|Year : 2018 | Volume
| Issue : 2 | Page : 178-183
Pathophysiology and management of Raynaud's phenomenon
Lauren E Stone1, Vikas Yellapu1, Farhan Ali2, Sahil Agrawal1, Amitoj Singh3, Lohit Garg4, Santo Longo1, Sudip Nanda5
1 Department of Medicine, St. Luke's Bethlehem, Bethlehem, PA, USA
2 Department of Medicine, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
3 Department of Cardiology, Brigham and Women's, Boston, MA, USA
4 Department of Cardiology, Lehigh Valley Hospital, Allentown, PA, USA
5 Department of Cardiovascular Medicine, St. Luke's University Hospital Network, Fountain Hill, PA, USA
|Date of Submission||05-Nov-2017|
|Date of Acceptance||14-Apr-2018|
|Date of Web Publication||30-Aug-2018|
Dr. Sudip Nanda
Department of Cardiovascular Medicine, St. Luke's University Hospital Network, Fountain Hill, PA
Source of Support: None, Conflict of Interest: None
Raynaud's phenomenon (RP) is a multi-etiological vasospastic condition requiring individualized treatment. This case presents a patient with classic primary RP whose symptoms improved after being treated for depression. Her example demonstrates that medication regimen sometimes have unexpected, but positive outcomes.
The following core competencies are addressed in this article: Patient care, Medical knowledge.
Keywords: Polypharmacy, Raynaud's phenomenon, comorbidity management
|How to cite this article:|
Stone LE, Yellapu V, Ali F, Agrawal S, Singh A, Garg L, Longo S, Nanda S. Pathophysiology and management of Raynaud's phenomenon. Int J Acad Med 2018;4:178-83
|How to cite this URL:|
Stone LE, Yellapu V, Ali F, Agrawal S, Singh A, Garg L, Longo S, Nanda S. Pathophysiology and management of Raynaud's phenomenon. Int J Acad Med [serial online] 2018 [cited 2022 Jan 29];4:178-83. Available from: https://www.ijam-web.org/text.asp?2018/4/2/178/240142
| Introduction|| |
Raynaud's phenomenon (RP) is defined as end-extremity pallor with subsequent purplish cyanosis and reactive hyperemic response to a trigger, such as cold exposure, emotional, or physical stress.,, While the digits are the most commonly affected site, the toes, palms, soles, earlobes, and nose have also been indicated, [Figure 1] and [Figure 2]. Other clinical symptoms during attacks can include loss of sensation and reperfusion pain depending on the severity and frequency of occurrences.,, Frequent and prolonged attack can eventually lead to ulceration of the affected extremities.,,
|Figure 1: The patient's hands during a Raynaud's event. Note the purplish discoloration of the distal digits|
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|Figure 2: The most common sites of Raynaud's manifestations are the hands, feet, nose, and earlobes|
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Although clinical presentation is relatively consistent, Raynaud's is divided into several categories by etiology. Primary RP (PRP) is a diagnosis of exclusion whose diagnosis requires the following criteria as follows: (1) normal nail-fold capillaroscopy, (2) absence of a positive antinuclear antibodies titer, and (3) absence of any other precipitating factors, that is, drugs, mechanical trauma, or nerve impingement.,,, It is believed to be due to dysfunctional arteriovenous anastomoses (AVAs) in the palms and soles.,, These anastomoses are unique in that they do not contain a capillary bed, allowing for rapid movement of blood to and from cutaneous circulation., This unique feature, when properly functioning, allows for efficient extremity thermoregulation., Several studies suggest that patients with PRP suffer from an increased number of AVAs with increased alpha-2 adrenergic receptors and sympathetic innervations., These innervations, which dilate and constrict vessels in response to various stimuli, mediate a reflexive vasoconstrictive response,, [Figure 3]. In RP, the cold or stress acts as an aggravating factor, which promotes digital ischemia through an exaggerated sympathetic-induced vasoconstriction.,
|Figure 3: Mechanisms of smooth muscle modulation at the site of an arteriovenous anastomosis PIP2: phosphatidylinositol bisphosphate; IP3: Inositol Triphosphate; GMP: Guanosine monophosphate, AMP: Adenosine monophosphate, cGMP: Cyclic guanosine monophosphate, cAMP: Cyclic adenosine monophosphate, PKG: Protein kinase G, PKA: Protein kinase A|
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Secondary RP (SRP) is multi-etiological. Presentation is similar to primary Raynaud's; however, there are several factors that suggest PRP over SRP, including a milder, painless presentation, and onset of symptoms before the age of 20., [Table 1] shows the discussion of secondary Raynaud's etiologies.
