Samantha C. Shapiro, MD Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine; Postdoctoral Fellow, Johns Hopkins Division of Rheumatology, Baltimore, MD
Fredrick M. Wigley, MD Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine; Martha McCrory Professor of Medicine, Johns Hopkins Division of Rheumatology, Baltimore, MD
Address: Samantha C. Shapiro, MD, Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine; 5200 Eastern Avenue, Suite 4100, Mason F. Lord Building, Center Tower, Baltimore, MD 21224; sshapi28@jhmi.edu
ABSTRACT
Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms in the digits. It can be idiopathic (primary) or secondary to another condition; the latter can be more severe and more apt to lead to ischemic complications such as digital ulceration and even loss of digits. If nonpharmacologic interventions prove inadequate, then vasodilator agents are used.
KEY POINTS
Primary Raynaud phenomenon occurs in the absence of any underlying disease process. Secondary Raynaud phenomenon occurs in concert with another disease, frequently rheumatic.
Young patients with mild Raynaud phenomenon, normal nailfold capillaries, and no additional symptoms or signs to suggest a rheumatic or other underlying disease can be followed carefully by the primary care doctor and do not require further serologic workup or referral to a specialist.
Nonpharmacologic interventions, ie, cold avoidance and stress management, are first-line for all patients.
Calcium channel blockers are first-line drugs and should be titrated to the maximum tolerated dose before adding or switching to other agents.
The goal of treatment should not be to eliminate Raynaud attacks completely but to improve quality of life and prevent ischemic complications.
PRIMARY VS SECONDARY RAYNAUD PHENOMENON
To distinguish between primary and secondary Raynaud phenomenon, a careful history and physical examination are paramount.
Primary Raynaud phenomenon
In uncomplicated primary Raynaud phenomenon, the episodes typically last 15 to 20 minutes after rewarming and usually start in a single finger and spread to other digits symmetrically and bilaterally.7 The thumb is often spared, and ischemic digital ulcers do not occur. Vasoconstrictive episodes are mild.
Females under age 20 are most commonly affected. In our experience, a young woman with the above clinical picture, no signs or symptoms suggestive of connective tissue disease (see below), and normal nailfold capillaries can be diagnosed as having primary Raynaud phenomenon without any further workup.
Careful clinical follow-up is recommended, because if an occult secondary process is indeed present, most patients will begin to show additional symptoms or signs of it within 2 years of the onset of Raynaud phenomenon.
Should a clinician be unfamiliar with nailfold capillary examination, or if symptoms (eg, fatigue or arthralgia) or signs (eg, rash, arthritis) suggestive of connective tissue disease are present, referral to a rheumatologist for further evaluation is appropriate. Results of further diagnostic testing dictated by the history and physical such as a screening antinuclear antibody test can be sent before referral.
Secondary Raynaud phenomenon
Several clinical features suggest secondary Raynaud phenomenon and warrant referral to a rheumatologist:
Age 20 or older at onset
Frequent severe vasoconstrictive episodes
Male sex
Thumb involvement
Figure 2. (A) Dilated nailfold capillaries in a patient with scleroderma (blue arrow); (B) dilation and dropout of nailfold capillaries (white arrow) viewed with a magnifier.
Signs of an autoimmune rheumatic disease, eg, sclerodactyly, cutaneous or mucosal matted telangiectasia, inflammatory arthritis, an abnormal lung examination, severe digital ischemia with ulceration or gangrene, or nailfold capillary dilation or dropout (Figure 2)8
Isolated single-limb or 1-finger ischemic events, seen in macrovascular occlusive disease or inflammatory disease mimicking Raynaud phenomenon (eg, atherosclerosis, vasculitis); when isolated acute ischemic events occur in the upper or lower extremity, a further workup is necessary.
Figure 3 shows our approach to evaluation.
NONPHARMACOLOGIC THERAPY
Figure 3. Our approach to diagnosis of Raynaud phenomenon and differentiating primary from secondary Raynaud phenomenon.
Cold avoidance and stress management are first-line therapies for preventing Raynaud attacks and must be part of any treatment strategy. Digital arteries and thermoregulatory vessels of the skin are predominantly under sympathetic adrenergic control, so temperature changes and emotional stressors trigger vasoconstriction. Patients should be counseled to:
Keep the whole body warm. Patients should wear multiple layers of clothing, a hat, warm gloves, and warm socks. Commercially available hand-warmers can help, especially for patients who live in cold climates.
Learn to avoid or manage stress. Good communication, attention to the patient’s needs, and regular follow-up for reassurance are paramount. For some patients, psychotropic medications to manage mood may help. Behavioral approaches have been suggested for acute stress management. One approach, autogenic training, is a form of relaxation with temperature biofeedback in which finger temperature data are provided to patients to help them learn to relax by monitoring their internal states and changes in temperature. However, there are no strong data to support the routine use of this technique or the use of one behavioral approach over another. Trials have generally been of low quality and limited by small sample size.9
Stop smoking!10
Stop a Raynaud attack should one occur, eg, place the hands under warm water or in a warm part of the body, such as under legs when sitting. This can help speed recovery.
In addition, the physician should:
Eliminate vasoconstricting agents such as nonselective beta-blockers, ergots, triptans, and amphetamines.
PHARMACOLOGIC THERAPY
For many patients, nonpharmacologic interventions are enough to decrease the severity and frequency of attacks. However, if Raynaud phenomenon continues to negatively affect quality of life, drug therapy can be added (Table 1).
Calcium channel blockers
Calcium channel blockers are first-line agents for both primary and secondary Raynaud phenomenon that does not adequately respond to nonpharmacologic interventions. These agents are effective, available, and reasonably inexpensive.
Dihydropyridine calcium channel blockers such as nifedipine and amlodipine are commonly used. Both drugs are acceptable options, though some patients may respond better to one than the other in terms of symptoms and side effects. Nondihydropyridines such as diltiazem can also be used, but they have less potent vasodilatory effects because they are less selective for vascular smooth muscle.
These medications should be started at the lowest dose and titrated up over several weeks as tolerated to achieve their maximal effect. Intermittent therapy (eg, during the winter months only) is reasonable for primary Raynaud without risk of digital ulceration, as relief of symptoms and improvement in quality of life are the main indications for therapy in this circumstance.
A 2016 Cochrane review and meta-analysis of the use of calcium channel blockers to treat primary Raynaud phenomenon included 7 randomized controlled trials with 296 patients treated with either nifedipine or nicardipine.11 There was moderate-quality evidence that these drugs minimally decreased the frequency of attacks (standardized mean difference of 0.23; 95% CI 0.08–0.38, P = .003). This translated to 1.72 fewer attacks per week with treatment than with no pharmacologic therapy (95% CI 0.60–2.84). When analyzed individually, only nifedipine was effective; nicardipine did not decrease the frequency of attacks.
Unfortunately, calcium channel blockers failed to decrease the severity of attacks (according to unvalidated severity scoring systems) or make any differences in physiologic measurement outcomes. Attacks were not completely eliminated, just less frequent than before treatment.11
Most commonly reported side effects included headache, flushing, hypotension, edema, and, rarely, gastrointestinal reflux. Use of these medications may be limited by hypotension.
The review was limited by the small sample size, short duration of treatment, and relatively low doses of calcium channel blockers used in the available studies.11
A 2005 meta-analysis also indicated a statistically significant decrease of 2.8 to 5 attacks per week with nifedipine treatment, though this study also included some patients with secondary Raynaud phenomenon.12
