Pathophysiology and clinical consequences of Raynaud's phenomenon related to systemic sclerosis
Department of Dermatology and Venereology, University Hospital Münster and 1Department of Medicine (Rheumatology and Clinical Immunology), Charité University Hospital, Humboldt-University of Berlin, Germany.
Correspondence to: Prof. Dr Cord Sunderkötter, Department of Dermatology and Venereology, University Hospital Münster, von-Esmarch-Str. 58, 48149 Münster, Germany. E-mail: cord.sunderkoetter{at}ukmunster.de
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Abstract |
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 Top Abstract IntroductionDefinition and clinical...The differences between primary...Pathophysiology of SSc-related...The clinical consequences of...AcknowledgementsReferences |
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According to the so-called vascular hypothesis, Raynaud's phenomenon (RP) is one initial event in the pathophysiological cascade leading to sclerosis in systemic sclerosis (SSc). It is characterized by recurrent, reversible spasms of small arterioles and digital arteries, usually triggered by cold and emotional stress. Clinical signs of RP are a sudden pallor of single digits of fingers followed by reactive hyperaemia and in severe cases also by cyanosis. Besides imbalances between vasoconstrictive and vasodilatory processes, structural alterations of the involved vessels are fundamental to secondary RP in SSc. The latter is the reason why secondary RP in SSc, in contrast to primary RP, often leads to ischaemia and re-perfusion injuries. New insights into the pathophysiology of RP feature a special role for
2c-adrenoreceptors, Rho-kinase signalling pathways and soluble mediators. They have resulted in promising therapeutic options, including antagonism of endothelin receptors, inhibition of phosphodiesterases or selective blockade of 2c-adrenoreceptors. They should also have a positive impact on the course of SSc in general. |
Introduction |
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According to the vascular hypothesis by LeRoy [1], vascular dysfunctions featuring enhanced vascular permeability and vasospasm due to dysregulated contractile response of the muscular vessel wall are initial events in the pathophysiological cascade leading to sclerosis in systemic sclerosis (SSc). On the skin they present as Raynaud's phenomenon (RP), but they may also be present in other organs.
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Definition and clinical characterization of Raynaud's phenomenon |
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TopAbstractIntroductionDefinition and clinical...The differences between primary...Pathophysiology of SSc-related...The clinical consequences of...AcknowledgementsReferences |
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RP is due to recurrent, reversible vasospasms of small arteries and arterioles, involving usually the digital arteries in fingers and toes, triggered primarily by cold or emotional stress.
Clinically RP is characterized by the typical dual or tricolour changes in skin colour, affecting primarily acral body parts. They consist of a sudden pallor of mostly single [1–3] digits of fingers (white ischaemia), followed, usually after rewarming, by reactive erythema (red hyperaemia); in severe attacks, ischaemia is followed by a phase of livid deoxygenation of blood (cyanosis) prior to hyperaemia. It is often accompanied by pain or dysaethesia.
Differential diagnosis for RP encompasses cold-induced pallor, disturbed blood flow due to hypercholesterinaemia, acute embolic events, paroxysmal haematoma of the finger, acral erythema after chemotherapy or erythromelalgia.
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The differences between primary and secondary Raynaud's phenomenon |
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TopAbstractIntroductionDefinition and clinical...The differences between primary...Pathophysiology of SSc-related...The clinical consequences of...AcknowledgementsReferences |
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The term primary RP applies when no underlying condition is known, whereas the term secondary RP is used when there is a causal relation to an underlying disease or intake of certain drugs. Secondary RP is most frequently encountered in SSc, but is also associated with other autoimmune diseases (systemic lupus erythematodes and dermatomyositis), as well as with cryoglobulinaemia, paraneoplasia or a thoracic outlet syndrome. Eliciting drugs are vinblastine or interferon-
, while non-selective beta blockers do not necessarily trigger RP (yet, they should be avoided if possible). Clinically, secondary RP can usually be distinguished from primary RP by (i) a later onset (>30 yrs), (ii) presence or higher severity of pain and discomfort, (iii) presence of relevant titres of antinuclear antibodies, (iv) certain morphological alterations of nailfold capillaries, (v) complications such as ulcerations and (vi) by definition, symptoms of the underlying connective tissue disease such as fibrosis in SSc.
