The relation between periungual erythema and nailfold capillary abnormalities in patients with connective tissue diseases

ARTICLE

It is well known that nailfold capillary microscopy is useful for detecting connective tissue diseases, mainly scleroderma, and other diseases and/or conditions such as dermatomyositis/polymyositis, mixed connective tissue disease and Raynaud's phenomenon [1, 2]. In addition, the nailfold is known to show periungual erythema [3]. There has been, however, no report which has studied the relationship between nailfold capillary abnormalities and periungual erythema. The aim of the present study was to gain a better insight into the relationship between the two findings.

Materials and methods

Subjects

The subjects studied were as follows: 60 normal controls (male:female = 30:30, age 13-84 years, mean 49.7 years), 55 scleroderma patients (male:female = 6:49, age 24-71 years, mean 51.5 years), 18 patients with mixed connective tissue disease (male:female = 1:17, age 28-62 years, mean 46.2 years), 19 patients with dermatomyositis/polymyositis (male:female = 7:12, age 4-77 years, mean 45.4 years), 30 patients with systemic lupus erythematosus (male:female = 6:24, age 23-63 years, mean 44.7 years), 22 patients with primary Sjögren's syndrome (male:female = 0:22, age 32-80 years, mean 52.1 years), 84 patients with unclassified connective tissue disease (male:female = 7:77, age 15-72 years, mean 49.8 years), 26 patients with primary Raynaud's phenomenon (male:female = 3:23, age 16-62 years, mean 46.8 years), 43 patients with diabetes mellitus (male:female = 20:23, age 21-83 years, mean 56.2 years) and 62 patients with psoriasis (male:female = 43:19, age 9-80 years, mean 50.5 years).

More of the normal controls had any history of disease, and physical and routine laboratory examinations were within normal limits. The patients with scleroderma met the ACR's criteria for scleroderma [4]. The patients with dermatomyositis/polymyositis, systemic lupus erythematosus, mixed connective tissue disease and primary Sjögren's syndrome met the criteria for dermatomyositis/polymyositis by Bohan [5], the revised ACR's criteria for systemic lupus erythematosus [6], those of Sharp et al. [7] and those of Daniels and Talal [8], respectively. None of the patients with Raynaud's phenomenon satisfied these criteria nor those for rheumatoid arthritis [9]. The patients with Raynaud's phenomenon were designated as unclassified connective tissue disease when they had sclerodactyly and/or a specific anti-nuclear antibody, such as anticentromere antibody or anti-nRNP antibody. Most of the patients (90.4%) showed symptoms of scleroderma, 6.0% showed symptoms of systemic lupus erythematosus, and 3.6% symptoms of dermatomyositis/polymyositis. The National Diabetes Data Group Classification served as a guideline for the diagnosis of diabetes mellitus [10]. Patients with psoriasis were characterized by the extent of affected body surface (%), PASI score based on erythema, induration, desquamation and area affected [11], nail involvement included pitting, onycholysis, hyperkeratosis, discoloration, disfigurement and hemorrhages [12].

Periungual erythema and nailfold capillary microscopy findings

Periungual erythema [3] could be observed without magnification (Fig. 1). It was seen characteristically in patients with scleroderma and with dermatomyositis/polymyositis [3]. Nailfold capillary microscopy was performed using a technique described previously [1]. In brief, the dorsum of the middle finger or, alternatively, the ring finger was placed on the microscope stage at heart level at an ambient temperature of 20-23° C. Capillary loops were observed under immersion oil at x 400 magnification with a light microscope (Kashimura, Japan) illuminated with a fiber halogen light. The photographs of capillary loops (Fig. 2) were recorded on videotape with a videocamera connected to a videotape recorder (Victor BR-2100). The videographs were quantitatively analyzed with a PC (NEC PC9801VX) and an image processor (Nippon Avionics SPICCA-2). The same four parameters were chosen as mentioned in the previous report [1] (apical limb width = ALW, capillary width = CW, root area = RA, and capillary length = CL) (Fig. 3). These four parameters showed symmetric distribution curves (Gaussian). ALW represented the capillary width at the apex. CW represented the largest loop width. The RA was measured directly with the image processor. The outer and inner lengths of a capillary loop were measured from the first visible portion of the afferent limb to the last visible portion of the efferent limb with the image processor and the mean value used as CL. There were no significant differences between the values of these parameters measured at the central and lateral parts of a finger, found in any of the various fingers examined, which indicated the reproducibility of the results.

Statistics

Statistical analysis was carried out with analysis of variance for the comparison of means, and Fisher's exact probability test for the analysis of contingency. Nailfold capillary patterns were statistically defined with canonical discriminant analysis, which is a way of weighting the information from several different sources into distinct groups [13-15]. A PC (NEC PC9801VX) and its software was used in the actual calculation [16].

