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Scleroderma is a rare, chronic disease characterized by excessive deposits of collagen. Progressive systemic scleroderma or systemic sclerosis, the generalised type of the disease, can be fatal. The localised type of the disease tends not to be fatal. more...

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The term 'localised, generalised sclerderma' can be used to describe cases where the disease covers a large area of the body - typically more than 40%.

Signs and symptoms

Scleroderma affects the skin, and in more serious cases, it can affect the blood vessels and internal organs. The most evident symptom is the hardening of the skin and associated scarring. Typically the skin appears reddish or scaly in appearance. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage will weaken limbs and affect appearance.

The seriousness of the disease varies hugely between cases. The two most important factors to consider are, the level of internal involvement (beneath the skin), and the total area covered by the disease. For example there are cases where the patient has no more than one or two lesions (affected areas), perhaps covering a few inches. These are less serious cases and tend not to involve the internal bodily functions.

Cases with larger coverage are far more likely to affect the internal tissues and organs. Where an entire limb is affected, symptoms will almost certainly have serious consequences on the use of that limb. The heart and lungs will be affected when the disease covers this area of the torso. Some patients also experience gastrointestinal problems, including heartburn and acid reflux. Internal scarring may sometimes spread beyond what can be seen by the naked eye.

There is discoloration of the hands and feet in response to cold. Most patients (>80%) have Raynaud's phenomenon, a vascular symptom that can affect the fingers, and toes.

Systemic scleroderma and Raynaud's can cause painful ulcers on the fingers or toes, which are known as digital ulcers.


There are three major forms of scleroderma: diffuse, limited (CREST syndrome) and morphea/linear. Diffuse and limited scleroderma are both a systemic disease, whereas the linear/morphea form is localized to the skin. (Some physicians consider CREST and limited scleroderma one and the same, others treat them as two separate forms of scleroderma.)

Diffuse scleroderma

Diffuse scleroderma is the most severe form - it has a rapid onset, involves more widespread skin hardening, will generally cause much internal organ damage (specifically the lungs and gastrointestinal tract), and is generally more life threatening.

Limited scleroderma/CREST syndrome

The limited form is much milder: it has a slow onset and progression, skin hardening is usually confined to the hands and face, internal organ involvement is less severe, and a much better prognosis is expected.

The limited form is often referred to as "CREST" syndrome. CREST is an acronym for:


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Primary Pulmonary Hypertension Is Not Associated With Scleroderma-Like Changes in Nailfold Capillaries - )
From CHEST, 9/1/01 by Eric L. Greidinger

Study objectives: To determine whether primary pulmonary hypertension (PPH) is associated with scleroderma-like changes in nailfold capillaries.

Design: Blinded, prospective, ease-control study.

Setting: University medical centers in Baltimore, MD.

Patients: Thirty-seven patients with PPH, 15 patients with seleroderma, and 13 healthy control subjects.

Measurements: Subjects underwent nailfold capillary videomicroscopy of the fourth digits of both hands. Capillary images were evaluated by two blinded, trained graders according to standardized criteria for the presence of scleroderma nailfold changes.

Results: The prevalence of seleroderma-associated nailfold changes in patients with PPH (1 of 37 patients) was dramatically lower than that in patients with seleroderma (9 of 15 patients; p [is less than] 0.0001). The distribution of nailfold grades for the PPH patients was indistinguishable from that of the healthy control subjects.

Conclusion: PPH is not associated with seleroderma-like vasculopathy of nailfold capillaries. (CHEST 2001; 120:796-800)

Key words: primary pulmonary hypertension; scleroderma; nailfold capillaroscopy

Abbreviations: PPH = primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is a frequently fatal condition, the causes of which remain uncertain.[1] Mutations of the BMPR-II gene have been associated with the familial form of the disease but have been found in only a minority of sporadic cases.[2] Pulmonary hypertension is also a leading cause of mortality and morbidity in patients with systemic sclerosis (scleroderma).[3,4] Histologic studies of the lung lesions in patients with PPH demonstrate a diffuse vasculopathy that is similar to that seen in those with scleroderma.[5,6] Some patients who have received diagnoses of PPH have other features that overlap with scleroderma, such as Raynaud's phenomenon and antinuclear antibodies.[7] Moreover, prostaglandin therapy has proved to be effective both for PPH and for scleroderma-associated pulmonary hypertension.[8,9] Given the similarities between PPH and scleroderma, the possibility has been raised that cases of PPH represent a forme fruste of scleroderma.[10] Therefore, we investigated whether PPH also was associated with a form of extrapulmonary vascular disease that is prominent in patients with scleroderma.