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Pathophysiology of SSc-related Raynaud's phenomenon |
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TopAbstractIntroductionDefinition and clinical...The differences between primary...Pathophysiology of SSc-related...The clinical consequences of...AcknowledgementsReferences |
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In SSc, secondary RP is the initial or heralding symptom in over 90% of patients, and it may also present the overture in the pathophysiology of SSc, setting the tone for the processes leading to sclerosis [1]. Also, vascular changes in the skin may at least partially reflect vascular alterations in other organs and thus allow the study of general pathomechanisms in SSc. Therefore, insights into pathomechanisms of RP should improve treatment of both RP and SSc.
Vascular tone is controlled by complex interactions between endothelial cells, the muscular layer, soluble mediators and neuronal stimulation. The imbalance between strong vasoconstricting and weaker vasodilatory events is central to the pathophysiology. Some of the underlying pathomechanisms may be intrinsic disturbances of endothelial or vascular smooth muscle cells; some may be extrinsic, encompassing neuroregulation and soluble mediators.
Mechanisms of cold-induced vasculopathy
The vascular system of acral parts of the body has major thermoregulatory functions and, as such, is influenced by environmental temperature. Therefore, RP affects primarily digits or toes.
Primary and secondary RP appear to have in common an unphysiologically increased contractile response to sudden cooling and to 2-adrenergic agonists. The cold-induced vascular reactivity was recently shown to be associated with increased activity of protein tyrosine kinase (PTK) [2]. It is of therapeutic interest that this high vascular reactivity can be abolished by an inhibitor of PTK (genistein) [2]. However, at present, it is unknown which of the proteins phosphorylated by the kinase would be responsible for inducing RP. The 2c-adrenergic receptors are the main mediators for cold-induced vasoconstricting signals to smooth muscle cells in cutaneous arteries [3]. Their increased reactivity may even precede other endothelial dysfunctions in SSc [4]. Cooling also induces activation of the Rho/Rho kinase signalling pathway and was shown to increase the transport of 2c-adrenergic receptors from their storage site in the Golgi complex to the cellular membrane. This was associated with an increased sensitivity of the cells to cold-induced adrenergic constrictive signals [5] and with a higher reagibility of contractile proteins to Ca++.
These observations encourage the pursuit of two therapeutic strategies:
- Blockade of 2c-adrenoreceptors: while unselective blockade of 2-receptors (e.g. by prazosin) has moderate clinical effects, the selective blockade of 2c adrenoreceptors yielded new promising results in two clinical studies [6, 7].
- Inhibition of Rho-kinase signalling pathway: experimental use of an inhibitor (fasudil) abolished both the translocation of the receptors and the 2 adrenergic constrictive response [5].
The sensitivity of contractile smooth muscle proteins to Ca++ also explains how it could become such a long-standing strategy to use calcium channel blockers in RP; especially in primary RP they have exhibited relevant vasodilatory and spasm-relieving effects.
Role of soluble mediators for the vascular tone
Vascular tone is additionally regulated by soluble vasoconstrictive (e.g. endothelin-1, angiotensin-II, thromboxan-A2, serotonin) and vasodilatory (e.g. prostacyclin, NO, substance P, calcitonine gene-related peptide and acethylcholine) mediators, most of which are produced by endothelial cells.
There is usually a fine interactive balance between endothelin and NO, with endothelin inducing release of NO, which in turn suppresses activity of endothelin. The vasodilatory effects of NO and prostacyclines are mediated via the cyclic nucleotides cAMP and cGMP. Their degradation is controlled by several phosphodiesterases. These processes are exploited therapeutically by the use of antagonists to endothelin receptors (e.g. bosentan) and inhibitors of phosphodiesterases (e.g. sildenafil).
The therapeutic efficacy of inhibitors of phosphodiesterase or prostacyclin analogues (iloprost) in RP, or of substances neutralizing the effects of endothelin, suggests the presence of a disturbed balance between these factors in secondary RP. However, such an impaired homoeostasis has not been unequivocally demonstrated yet for RP. One study showed increased concentrations of inhibitors to endothelial NO production and of endothelin [8] in patients with RP, but the latter could not be confirmed [9]. Furthermore, it remains unproven if the measured endothelin represented biologically active endothelin. In skin biopsies of patients with SSc-associated RP, density of receptors for endothelin was higher than in primary RP or healthy skin [10]; however, it was not analysed if these receptors were localized to the digital arteries, whose spasms actually elicit RP.
