Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease

Eighty-seven patients diagnosed as having primary Raynaud's phenomenon (Raynaud's disease) were reexamined after this symptom had been present for a mean of 8.8 years (range 2.0-34.5). One or more additional clinical feature(s) suggesting an underlying connective tissue disease were found in 12 patients (14%) at first evaluation, and in 23 (26%) by the last evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients), and digital tip ulcerations (6 patients). Distal esophageal hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients. Only 4 individuals (5%) developed clear evidence of a connective tissue disease, and in all cases, the diagnosis was the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome variant of systemic sclerosis. This condition became obvious 8-17 years after the onset of Raynaud's phenomenon. One or more serologic test values were initially abnormal in 2 of these CREST syndrome patients, as well as in 12 patients who continued to have primary Raynaud's phenomenon at the last evaluation. The combination of puffy fingers, digital pitting scars, and serum anticentromere antibody, all consistent with CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were repeated during followup had a change in the serologic profile. These results suggest that only a small proportion of patients with primary Raynaud's phenomenon develop one of the connective tissue diseases during the first decade after onset. When such a disorder does appear, systemic sclerosis with the CREST syndrome variant is the most likely eventual diagnosis.     

Raynaud's phenomenon

Raynaud's phenomenon (RP) is common, affecting approximately 5% of the population, and is important to the rheumatologist because it is often the presenting symptom of connective tissue disease, especially of systemic sclerosis (SSc)-spectrum disorders. RP therefore provides a window of opportunity for early diagnosis. When RP is associated with SSc it is particularly challenging to treat.This review begins with a discussion of some of the recent advances in our understanding of the pathogenesis of RP: it is through increased understanding of the complex pathophysiology of RP that we are most likely to develop new therapies. The following questions are then addressed (with three clinical scenarios demonstrating key principles of assessment and management):1. How can we predict underlying connective tissue disease in the patient presenting with Raynaud's?2. How can we measure severity of Raynaud's?3. What are the latest advances in treatment of connective tissue disease-related digital vasculopathy?     

Raynaud's phenomenon

Raynaud's phenomenon (RP) is a vasospastic disorder characterized by episodic color changes of blanching, cyanosis, and hyperemia in response to cold and/or emotional stress. Although most typically noted in the fingers, the circulation of the toes, ears, nose and tongue is also frequently affected. Population studies have shown that RP in adults is more common in women than men, with prevalence estimates ranging from 4% to 30%. Geographic variations in the prevalence reflect differences in climate. RP may be a primary or a secondary process. LeRoy and Medsger suggested criteria for primary RP: symmetric attacks, the absence of tissue necrosis, ulceration or gangrene, the absence of a secondary cause, negative antinuclear antibodies, normal nailfold capillaroscopy and a normal erythrocyte sedimentation rate. Secondary RP is characterized by an age of onset of more than 30 years, painful and asymmetric attacks, ischemic skin lesions, positive autoantibodies, capillaroscopic abnormalities and/or clinical features suggestive of connective tissue diseases (CTDs). Among the CTDs, systemic sclerosis has the highest frequency of RP. Finding a cause for RP requires a knowledge of the patient's occupational, smoking, drug history, physical examination, nailfold capillaroscopy, routine laboratory tests and autoantibodies. Furthermore, RP should be distinguished from acrocyanosis, a condition characterized by continuous cyanosis of the hands or feet that is aggravated by cold temperature. The most important instruction to the patient is abstinence from any smoking, offending drugs should be discontinued, and abrupt changes in temperature. If these measures are inadequate, calcium-channel blockers are the most widely used (nifedipine 30 mg up to 90 mg daily). Alternatively, sympatholytic agent (prazosin), angiotensin II -receptor type I antagonist (losartan), selective sertonin-reuptake inhibitor (fluoxetine) may be useful. In the severe cases the role of prostaglandins is well established, but standard therapeutic protocols are not jet available.     

Raynaud's phenomenon

Raynaud's phenomenon (RP) is a major cause of pain and disability in patients with autoimmune connective tissue diseases (CTDs), particularly systemic sclerosis (SSc). The clinician must perform a comprehensive clinical assessment in patients with RP to differentiate between primary (idiopathic) and secondary RP, in particular (for rheumatologists), secondary to an autoimmune CTD, as both the prognosis and treatment may differ significantly. Key investigations are nailfold capillaroscopy and testing for autoantibodies (in particular, those associated with SSc). Patients with RP and either abnormal nailfold capillaroscopy or an SSc-specific antibody (and especially with both) have a high risk of transitioning to an autoimmune CTD. Both nailfold capillaroscopy and autoantibody specificity may help the clinician in predicting organ-based complications. The management of CTD-associated RP requires a multifaceted approach to treatment, including patient education and conservative (‘non-drug’) measures. Patients with CTD-associated RP often require pharmacological treatment, which in the first instance is usually a calcium channel blocker, although other agents can be used. There is an increasing tendency to use phosphodiesterase type 5 inhibitors early in the treatment of CTD-associated RP. Oral therapies are commonly associated with side effects (often due to systemic vasodilation) that may result in failure of dose escalation and/or permanent discontinuation. Intravenous prostanoid therapy and surgery (e.g., botulinum toxin injection and digital sympathectomy) can be considered in severe RP. Patients with CTD-associated RP can develop a number of ischaemic digital complications (primarily ulcers and critical ischaemia), which may be associated with significant tissue loss. Future research is required to increase the understanding of the pathogenesis and natural history of RP (to drive therapeutic advances), and to explore/develop drug therapies, including those that target the mechanisms mediating cold-induced vasoconstriction, and locally acting therapies free of systemic side effects.     