Examination of the nailfold capillaries has been made popular as a means of evaluating small blood vessels in the peripheral circulation in humans.[11] Scleroderma-specific nailfold capillary abnormalities have been identified and have been found to be consistently distinguishable by a blinded observer.[12] The classic changes observed in the scleroderma are nailfold capillary dropout with decreased capillary density and giant nailfold capillaries. The presence of scleroderma-associated nailfold abnormalities has been associated with progression to scleroderma in a cohort of patients presenting with Raynaud's phenomenon.[13] To our knowledge, there have been no investigations that examine the nailfold capillaries of PPH patients to determine whether changes comparable to those in patients with scleroderma are found.

This study examined the nailfold capillaries from PPH patients, scleroderma patients, and healthy control subjects. The prevalence of nailfold capillary abnormalities in PPH patients was much lower than that in scleroderma patients and was not significantly different from that in healthy control subjects. Thus, the features of systemic vasculopathy that are seen in scleroderma patients do not develop in PPH patients.



A cohort of 37 PPH patients, 8 scleroderma patients with pulmonary hypertension, 8 patients with other forms of secondary pulmonary hypertension, 7 scleroderma patients without pulmonary hypertension, and 13 control subjects was recruited between May and October 1998 at university medical subspecialty clinics in Baltimore, MD. Consecutive patients attending the clinics were recruited until enrollment targets were met. Family history was obtained. No known eases of familial PPH were included in this cohort. Study protocols were approved by the institutional review board committees for the clinics from which the patients were recruited.

Clinical Data

Pulmonary hypertension was defined to be present if the mean pulmonary artery pressure was [is greater than] 25 mm Hg, as determined by right heart catheterization, or the estimated right ventricular systolic pressure was [is greater than] 35 mm Hg by Doppler cardiac ultra-sonography.[14] Patients with pulmonary hypertension were classified as having PPH if they had no other disease process known to be associated with pulmonary hypertension.[14] The American Rheumatism Association criteria were used to confirm the diagnosis of scleroderma.[15] Raynaud's phenomenon was identified using a standardized questionnaire.[16] The epoprostenol infusion history was determined by chart review.

Nailfold Imaging

Nailfold capillary videomicroscopy was performed on the fourth fingers of both hands by an operator (E.L.G.) who was blinded to the subjects' clinical status. Mock infusion pumps were randomly placed on subjects to blind the operator to their epoprostenol treatment status. Imaging was performed after at least 30 rain of equilibration in a 24 [degrees] C temperature-controlled room.

Immersion oil was applied to the nailfold before imaging. Recordings were made using a video camera (model KP-160; Hitachi; Brisbane, CA) and a video recorder (S-VHS; Panasonic; Secaucus, NJ) mounted on an stereo zoom microscope (model 52-Tr; Olympus; Melville, NY). Lighting was supplied by a high-intensity fiber-optic light source. A 5-mm measurement standard was applied to the digit and was included in each image.

Grading and Classification of Nailfold Images

As part of the prospective design of the study, the nailfold recordings were presented in random order to two blinded, trained graders (F.M.W. and R.A.W.) for classification. The graders both had participated in a previous multicenter trial performing nailfold capillary grading[17] and had been further trained using a video atlas to assess for capillary loop enlargement, capillary loop dropout, capillary density, and tortuous or bushy capillaries. The graders summarized their assessment of each digit as "scleroderma" (ie, corresponding to Maricq class II or class III changes[18]), "abnormal but not scleroderma," or "normal" (Fig 1). Also, the graders assessed the quality of the images as "good" (ie, the number and pattern of all nailfold loops clearly visible over at least a 5-mm span), "fair" (ie, the number of total loops but not the morphology of all loops clearly visible over the best 5-mm span), or "poor" (ie, the number and morphology of loops uncertain over the best 5-mm span). The blinded graders met to resolve all divergences in grading. Nailfold scores on the most abnormal hand were used for analysis. For secondary outcome measures, a single, blinded, trained grader (E.L.G.) evaluated each nailfold image strictly for capillary density and the presence or absence of tortuous or bushy capillaries.


Statistical Analysis

Group means were compared with Student's t test results. Independent group proportions were compared using Fisher's Exact Test or the [chi square] test. Agreement between test conditions was assessed with the [Kappa] statistic.[19] Statistical significance was set at p [is less than] 0.05. The Bonferroni correction was used in cases in which multiple comparisons were performed. Results were calculated using computer software (Prism, version 3.0 for Windows; Graphpad Software; San Diego, CA; and SPSS, version 10.0 for Windows; SPSS; Chicago, IL).


