Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders.код для вставкиСкачать
183 DIAGNOSTIC POTENTIAL OF IN VIVO CAPILLARY MICROSCOPY IN SCLERODERMA AND RELATED DISORDERS H. R. MARICQ, E. C. LeROY, W. A. D’ANGELO, T. A. MEDSGER, Jr., G. P. RODNAN, G. C. SHARP, and J. F. WOLFE The prevalence of scleroderma-type capillary abnormalities, as observed by in vivo microscopy, was determined in 173 patients from three rheumatic disease centers. The patients had a variety of connective tissue diseases: scleroderma (systemic sclerosis) 50; systemic lupus erythematosus 60,mixed connective tissue disease 26; Raynaud’s disease 11; other rheumatic disorders 26. Enlarged and deformed capillary loops surrounded by relatively avascular areas, most prominently in the nailfolds, were found in 82%of patients with scleroderma and in 54% with mixed connective tissue disease. The rarity of these abnormalities in systemic lupus erythematosus (2%)despite the presence of Raynaud’s phenomenon suggests that they are not an expression of the Raynaud’s phenomenon frequently associated with scleroderma and mixed connective tissue disease. The single patient with Raynaud’s disease and sclerodermatype capillary changes subsequently developed scleroderma. Supported in part by grants from the National Institutes of Health (AM20571), the State of South Carolina, the RGK Foundation, the Charlotte and Sidney Lifschultz Foundation, the South Carolina Chapter of the Arthritis Foundation, the Lupus Foundation, and the National Institutes of Health Biomedical Research Grant (RR05420) to the Medical University of South Carolina. H. R. Maricq, MD: Medical University of South Carolina; E. C. LeRoy, MD: Medical University of South Carolina; W. M. D’Angelo, MD: State University of New York at Stony Brook; T. A. Medsger, Jr., MD: University of Pittsburgh School of Medicine; G. P. Rodnan, MD: University of Pittsburgh School of Medicine; G. C. Sharp, MD: University of Missouri School of Medicine, Columbia; J. F. Wolfe, MD: University of Missouri School of Medicine. Address reprint requests to H. R. Maricq, MD, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29403. Submitted for publication August 15, 1979; accepted in revised form October 10, 1979. Arthritis and Rheumatism, Vol. 23, No. 2 (February 1980) Although the diagnosis of scleroderma (systemic sclerosis) presents no problem once the full clinical picture of hidebound skin has developed, there is no single symptom, sign, or laboratory test that is pathognomonic in the early stages of the disease. An early diagnostic test is needed to study pathogenetic mechanisms in incipient scleroderma before these become obscured by the fibrotic process. Raynaud’s phenomenon and involvement of skin (scleroderma) usually precede clinically apparent visceral disease (systemic sclerosis) but, unfortunately, the skin biopsy is generally of little or no assistance in early diagnosis (1). Moreover, by the time the most characteristic histopathologic changes are found (e.g. in the kidney) the patient is already seriously and often terminally ill (2). In previous studies utilizing in vivo microscopy we have observed a characteristic pattern of skin capillary abnormalities in 86% of patients with scleroderma (3,4). The present study was designed to determine the usefulness of skin capillary abnormalities in distinguishing scleroderma from other connective tissue diseases, i.e. the specificity of “scleroderma pattern” capillary abnormalities previously described (5). To obtain a large sample of patients with connective tissue disease in a short period of time and to compare our earlier findings on a cross-section of patients diagnosed by physicians with various backgrounds and locales (with possibly different patient populations and diagnostic habits), a field study was carried out. MATERIALS AND METHODS Subjects. One hundred seventy-three patients were examined at the following Arthritis Centers: the University of Pittsburgh, Pittsburgh, Pennsylvania (65), the Catholic Medi- 184 MARICQ ET AL Table 1. Disease duration: From first symptoms Median Scleroderma Systemic lupus erythematosus Mixed connective tissue disease Raynaud’s disease Range From diagnosis Median Range 9.2 0.8-36 4.3 0.1-23 8.5 1-40 5.5 0.2-39 5.7 4.3 0.6-17 1-32 3.5 1.0 0.1-8 0.417 In years. cal Affiliation, Queens General Hospital, New York City, (89), and the University of Missouri, Columbia, Missouri (19). Patients were categorized according to the clinical diagnosis provided by the center physicians, all experienced in their field, without knowledge of the capillary studies. The following diagnostic