Raynaud's phenomenon

Raynaud's phenomenon is characterized by repeated daily attacks of ischemia followed by reperfusion at the acrallevel. It is a frequent syndrome found in medical practice; and it can be considered as primary or secondary to other conditions, including rheumatic autoimmune diseases. Current classification had clinical and therapeutic implications. Careful clinical evaluation is the most reliable and reproducible method in the diagnosis of Raynaud's phenomenon. Several risk factors had been associated in the genesis of Raynaud's phenomenon; however, its pathogenesis remains elusive although recently, considerable progress in disease mechanism had been described. Such advances are directing new lines of therapy.     

Raynaud's phenomenon in mixed connective tissue disease

Raynaud's phenomenon affects most patients who have mixed connective tissue disease (MCTD) and frequently represents the initial manifestation of the disease. It is the cutaneous symptom of a systemic vasculopathy that is characterized by intimal fibrosis and blood vessel obliteration that frequently leads to visceral involvement, particularly pulmonary hypertension. An association between Raynaud's phenomenon and the characteristic autoantibody in MCTD, anti-U1-RNP (ribonucleoprotein), is found across the spectrum of rheumatic diseases, including undifferentiated connective tissue disease, scleroderma, and systemic lupus erythematosus. Capillary nailfold examination represents a valuable tool to identify patients who are at risk for MCTD. The goal in the therapy of Raynaud's phenomenon in MCTD is to decrease the frequency of attacks, to prevent digital ulceration, and to limit progressive vascular damage. Therapeutic regimens include the traditional use of calcium channel blockers and novel vascular therapies.     

Paraneoplastic Raynaud's phenomenon

Summary A testicular tumour could be diagnosed by the occurrence of a Raynaud's phenomenon complicated by severe digital arteritis. The arteritis rapidly regressed under prostacyclin therapy. Such vascular manifestations are frequent in testicular carcinoma, but they usually develop after chemotherapy. To our knowledge, this is the first case where they preceded the diagnosis and specific treatment of a tumour of the testis.     

Raynaud's phenomenon.

Raynaud's phenomenon is episodic digital ischemia provoked by cold and emotion; it is associated with other disorders, such as Raynaud's syndrome, especially the connective tissue diseases. Recent information suggests links with Sj?gren's syndrome, malignancy, and obstructive vascular disease. The vasospasm can affect areas outside the periphery such as the inner ear in vibration white finger syndrome and the placental vessels in pregnancy. The initial presence of autoantibodies increases the chance by 63-fold of developing connective tissue diseases, and such immunologic testing can be usefully combined with nailfold vessel microscopy. Several factors are considered to be of etiologic importance in Raynaud's phenomenon, such as the augmenting effect of cold on the responsiveness of alpha 2-adrenoceptors to agonists. Deficiency in the vasodilator neuropeptide calcitonin gene-related peptide has been detected, as have excess amounts of the vasoconstrictor endothelin. Treatment of vasospasm remains symptomatic, and directed towards the vasospasm and altered blood constituents.     

Raynaud's phenomenon.

Much has been learned about the complexity of the local, humoral and nervous factors regulating the normal behavior of the skin blood vessels, and many studies have addressed how this knowledge might relate to the causation of primary Raynaud's disease. Despite this, the mechanism(s) responsible for the attacks of digital vasospasm remain an enigma. A key question is whether these attacks represent an exaggeration of the normal mechanisms causing constriction of the digital vessels with local cooling, or are due to a specific abnormality. In this article it is suggested that multiple factors are responsible, including the possibility of co-transmitters released with norepinephrine from the sympathetic nerves, increased activation of beta 2-adrenoceptors on the nerve endings, a shift in the balance of alpha 1 and alpha 2 adrenoceptors on the vascular smooth muscle and in endothelium-derived relaxing and contracting factors, and altered interactions of the endothelium with the blood elements including the effects of increased platelet serotonin.     

Raynaud's phenomenon.

Raynaud's phenomenon occurs in about 5% of the adult population, and most individuals do not seek medical attention for the condition. In symptomatic patients with Raynaud's phenomenon, it is useful to categorize the condition as primary or secondary. In addition to providing a framework for epidemiologic and therapeutic protocols, such classification may reflect basic pathophysiologic differences. Occupation-related Raynaud's phenomenon has been recognized recently as a major cause of lost wages and productivity. Neurogenic and "local fault" hypotheses to explain primary Raynaud's phenomenon are still being studied. In secondary Raynaud's phenomenon, obliterative arteriopathy and the role of endothelial-derived products have been the focus of intense research interest. Under some circumstances, the combination of nailfold capillary microscopy and autoantibody analysis can identify patients with primary Raynaud's phenomenon that is likely to evolve into a secondary form of Raynaud's phenomenon. Although information from this type of analysis may be overinterpreted, the prognostic yield is highest for patients destined to develop systemic sclerosis-related disorders. Newer vasodilating agents and antithrombotic drugs may offer benefit for patients with both primary and secondary Raynaud's phenomenon.