Clinical Features of the Cohort

This project recruited 52 patients with pulmonary hypertension, 8 additional patients with scleroderma, and 13 healthy control subjects. Of the 52 subjects with pulmonary hypertension, 37 had PPH, 7 had scleroderma, and 8 had other forms of secondary pulmonary hypertension. Of the eight patients recruited who had received a diagnosis of scleroderma, one also had pulmonary hypertension (transthoracic echocardiography was performed in every scleroderma patient who was enrolled except for two who had no clinical signs of pulmonary hypertension and normal diffusing capacity results on pulmonary function testing). Clinical characteristics of the patient groups were compared (Table 1). A trend toward an older mean age in the scleroderma patients compared to the healthy control subjects and PPH patients did not reach significance (p [is greater than] 0.03). Compared to the healthy control subjects, more of the scleroderma patients were women (p = 0.005). Raynaud's phenomenon was significantly more common in the scleroderma patients (100%) than in the healthy control subjects (7.7%; p [is less than] 0.0001), the PPH patients (8.1%; p [is less than] 0.0001), or the patients with nonscleroderma secondary pulmonary hypertension (25.0%; p = 0.0003).

Performance of Video Assessment Protocol

Video images of the fourth fingers of both hands for all 73 subjects (146 images) were presented in random order to two blinded graders. Image-quality assessments were concordant in 87 fingers (59.6%). The graders' clinical assessments of each nailfold image were concordant in 79 fingers (54.1%), and there were only 5 fingers (3.4%) in which one grader judged the nailfold to be scleroderma while the other grader judged the nailfold to be normal. Overall, fair agreement in clinical assessments existed between the two graders for each digit ([Kappa] = 0.29).

To assess the consistency of nailfold capillary changes, the grades for the right hand were compared with the left hand for all 73 study subjects (Table 2). Fair agreement was noted in the assessments of the paired hands for each patient ([Kappa] = 0.37). All analyses were repeated with patients classified by their least abnormal hand, their right hand, or their left hand, and they did not significantly differ from those presented using the most abnormal hand.

PPH vs Scleroderma Nailfold Comparisons

The prevalence of nailfold grades was compared between groups using the 2 x 3 [chi square] test (Table 3). The healthy control subjects and the PPH patients each were clearly different from the scleroderma patients in nailfold grading results ([chi square] test, p = 0.002 and p [is less than] 0.0001, respectively) and were not significantly different from each other. The mean nailfold capillary density was also lower in the scleroderma patients (mean [ [+ or -] SD], 25.9 [+ or -] 12.8 loops per 5 mm) than in the healthy control subjects (mean, 36.5 [+ or -] 8.7 loops per 5 mm; p = 0.019) or the PPH patients (mean, 41.2 [+ or -] 10.7 loops per 5 mm; p [is less than] 0.0001). The only PPH patient with nailfolds that graded as scleroderma had a history of recent-onset Raynaud's phenomenon.

Nailfold grading was not different in scleroderma patients with pulmonary hypertension (normal, 1 of 8 patients; abnormal not scleroderma, 2 of 8 patients; scleroderma, 5 of 8 patients) compared to scleroderma patients without pulmonary hypertension (normal, 0 of 7 patients; abnormal not scleroderma, 3 of 7 patients; scleroderma, 4 of 7 patients). Overall, nailfold grade prevalence also was not affected by epoprostenol treatment status (Table 4). No differences in nailfold capillary density were observed between epoprostenol-treated and untreated subgroups of PPH patients or scleroderma patients (not shown). Bushy or tortuous capillaries tended to be more prevalent in the nailfolds of PPH patients who had been treated with epoprostenol (76.2%) than in those of untreated PPH patients (50.0%; p = 0.027 [Fisher's Exact Test]). The prevalence of busily or tortuous capillaries was [is greater than] 85% in the nailfolds of both treated and untreated scleroderma patients.


While PPH and scleroderma share pulmonary vessel abnormalities and some clinical features, this study found no evidence that cases of PPH are a forme fruste of scleroderma. Using previously validated criteria for the evaluation of nailfold capillary images and a blinded case-control study design, PPH was not associated with scleroderma-like extrapulmonary vasculopathy in the digital bed. The results of nailfold capillary microscopy of patients with PPH were substantially different from those of scleroderma patients and were indistinguishable from those of healthy control subjects. Only 1 of 37 patients who had received diagnoses of PPH showed scleroderma-like nailfold abnormalities. This patient also had severe Raynaud's phenomenon.

The proportion of scleroderma patients with classic nailfold changes observed in the current study (9 of 15 patients; 60%) is similar to that in an earlier study[20] of videomicroscopy on the fourth digit nailfolds of scleroderma patients in which 43% of patients had classic nailfold changes. The presence in our cohort of one scleroderma patient who both graders agreed had normal capillary morphology on one hand and classic scleroderma changes on the contralateral ]land emphasizes that inspection of multiple nailfolds be performed before concluding that scleroderma nailfold changes are absent. In an earlier trial[21] of nailfold microscopy, classic nailfold changes were also inconsistent in the fingers of scleroderma patients. Dilated capillaries were present in 42% of digits, markedly decreased capillary density was present in 38%, and avascular areas were present in 26%.