There appears to be partial organ specificity of vasoactive mediators with regard to their effects on vascular complications and RP-like symptoms in SSc. As such, inhibitors of ACE and endothelin receptor antagonists, respectively, have undisputed effects in treating renal crisis and pulmonary hypertension, respectively [11, 12]. Yet, their effects on secondary cutaneous RP in SSc were not always significant [13] or require further analysis.
The heterogeneity of vascular complications and of organ involvement in different patients suffering from secondary RP may reflect differences in the extent to which certain pathogenetic mechanisms contribute to the disease in different individuals.
Other pathomechanisms suggested in RP encompass unphysiological activation of platelets, dysfunctions of fibrinolysis or of other components of the coagulation system, as well as disturbances of blood flow due to increased viscosity [14].
The contribution of platelets to RP and SSc has not been defined yet, but they clearly have a potential role in increasing vasoconstriction by release of serotonin and thromboxane-A2 as well as by inducing fibrosis via release of TGF-ß.
Structural vascular alterations in secondary RP
In addition to increased contractile responses, secondary RP in SSc characteristically is also associated with structural alterations of the involved vessels. In primary RP such changes are usually absent so that even a total shut down of the thermoregulatory blood flow still leaves sufficient nutritional blood flow (about 10% of total blood flow) and does not result in ischaemia. In secondary RP, structural vascular changes in small- and medium-sized arteries lead to fixed narrowing of the lumen. They consist of intima proliferation and fibrosis as a result of aberrant migration of activated smooth muscle cells into the intima, their differentiation in myofibroblasts and their concomitant release of collagen and other components of extracellular matrix (ECM). As a result of this intimal fibrosis, these vessels cannot compensate for a major impairment of blood flow during severe attacks of secondary RP. This then leads to critical impairment of blood flow and to so-called ischaemia-reperfusion reactions. They may include (i) activation of endothelial adhesion molecules, (ii) higher release of vasoconstrictors or reduced release of vasodilators, (iii) increase of oxygen radicals and of other toxic products that could modify antigens to induce autoimmunity, (iv) activation of platelets with release of the vasoconstrictors serotonin and thromboxane and (v) possibly a procoagulant endothelial surface. These factors increase the propensity for new attacks of RP and thus induce further structural alterations of the vessels [14], a vicious circle.
Inflammation of blood vessels
In addition, vascular complications in SSc may result not only from a vasospastic and prothrombotic constellation but also from an inflammatory response with potentially damaging effects to the vessel wall. Most inflammatory reactions do not directly harm endothelial cells. However, in secondary RP and SSc, the unphysiological stimulation of endothelial adhesion molecules, the initial presence of leucocytes, and the pro-coagulant constellation may present such a vessel-damaging constellation as has been described in other models [15].
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The clinical consequences of SSc-related Raynaud's phenomenon |
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TopAbstractIntroductionDefinition and clinical...The differences between primary...Pathophysiology of SSc-related...The clinical consequences of...AcknowledgementsReferences |
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RP and vascular complications as an inductor for fibrosis
The vascular hypothesis states that the alterations caused by secondary RP are direct triggers for the devastating fibrotic processes in SSc.
There is increasing evidence for this hypothesis on the molecular level: endothelin has profibrotic effects, NO inhibits proliferation of smooth muscle cells and hypoperfusion or ischaemia generally induce fibrotic reactions in the tissue. A proof of this hypothesis would be if successful therapeutic prevention of RP would also stop fibrosis.
Vascular complications as direct consequences of vascular alterations in SSc
While pulmonary hypertension is one of the most critical complications of the vascular system in SSc, digital ulcers are a frequent complication secondary to RP on the skin. They are a result of ischaemia due to the structural vascular alterations in SSc. Perivascular sclerosis in advanced stages of SSc additionally contributes to severe and continuing hypoperfusion. This hypoperfusion and fibrosis around skin appendages lead to the characteristic dryness, fissuring and crusting of the skin of the digits in SSc. Later on, vascular complication may thus progress to gangrene and to amputation of digits.
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Acknowledgements |
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This work was supported by grants from BMBF Fkz 01 GM 0310 (C.S. and G.R.).
C.S. received speaker's honorarium for participation at Actelion Winter School.
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References |
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