Update on Raynaud’s: Nothing Phenomenal

Abstract & Commentary

Synopsis: Vasospasm, the hallmark of Raynaud’s phenomenon, may have visceral as well as digital manifestations.

Source: Ho M, Belch JJF. Scand J Rheumatol 1998;27: 319-322.

White, red, blue: the name of maurice raynaud comes to mind when cold causes fingers or toes to turn the colors of the French Tricolor. Ho and Belch have provided a brief update on Raynaud’s phenomenon (RP). They stress RP as being indicative of a systemic disorder with an increased prevalence of angina and migraine, decreased renal perfusion on cold challenge, and loss of the normal increase in pulmonary diffusing capacity that ordinarily accompanies cold exposure. On the diagnostic front, they stress the usefulness of physical findings, such as digital ulcers and pitted scars from skin ischemia, in identifying patients with systemic sclerosis (SSc). They review the characteristics of serologic tests in patients with RP and cite a 60% sensitivity and 98% specificity of anti-centromere antibodies in the limited form of SSc (CREST syndrome).1 The anti-topoisomerase assay (anti-SCl-70) has a lower sensitivity for diffuse SSc (38%) but excellent specificity (almost 100%). The presence of anti-nuclear antibodies (ANA) increases the likelihood of progression to some connective tissue disease even if none can be diagnosed when patients first present with RP, while sero-negative patients have only a 10% progression when followed for 2-5 years.

The importance of capillary nailfold microscopy is also stressed. Loss of capillary loops or dilated loops correlates well with the presence of, or the eventual development of, some connective tissue disease.2 Ho and Belch refer to those patients who have RP, a positive ANA, and abnormal capillary nailfold microscopy as having pre-scleroderma.

Ho and Belch review some of the evidence supporting the theory that abnormal function of the endothelium plays a major role in the pathophysiology of RP. They also note that direct vasodilators, such as nitroprusside, are less potent in subjects with RP than in normal controls, suggesting the presence of abnormalities that are independent of the endothelium.

Palliation of RP with calcium channel blocking drugs remains the mainstay of therapy, and, in Ho and Belch’s opinion, nifedipine is the "gold standard." The usefulness of the prostacyclin analog, iloprost, when given intravenously in healing digital ulcers, and the disappointing lack of efficacy of of oral iloprost in patients with RP is discussed. Some promising new experimental therapies are reviewed including defibrotide, L-carnitine, and relaxin. Relaxin in particular was cited for its efficacy in digital ulcer healing in a recent trial in patients with SSc in an abstract but a peer reviewed publication has yet to appear.3

Comment by Jerry M. Greene MD

The phenomenon Raynaud described 136 years ago is still with us.4 A recent case-control study found a prevalence of RP of 5.5% based on a questionnaire and of 2.8% based on interview and examination in a population in the northern United States.5 The normally adaptive response of decreasing peripheral blood flow in response to cold exposure is exaggerated in RP and can lead to digital infarction, ulceration, and even amputation in severely affected individuals. In addition to treating symptoms and trying to prevent the complications of Raynaud’s, the other major challenge to physicians is trying to determine the prognosis for individual patients. Predicting which have a mild self-limited disorder and which have RP as a manifestation of an underlying collagen/vascular disorder is especially helpful in deciding on the frequency of follow-up and the intensity of laboratory monitoring. Patients with diffuse SSc may develop life-threatening visceral involvement early in the course of their disease. Those with limited SSc have a more protracted course but may succumb to pulmonary hypertension and associated cor pulmonale.

The usefulness of capillary nailfold microscopy in prognostication, which Ho and Belch stress, has been further supported by Spencer-Green, whose meta-analysis of 10 studies in which capillary nailfold microscopy was evaluated in a prospective fashion found that the technique had a positive predictive value of 47% (substantially better than serologic testing, which had a positive predictive value of 30%).6 Capillary nailfold microscopy is a simple addition to the physical examination of patients with RP which can be easily performed with a hand held ophthalmoscope, a cover slip, and some immersion oil between skin and cover-slip. With the use of a +20 diopter lens, the capillary loops along the nail fold can be seen. Avascular areas (capillary drop out) or dilated capillary loops are abnormal and suggest the presence of, or eventual development of, a connective-tissue disease.

Nitroglycerin transdermal patches, which have been helpful to some patients, should be added to the list of useful treatments, though there is a high incidence of headache with this therapy.7 Although Ho and Belch are discouraging the use of oral iloprost, investigators who conducted a recent, large multicenter, randomized controlled trial of iloprost found that either a 50 or 100 mcg dose of oral iloprost given twice daily was superior to placebo in reducing the frequency and duration (but not the number) of attacks of RP in patients with SSc.7 Even though no phenomenal breakthroughs have occurred lately in the study of RP, some spasmodic progress continues to be made in our understanding and treatment of this colorful disorder.

References

1. Gerbracht DD, et al. Arthritis Rheum 1985;28:87-89.

2. Marique HR, et al. Am J Med 1976;61:862-870.

3. Seibold TA, et al. Arthritis Rheum 1997;(Suppl) 40:S123.

4. Raynaud M. These de Paris 1862 in Arch Gen de Med (Paris) 1874;1:189.

5. Freedman RR, Mayes MD. Arthritis Rheum 1996; 39:1189-1191.

6. Spencer-Green G. Arch Intern Med 1998;158:595-600.

7. The LS, et al. Br J Rheumatol 1995;34:636-641.

8. Black CM, et al. Br J Rheumatol 1998;37:952-960.