6, respectively. No differences between the whole group of patients with biopsy-proven EN and controls were observed for either polymorphism. This was also the result when patients with idiopathic and secondary EN were compared (Table 1). Similarly, no differences between patients with EN associated with sarcoidosis and the remaining group of EN secondary to other etiologies were found (Table 2). A small increase was observed in the frequency of R/G heterozygous for ICAM-1 (241 R/G) polymorphism in patients with EN associated with sarcoidosis compared to the controls (23% versus 13%) (p = 0.2, OR 1.9, 95% CI 0.75.1). Given the sample sizes and the allele frequencies of these polymorphisms, we can exclude with 80% certainty a genetic relative risk of 2.7 for ICAM-1 polymorphism at codon 241 and a genetic relative risk of 3.0 at codon 469 for sarcoidosis in Lugo.
ICAM-1 polymorphisms have been investigated in several diseases where diverse genetic and environmental factors are implicated in the development of an inflammatory response. Patients with ulcerative colitis who were antinuclear cytoplasmic antibody-negative had a significantly increased frequency of allele R241 compared with antibody-positive patients6. In patients with multiple sclerosis a significantly higher frequency of the exon 6 homozygote K469 genotype was found compared to controls7. This was independent of the association attributed to HLA-DR27. In renal transplant recipients allograft failure was associated with R at codon 241, and a more rapid failure of the allograft in the presence of E at codon 469 was also found8. ICAM-1 gene polymorphisms have also been implicated in the pathogenesis of some systemic vasculitides such as in Behçet's disease and giant cell arteritis9,10. Our analysis constitutes the first attempt to assess the influence of ICAM-1 polymorphisms in a large series of biopsy-proven EN. Given the sample sizes and the allele frequencies of these polymorphisms, we can exclude a genetic relative risk of those ICAM-1 polymorphisms for EN in Northwest Spain. However, interpretation of these results could to some extent be limited because EN is a very heterogeneous entity.
MAHSA M. AMOLI, MD, PhD; WILLIAM E.R. OLLIER, PhD, FRCPath, Centre for Integrated Genomic Medical Research, School of Epidemiology and Health Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK; MERCEDES LUEIRO, MD; MARIA L. FERNANDEZ, MD, Dermatology Division; CARLOS GARCIA-PORRUA, MD, PhD; MIGUEL A. GONZALEZ-GAY, MD, PhD; Rheumatology Division, Hospital Xeral-Calde, c) Dr. Ochoa s/n 27004, Lugo, Spain.
REFERENCES 1. Gonzalez-Gay MA, Garcia-Porrua C, Pujol RM, Salvarani C. Erythema nodosum: a clinical approach. Clin Exp Rheumatol 2001;19:365-8. 2. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301-14. 3. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 1993;11:767-804. 4. Vora DK, Rosenbloom CL, Beaudet AL, Cottingham RW. Polymorphisms and linkage analysis for ICAM-1 and the selectin gene cluster. Genomics 1994;21:473-7. 5. Amoli MM, Shelley E, Mattey DL, et al. Lack of association between ICAM-1 gene polymorphisms and giant cell arteritis. J Rheumatol 2001;28:1600-4. 6. Yang H, Vora DK, Targan SR, Toyoda H, Beaudet AL, Rotter JI. Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease. Gastroenterology 1995;109:440-8. 7. Mycko MP, Kwinkowski M, Tronczynska E, Szymanska B, Selmaj KW. Multiple sclerosis: the increased frequency of the ICAM-1 exon 6 gene point mutation genetic type K469. Ann Neurol 1998;44:70-5. 8. McLaren AJ, Marshall SE, Haldar NA, et al. Adhesion molecule polymorphisms in chronic renal allograft failure. Kidney Int 1999;55:1977-82. 9. Verity DH, Vaughan RW, Kondeatis E, et al. Intercellular adhesion molecule-1 gene polymorphisms in Behcet's disease. Eur J Immunogenet 2000;27:73-6. 10. Salvarani C, Casali B, Boiardi L, et al. Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity. J Rheumatol 2000;27:1215-21. |
