MONTREAL, Quebec, Canada—Positive antinuclear antibodies (ANAs), positive systemic sclerosis (SSc) autoantibodies, and characteristic nailfold capillary microscopy (NCM) patterns can help identify patients with Raynaud's phenomenon (RP) who will progress to definite SSc.1

"Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of developing definite SSc, whereas their absence rules out this outcome."—Martial Koenig, MD
Martial Koenig, MD, and colleagues report in Arthritis & Rheumatism that:
  • Raynaud's phenomenon patients without the SSc pattern on NCM and SSc-specific autoantibodies rarely develop SSc
  • 65.9% of RP patients with both markers at baseline will develop SSc within 5 years
  • Patients with both markers at baseline are 50 times more likely to develop SSc than those without these markers (P<0.0001)
  • Patients with both abnormal NCM findings and SSc-specific autoantibodies are 5 times more likely to develop SSc than those with only the autoantibodies
  • Patients with SSc-specific autoantibodies and abnormal NCM are 8 times more likely to progress to SSc than those with only NCM abnormalities

"In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SSc-specific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of developing definite SSc, whereas their absence rules out this outcome,” said Dr. Koenig, who is at Notre-Dame Hospital at Montreal University in Montreal, Quebec, Canada.

The 20-year prospective study included 586 patients who were followed for 3,197 person-years. All had been referred for evaluation of Raynaud's phenomenon, defined as a history of at least 2 of 3 phases of color change (white, blue, red), usually due to cold exposure, and involving at least 1 finger of each hand. Eighty-eight patients (11.2%) had abnormal NCM at study entry. The most common NCM abnormality was definite or extreme capillary enlargement. Eighty of the 696 RP patients with normal NCM at entry had SSc autoantibodies. These were anti-CNP-B in 34 (42.5%), anti-Th/T0 in 12 (15%), anti-topo I in 14 (17.5%) and anti-RNAP III in 25 (31.3%). Five patients (6.3%) had more than one of these autoantibodies.

“[P]atients who had both risk factors at baseline were 60 times more likely to experience progression to SSc than were patients without these predictors (adjusted HR 60.08). However, the sensitivity of this pair of predictors of a definite SSc outcome was only 47%. In contrast, the presence of an abnormal NCM and/or SSc autoantibodies at baseline was associated with a sensitivity of 89% and a near-perfect negative predictive value (98%) (OR 20, P<0.0001),” Dr. Koenig reported.

Early SSc was defined as patients with RP who had abnormal findings on NCM and an SSc-specific autoantibody. Seventy-four patients (12.6%) with early SSc at baseline developed definite SSc. During this process the researchers identified a characteristic sequence of microvascular damage: enlarged capillaries, then capillary loss, then capillary telangiectases. Definite SSc appeared soon after capillary loss. Patients with early SSc were 17 times more likely to progress to definite SSc than were patients with pre-connective tissue disease (pre-CTD), defined as clinical signs of CTD such as puffy fingers and/or abnormal lab values and/or positive autoantibody assays but not for any of the SSc-specific autoantibodies.

Translating research into practice

“[P]atients with RP who present to a specialized center should be evaluated both for nailfold capillary abnormalities by NCM and for SSc-specific autoantibodies, including anti-Th/T0 and anti-RNAP III,” Dr. Koenig advised. The data from this trial suggest that by the time definite SSc is diagnosed, a “sustained and cumulative burden of microvascular damage” has already occurred.

“Taken together, these data suggest that the concurrent presence at baseline of both criteria indicates a very high probability that a patient will develop definite SSc, whereas their absence rules out this outcome,” the researchers concluded.

Reference

1. Koenig M, Joyal F, Fritzler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis. A twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58:3902-3912.