groups were represented: 1) scleroderma: 50 patients; 45 women and 5 men, 2) systemic lupus erythematosus: 60 patients; 58 women and 2 men, 3) mixed connective tissue disease: 26 patients; 24 women and 2 men, 4) Raynaud‘s disease: 11 patients; 10 women and 1 man, and 5) a variety of other rheumatic diseases (26 patients including 8 with polymyositis, 2 with dermatomyositis, 2 with discoid lupus erythematosus, 2 with rheumatoid arthritis, 2 with ankylosing spondylitis, 3 with scleroderma-polymyositis overlap, 2 with systemic lupus erythematosus--mixed connective tissue disease overlap, 3 with probable systemic lupus erythematosus, 1 with possible scleroderma, and 1 with scleredema). Only the results of patients in the first four groups were used for statistical analysis (n = 147). The ages of these patients were as follows: scleroderma: range 27-78, mean 52 years; systemic lupus erythematosus: range 17-64, mean 41 years; mixed connective tissue disease: range 17-55, mean 40 years; and Raynaud‘s disease: range 23-69, mean 42 years. The disease duration is shown in Table 1. Techniques. Observations and photography of skin capillaries were performed by in vivo widefield capillaroscopic technique on all patients as previously described (6,7). The following sites were examined: nailfold and dorsum of the distal phalanx of at least 4 fingers, dorsum of the middle phalanx, dorsum of the proximal interphalangeal joint and of the fingerpad of at least 2 fingers. All capillary observations were performed by the senior author (HRM) during the field trips undertaken with technical support and portable equipment. A minimum of two photomicrographs was obtained from each patient and coded for “blind” analysis. Capillary pattern analysis was performed by the senior author (HRM), after the field trips, from coded observation notes and coded photographs; the results were then combined for final ratings of subjects. Our previous experience has shown an excellent correlation (P < 0.0005) between results based on direct observations and those based on coded photographic data on the same subjects rated “blindly” by an independent investigator (4). This study was focused primarily on estimating the prevalence of the scleroderma-pattern capillary abnormalities which consist of enlarged and deformed capillary loops often surrounded by relatively avascular areas especially visible in the nailfold capillary bed. Figures 1 through 4 illustrate typical scleroderma-pattern abnormalities in the nailfold. In addition, other microvascular abnormalities were noted when encountered, i.e. patterns not seen in our previous experience with over 800 healthy control subjects (8). Figure 1. Nailfold capillaries in an average subject (normal pattern) CAPILLARY MICROSCOPY IN SCLERODERMA Figure 2. Large dilated capillaries at the edge of the nailfold (scleroderma pattern). Figure 3. Dilated capillaries contrasting with adjacent avascular areas (scleroderma pattern). 185 MARICQ ET AL 186 Figure 4. Extensive loss of capillaries combined with dilatation of some capillary loops (scleroderma pattern). RESULTS Distribution of capillary pattern abnormalities. The prevalence of scleroderma-pattern capillary abnormalities in the four diagnostic groups is shown in Figure 5. The number of patients with scleroderma pattern in each group was as follows: scleroderma 41 (82%); systemic lupus erythematosus 1 (2%); mixed connective tissue disease 14 (54%); and Raynaud’s disease 1 (9%). Three of the 26 patients with the rheumatic disorders listed in the Materials and Methods section showed the scleroderma-pattern capillary abnormalities. Their diagnoses were ( 1 each): dermatomyositis, polymyositis, and the systemic lupus erythematosus-mixed connective tissue disease overlap. Tortuous capillaries, some resembling the “meandering” capillary loops described by Redisch et a1 (9), were noted in 25 patients with systemic lupus erythematosus (42%), 3 patients with scleroderma (6%), 3 patients with mixed connective tissue disease (12%), and 4 patients with Raynaud’s disease (36%). Two additional patients with mixed connective tissue disease displayed both a scleroderma pattern and tortuous capillaries. (They were already included among the 14 with scleroderma pattern reported above.) Nonspecific mi- crovascular changes were present in 17 patients with systemic lupus erythematosus (28%), 4 patients with scleroderma (8%), 3 with mixed connective tissue disease (12%), and 2 with Raynaud’s disease (18%). Many individuals with systemic lupus erythematosus (17,28%) and Raynaud’s disease (4,36%) showed no capillary ab- SD MCTD RD SLE Figure 