In addition to its immediate vasodilatory effects on the pulmonary vasculature, epoprostenol gradually reduces pulmonary vascular resistance with prolonged infusion, presumably due to the remodeling of pulmonary vessels.[22] Our study noted an increased prevalence of tortuous and bushy capillaries after PPH patients had received epoprostenol therapy. Although this difference was not statistically significant, the trend of differences is of interest. Additional studies will be needed to establish whether epoprostenol therapy leads to the remodeling of nailfold capillary vessels. Epoprostenol infusion is known to be an effective treatment for Raynaud's phenomenon.[23]

This study provides evidence that PPH and scleroderma are distinct entities, even though they lead to similar histologic lesions in the pulmonary vascular bed. The presence of clear-cut scleroderma nailfold changes in a patient with pulmonary hypertension should lead to a high index of suspicion for a scleroderma-spectrum disorder.

ACKNOWLEDGMENT: The authors are grateful to Dr. Lewis J. Rubin for his key roles in the conception of this study and in patient recruitment.


[1] Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension. Am J Cardiol 1995; 75:51A-54A

[2] Thompson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000; 37:741-745

[3] Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983; 75:65-74

[4] Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis 1998; 57:682-686

[5] Chadzova I, Loyd JE, Zhdanov VS, et al. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 1995; 146:389-397

[6] al-Sabbagh MR, Steen VD, Zee BC, et al. Pulmonary arterial histology and morphometry in systemic sclerosis: a case-control autopsy study, J Rheumatol 1989; 16:1038-1042

[7] Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107:216-223

[8] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: the Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 334:296-302

[9] Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 2000; 132:425-434

[10] Barst RJ, Loyd JE. Genetics and immunogenetic aspects of primary pulmonary hypertension. Chest 1998; 114(suppl): 231S-236S

[11] Maricq HR, Maize JC. Nailfold capillary abnormalities. Clin Rheum Dis 1982; 8:4-46

[12] Kenik JG, Maricq HR, Bole GG. Blind evaluation of the diagnostic specificity of nailfold capillary microscopy in the connective tissue diseases. Arthritis Rheum 1981; 24:885-891

[13] Luggen M, Belhorn L, Evan T, et al. The evolution of Raynaud's phenomenon: a long-term prospective study. J Rheumatol 1995; 22:2226-2232

[14] Rich S, Rubin L, Walker AM, et al. Anorexigens and pulmonary hypertension in the United States: results from the Surveillance of North American Pulmonary Hypertension. Chest 2000; 117:870-874

[15] American Rheumatism Association. Preliminary criteria for the classification of systemic sclerosis (scleroderma): Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostics and Therapeutics Criteria Committee. Arthritis Rheum 1980; 23:581-590

[16] Maricq HR, Carpentier PH, Weinrich MC, et al. Geographic variation in the prevalence of Raynaud's phenomenon: a 5 region comparison. J Rheumatol 1997; 24:879-889

[17] Thompson B, Geller NL, Hunsberger S, et al. Behavioral and pharmacologic interventions: the Raynaud's Treatment study. Control Clin Trials 1999; 20:52-63

[18] Maricq HR. Widefield capillary microscopy. Arthritis Rheum 1981; 24:1159-1165

[19] Landis J, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33:159-174

[20] Kabasakal Y, Elvins DM, Ring EFJ, et al. Quantitative nailfold capillaroscopy findings in a population with connective tissue disease and in normal healthy controls. Ann Rheum Dis 1996; 55:507-512

[21] Ranft J, Lammersen T, Heidrich H. In vivo capillary microscopy findings and ophthalmoscopy findings in scleroderma. Arthritis Rheum 1987; 30:1173-1175

[22] McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacylin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338:273-277

[23] Belch JJ, Newman P, Drury JK, et al. Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud's syndrome: a double-blind controlled trial. Lancet 1983; 1:313-315

(*) From the Division of Immunology and Rheumatology (Dr. Greidinger), University of Missouri, Columbia, MO; and the Divisions of Rheumatology (Dr. Wigley and Ms. Boling) and Pulmonary and Critical Care Medicine (Drs. Gaine and Wise and Ms. Housten-Harris), Johns Hopkins University, Baltimore, MD. Dr. Greidinger is supported by the National Institutes of Health K08 Award No. AI01842 and by a University of Missouri Research Board Award.

Manuscript received December 14, 2000; revision accepted April 6, 2001.

Correspondence to: Eric L. Greidinger, MD, MA427 Health Sciences Center, Columbia, MO 65212; e-mail: greidingere@ health.missouri.edn

COPYRIGHT 2001 American College of Chest Physicians
COPYRIGHT 2001 Gale Group

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