Results

Distribution of periungual erythema

The frequency of periungual erythema in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, systemic lupus erythematosus, primay Sjögren's syndrome, unclassified connective tissue disease, primary Raynaud's phenomenon and diabetes mellitus was significantly higher than that found in normal controls, but that found in psoriasis was not different from that for normal controls (Table I). On the other hand, the frequency of periungual erythema in systemic lupus erythematosus, primary Sjögren's syndrome, primary Raynaud's phenomenon psoriasis and normal control was significantly lower than that for scleroderma, but the observed frequency found in mixed connective tissue disease, dermatomyositis/polymyositis, unclassified connective tissue disease and diabetes mellitus was not different from that found in scleroderma.

Measurement of nailfold capillary parameters

Apical limb width in patients with scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, primay Sjögren's syndrome and unclassified connective tissue disease was significantly greater than that found in normal controls, but this parameter found in systemic lupus erythematosus, primary Raynaud's phenomenon, diabetes mellitus and psoriasis was not significantly different from that found in normal controls (Table II). Capillary width found in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, unclassified connective tissue disease and diabetes mellitus was significantly greater than that found in normal controls, but that found in primary Raynaud's phenomenon and psoriasis was not significantly different from that of normal controls. Root area found in patients with scleroderma, mixed connective tissue disease, dermatomyositis /polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, unclassified connective tissue disease, primary Raynaud's phenomenon and diabetes mellitus was significantly greater than that found in normal controls, but that found in psoriasis patients was significantly smaller than that of normal controls. Capillary length in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, primary Sjögren's syndrome, unclassified connective tissue disease and diabetes mellitus was significantly greater than that found in normal controls, but that found in systemic lupus erythematosus and primary Raynaud's phenomenon was not significantly different from that found in normal controls : capillary length found in psoriasis patients was significantly shorter than that found in normal controls. As a result, the subjects were divided into two groups; 1) scleroderma, mixed connective tissue disease, dermatomyositis/ polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, unclassified connective tissue disease and diabetes mellitus, 2) normal controls, primary Raynaud's phenomenon and psoriasis. Group 1 showed elevated values for more than two parameters, group 2 showed fewer than two parameters that were elevated.

Canonical discriminant analysis

There were two steps in this multivariate analysis. 1) Changes to standard distribution curves of mean = 0 and standard deviation = 1. 2) Canonical discriminant analysis [15-17].
As a result, the following equation was obtained: f < 0: normal capillary pattern, f > 0: abnormal capillary pattern, where f = ­ 1.07ALW + 2.31CW + 1.00RA ­ 1.53CL ­ 22.8. One normal control (2%), 52 cases of scleroderma (95%), 18 mixed connective tissue disease (100%), 19 dermatomyositis/polymyositis (100%), 16 systemic lupus erythematosus (53%), 10 primary Sjögren's syndrome (45%), 38 unclassified connective tissue disease (45%), primary Raynaud's phenomenon (31%), 28 diabetes mellitus (65%) and 2 psoriasis (3%) patients were defined demonstrating abnormal capillary patterns (Table III). The frequency of abnormal capillary pattern in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, unclassified connective tissue disease, primary Raynaud's phenomenon and diabetes mellitus was significantly higher than that found in normal controls.

The frequency of periungual erythema in patients with normal or abnormal capillary patterns

The frequency of periungual erythema found in patients with normal and abnormal capillary patterns was compared (Table IV). In scleroderma, unclassified connective tissue disease, primary Raynaud's phenomenon and diabetes mellitus, the frequency of periungual erythema in the subjects with an abnormal capillary pattern was significantly higher than that found in subjects with a normal capillary pattern, but in normal controls, systemic lupus erythematosus, primary Sjögren's syndrome and psoriasis, no significant difference in the frequency was found between patients with normal or abnormal capillary patterns. No statistical analysis was performed for the patients with mixed connective tissue disease and dermatomyositis/polymyositis, because all patients showed an abnormal capillary pattern. In all patients who demonstrated an abnormal capillary pattern, periungual erythema was also found.

Discussion

This study shows the close relationship between periungual erythema and nailfold capillary abnormalities. The statistical correlation between nailfold capillary abnormalities and periungual erythema has been reported in a previous study [1]. This study extends the findings to other diseases and conditions. In scleroderma, mixed connective tissue disease and dermatomyositis/polymyositis, periungual erythema was observed in all subjects with an abnormal capillary pattern. In unclassified connective tissue disease, the frequency of periungual erythema in the subjects with an abnormal capillary pattern was significantly higher than in subjects with a normal capillary pattern. These results indicate that the relationship between periungual erythema and nailfold capillary abnormalities is specific to scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis and unclassified connective tissue disease. A concept of scleroderma spectrum disorders, unifying definite scleroderma, early forms of scleroderma, and closely related disorders such as mixed connective tissue disease, has been proposed [17]. The prevalence of scleroderma spectrum disorders is 4.9 to 19.2 times higher than definite scleroderma, and the need for the early diagnosis of scleroderma spectrum disorders has been suggested. As periungual erythema and nailfold capillary abnormalities are specific to scleroderma spectrum disorders and dermatomyositis/polymyositis, these observations are useful for the early diagnosis of these diseases. Periungual erythema is known to be very frequent in dermatomyositis/polymyositis, and has been noted particularly in cases of malignancy [3]. Patients with the cutaneous form of dermatomyositis/polymyositis (amyopathic dermatomyositis) also show periungual erythema/telangiectasia [18]. Accordingly, periungual erythema is a useful indicator of the activity of dermatomyositis/polymyositis and its prognosis.