5. Prevalence of scleroderma-pattern capillary abnormalities in different diagnostic groups: scleroderma (SD), mixed connective tissue disease (MCTD), Raynaud‘s disease (RD), and systemic lupus erythematosus (SLE). CAPILLARY MICROSCOPY IN SCLERODERMA 8o I 187 N=60 N=SO SD PATTERN SPEC CAP ABN Figure 6. Capillary observations in scleroderma. N O N SPEC = nonspecific; TORT CAP = tortuous capillaries; N O ABN = no abnormalities. normalities, as did 6 patients with mixed connective tissue disease (23%) but only 2 with scleroderma (4%). The distribution of different capillary patterns in the several diagnostic groups is shown in Figures 6 through 8. This distribution is significantly different from that expected by chance ($dfg = 87.67; P < 0.001). Correlation of capillaroscopic findings with Raynaud’s phenomenon. The presence of Raynaud’s phenomenon was reported in 46 patients with scleroderma (92%), 37 patients with systemic lupus erythematosus (62%), and all patients with Raynaud’s disease and mixed connective tissue disease. Only one systemic lupus erythematosus patient with Raynaud’s phenomenon showed scleroderma-pattern capillary abnormalities. Correlation of capillary observations and disease activity. Information on disease activity was available for a limited number of study patients with mixed con*O Lu L N=26 t t PATTERN NON SPEC TORT CAP NO ABN Figure 8. Capillary observations in systemic lupus erythematosus. S D = scleroderma; NON SPEC = nonspecific; TORT CAP = tortuous capillaries; N O ABN = no abnormalities. nective tissue disease. Although a possible correlation between active disease (greater number of organs involved, more scleroderma features, higher requirements for corticosteroids and/or cyclophosphamide) and pronounced capillary abnormalities (combined with loss of capillary loops) was suggested by the data, the small number of cases did not allow reliable statistical analysis of this association. A followup from one clinic revealed that the single patient in the Raynaud’s disease group with scleroderma-type capillary abnormalities was found to have scleroderma 5 months after capillary examination. Another patient with apparently mild mixed connective tissue disease at the time she was studied was found to have pronounced scleroderma-type capillary abnormalities. She died the following year with severe proliferative obliterative vascular disease involving particularly the pulmonary and renal vasculature. There was no correlation between the duration of the disease (from first symptoms or from diagnosis) and the scleroderma-pattern capillary abnormalities in patients with scleroderma and mixed connective tissue disease. 401-LL DISCUSSION 20 SD PATTERN NON SPEC TORT CAP SD TORT NO ABN Figure 7. Capillary observations in mixed connective tissue disease. S D = scleroderma; N O N SPEC = non specific; TORT CAP = tortuous capillaries; N O ABN = no abnormalities. The results of this study confirm our earlier findings that a characteristic pattern of capillary abnormalities occurs in over 80% of patients with scleroderma (35). The same pattern is also seen in related disorders such as Raynaud’s disease, mixed connective tissue disease, and dermatomyositis but rarely in systemic lupus erythematosus (only 1 of 60 patients in this study). The presence of this pattern in some Raynaud’s disease patients is not surprising, since a proportion of them even- 188 tually develop scleroderma. Thus, the scleroderma-type capillary abnormalities may be of diagnostic or prognostic value in Prescleroderma RaYnaud’s syndrome: i.e. in patients with Raynaud’s syndrome who are destined to develop scleroderma but who have not yet developed typical skin changes. This hypothesis is supported by the change in diagnosis of the Raynaud’s disease patient with scleroderma-pattern capillary abnormalities and by our own experience with Raynaud‘s disease patients (10). Scleroderma-pattern capillary abnormalities were present in about half the patients with mixed connective tissue disease; this half tended to have more active disease, more organ involvement, more scleroderma features, and higher requirements for corticosteroids and/or cyclophosphamide to control the disease than those without scleroderma-pattern. Since followup reports of mixed connective tissue disease patients have shown a number of patients whose subsequent manifestations are mainly those of scleroderma, it is probable that the scleroderma-pattern capillary abnormalities indicate such a prognosis in this group of patients. The proportion of scleroderma-pattern capillary abnormalities found in mixed connective tissue