Nailfold capillary microscopy is known to be useful in identifying patients who could be at risk of developing connective tissue diseases. A distinctive microvascular pattern, characteristic of scleroderma and dermatomyositis/polymyositis has been reported [19, 20]. The author has reported nailfold capillary abnormalities in scleroderma [1] and dermatomyositis/polymyositis [1]. A close relationship between nailfold capillary abnormalities and Raynaud's phenomenon, sclerodactyly, telangiectasia and antinuclear antibody has been found [21, 22]. A prospective study of 32 patients with Raynaud's phenomenon alone and 19 with undifferentiated connective tissue diseases showed that patients who went on to develop scleroderma displayed a scleroderma pattern of capillary morphology at their initial examination [23]. Only capillaroscopy was able to differentiate between primary Raynaud's phenomenon and undifferentiated connective tissue diseases [24]. These studies showed the prospective value of nailfold capillary abnormalities in identifying patients with connective tissue diseases.

CONCLUSION

REFERENCES

1. Ohtsuka T, Ishikawa H. Statistical definition of nailfold capillary patterns in patients with systemic sclerosis. Dermatology 1994; 188: 286-9.

2. Maricq HR. Widefield capillary microscopy : technique and rating scale for abnormalities seen in scleroderma and related disorders. Arthritis Rheum 1981; 24: 1159-65.

3. Hidano A, Torikai S, Uemura T, Shimizu S. Malignancy and interstitial pneumonitis as fatal complications in dermatomyositis. J Dermatol 1992; 19: 153-60.

4. Subcommittee for scleroderma criteria of the American Rheumatism Association diagnostic and therapeutic criteria committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581-90.

5. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975; 292: 344-7.

6. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7.

7. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease ­ an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972; 52: 148-59.

8. Daniels TE, Talal N. Diagnosis and differential diagnosis of Sjögren's syndrome. In: Talal N, Moutsopoulos HM, Kassan SS, eds. Sjögren's syndrome: clinical and immunological aspects. Berlin/Heiderberg/New York: Springer-Verlag, 1987.

9. Arnett FC, Edworthy SM, Bloch DA, et al. The American Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24.

10. National Diabetes Data Group Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28: 1039-57.

11. Frederiksson T, Peterson U. Severe psoriasis-oral therapy with a new retinoid. Dermatologica 1978; 157: 238-44.

12. Tham SN, Lim JJ, Tay SH, et al. Clinical observations on nail changes in psoriasis. Ann Acad Med 1988; 4: 482-5.

13. Kendall. Multivariate analysis, 2nd edition Charles Griffin & Co. Ltd., High Wycombe, England, 1980.

14. Gnanadesikan R. Methods for statistical data analysis of multivariate observations, John Wiley & sons, Inc., New York, 1977.

15. Lachenbruch PA. Discriminant analysis, Macmillan publishing Co., New York, 1975.

16. Tanaka Y, Tarumizu T, Wakimoto K. Handbook of statistical analysis using personal computer (Part 2, multivariate analysis), Kyoritsu Publishing Co., Tokyo 1984.

17. Maricq HR, LeRoy EC, D'Angelo WA, et al. Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders. Arthritis Rheum 1980; 23: 183-18.

18. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis (dermatomyositis sine myositis). Presentation of six new cases and review of the literature. J Am Acad Dermatol 1991; 24: 959-66.

19. Maricq HR. The microcirculation in scleroderma and allied diseases. Adv Microcirc 1982; 10: 17-52.

20. Maricq HR, Weinrich MC, Keil JE, et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum 1989; 32: 998-1006.

21. Ohtsuka T, Yamakage A, Tamura T. Image analysis of nailfold capillaries in patients with Raynaud's phenomenon. Cutis 1995; 56: 215-8.

22. Ohtsuka T, Yamakage A, Tamura T. Image analysis of nailfold capillaries in patients with undifferentiated connective tissue syndrome. J Dermatol 1995; 22: 921-5.

23. Maricq HR, Harper FE, Khan MM, et al. Microvascular abnormalities as possible predictors of disease subsets in Raynaud's phenomenon and early connective tissue disease. Clin Exp Rheumatol 1983; 1: 195-205.

24. Lee P, Sarkozi J, Bookman AA, et al. Digital blood flow and nailfold capillary microscopy in Raynaud's phenomenon. J Rheumatol 1986; 13: 564-9.