disease patients in the present study is similar to the clinical impression at 5 years after the initial diagnosis of mixed connective tissue disease (1 1,12). In our earlier studies (3-6) most patients with dermatomyositis had nailfold capillary findings indistinguishable from the scleroderma-pattern, an observation also noted in the present study (1 of 2 patients with dermatomyositis showed such a change). A close relationship between scleroderma and dermatomyositis has been recognized for many years (13) and it is known that distribution and morphology of the visceral vascular lesions are often strikingly similar in these disorders (14). Thus it appears that the scleroderma-pattern capillary abnormalities may be characteristic of “scleroderma spectrum disorders,” including classic scleroderma, prescleroderma Raynaud’s disease, mixed connective tissue disease destined to become seleroderma, and dermatomyositis which may share common pathogenetic mechanisms but have different clinical expressions due to other as yet undetermined factors. At present the single specific indicator of scleroderma is (15,16) proximal skin involvement, a relatively late feature; capillary microscopy is proposed as a simple, practical procedure useful in early recognition of this disease, and of prognostic value. MARICQ ET AL ACKNOWLEDGMENTS The technical assistance of Joyce Hardin, Mary Pennington, Maureen Pupillo, and Vasu Nair is hereby gratefully acknowledged. REFERENCES 1. Jablonska S: Histopathology of scleroderma. Scleroderma and Pseudoscleroderma. Edited by S Jablonska. Warsaw, Polish Medical Publishers, 1975, pp 191-233 2. Cannon PJ, Hassar M, Case DB, Casarella WJ, Sommers SC, LeRoy EC: The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine 53:1 4 6 , 1974 3. Maricq HR, LeRoy EC: Patterns of finger capillary abnormalities in connective tissue disease by “wide-field” microscopy. Arthritis Rheum 16:619-628, 1973 4. Maricq HR, Spencer-Green G, LeRoy EC: Skin capillary abnormalities as indicators of organ involvement in scleroderma (systemic sclerosis), Raynaud‘s syndrome, and dermatomyositis. Am J Med 615362-870, 1976 5. Maricq HR, Gordon G, LeRoy EC: Studies in patients with connective tissue disorders, Ninth European Conference on Microcirculation, Antwerp, 1976. Bibl Anat 16:135-141, 1977 6. Maricq HR, Blume RS, LeRoy EC: Wide-field study of nailfold capillary bed in disorders of connective tissue. Sixth European Conference on Microcirculation, Aalborg, 1970. 1971, pp 116-122 7. Maricq HR: “Wide-field” photography of nailfold capillary bed and a scale of plexus visualization scores (PVS). Microvasc Res 2:335-340, 1970 8. Maricq HR: Variations in the skin microvascular patterns of the hand, Ninth European Conference on Microcirculation, Antwerp, 1976. Bibl Anat 16:164169, 1977 9. Redisch W, Messina EJ, Hughes G, McEwan C: Capillaroscopic observations in rheumatic diseases. Ann Rheum Dis 29:44253, 1970 10. Maricq HR, Weinberger AB, LeRoy EC: Early detection of scleroderma by in vivo capillary microscopy. In preparation 11. Bennett RM, OConnell DJ: The arthritis of mixed connective tissue disease. Ann Rheum Dis 37:397403, 1978 12. Bennett RM, Bong DM, Spargo BH: Neuropsychiatric problems in mixed connective tissue disease. Am J Med 65:955-962, 1978 13. Lewis T: Notes on scleroderma (dermatornyositis). Br J Dermatol 52:233-242, 1940 14. Banker BQ, Victor M: Dermatomyositis (systemic angiopathy) of childhood. Medicine 45:26 1-289, 1966 CAPILLARY MICROSCOPY IN SCLERODERMA 15. Masi AT, Rodnan GP, Medsger TA Jr, Fries JF, Altman RD, McShane DJ, Sharp GC, Mackenzie AH, LeRoy EC, Brown BW Jr, D’Angelo WA: Clinical criteria for early diagnosed systemic sclerosis: preliminary results of the ARA Multicenter Cooperative Study. Arthritis Rheum 21576-577. 1978 189 16. Masi AT, Medsger TA Jr, Rodnan GP, Fries JF, Altman RD, Brown BW, DAngelo WA, LeRoy EC, Mackenzie AH, McShane DJ, Sharp GC: Methodology and preliminary results of the scleroderma criteria cooperative study of the American Rheumatism Association. In preparation Thirty-Third Annual Stoneburner Lecture Series The Medical College of Virginia, Department of Continuing Medical Education and the Division of Immunology and Connective Tissue Diseases will sponsor the 33rd Annual Stoneburner Lecture Series, “Immunology and Immune Complexes,” April 11 and 12, 1980 in the Baruch Auditorium of the Medical College of Virginia in Richmond. This is approved for 13 AMA Category I credit hours. For further information contact Kathy E. Johnson, Department of Continuing Education, Box 48, MCV Station, Richmond VA 23298. Telephone: 804 786-0494.