Management of Raynaud's relies on addressing the underlying problem, lifestyle changes, and pharmacotherapy. The latter involves several medications targeting the vascular endothelium and smooth muscle to promote blood flow to the compromised tissue., [Table 2] discusses the various drugs used in the treatment of both primary and secondary Raynaud's.
| Case Report|| |
The patient is a 59-year-old female that presented for evaluation of palpitations. She has a medical history of hyperparathyroidism status-postthymectomy, depression, hypertension, and cold-induced color changes to her fingertips (RP) for the past 30 years [Figure 1]. In the clinic, her vitals were within normal limits. Physical examination did not disclose any abnormalities and revealed no ulceration of her fingers. Her antinuclear antibody test was negative. There were no abnormalities in her complete blood panel or complete metabolic panel. Her electrocardiogram did not show any abnormalities and her tilt table test was negative for autonomic dysfunction. No abnormal rhythm other than sinus arrhythmia was identified.
The patient's long-term medications included losartan, quetiapine, and trazodone. The patient notes that after she was started on quetiapine, her Raynaud's symptoms decreased significantly.
| Discussion|| |
The patient in this case report carries a diagnosis of Raynaud's and long-term depression. In the primary treatment of depression, she found relief of her Raynaud's symptoms without directly addressing this condition with pharmacotherapy. This unexpected result may be due to the mechanisms underlying her medications, which including losartan, quetiapine, and trazodone.
Losartan, an angiotensin-converting enzyme receptor blocker, increases circulating angiotensin II, leading to an increase in circulating blood volume, and decreased the effect of vasoconstriction in the extremities.,,, Trazodone is a serotonin antagonist and reuptake inhibitor that increases serotonin concentration. Serotonin is a vasoactive substance that causes vasodilation., Quetiapine is a serotonin and adrenergic receptor antagonist causing vasodilation. The overall effect of these medication causes increased blood flow, increased vasodilation, and decreased platelet aggregation, mechanisms that parallel normal pharmacological interventions for Raynaud's symptoms.,,, It is, therefore, quite possible that this patient's symptoms dramatically improved as an unexpected consequence of appropriately managing her other conditions. See [Figure 4] and [Figure 5] for a discussion of pertinent vascular receptors indicated in Raynaud's as well as management of both primary and secondary Raynaud's.
|Figure 4: (a) Pharmacological and natural mediators of arterial endothelium and smooth muscle. (b) Key: 5-HT: 5-Hydroxytryptamine, AT-II: Angiotensin 36 37 Receptor|
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|Figure 5: Management for patients with primary and secondary Raynaud's phenomenon|
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| Conclusion|| |
Managing patients with multiple conditions present a challenge when determining efficient pharmacologic intervention. In conditions whose medication choices overlap, such as RP and depression, it is possible to treat all simultaneously or at least wisely choose medications that will reduce symptom burden across multiple conditions. This approach is ideal and avoids the complications and inconvenience of polypharmacy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Ethical conduct of research
Established ethical guidelines for research were utilized during the conduct of this project.
| References|| |
Monro TK. Raynaud's Disease (Local Syncope, Local Asphyxia, Symmetrical Gangrene) its History, Causes, Symptoms, Morbid Relations, Pathology, & Treatment. Glasgow: Maclehose; 1899.
Herrick AL. Pathogenesis of Raynaud's phenomenon. Rheumatology (Oxford) 2005;44:587-96.
Cutolo M, Grassi W, Matucci Cerinic M. Raynaud's phenomenon and the role of capillaroscopy. Arthritis Rheum 2003;48:3023-30.
Gerhard-Herman M, Creager MA. Raynaud's Phenomenon and other Vasospastic Disorders. Atlas of Vascular Disease. London: Springer; 2003. p. 173-88.
Desai R, Korn JH. Diagnosis and management of Raynaud phenomenon: Presence of an underlying medical condition may warrant aggressive treatment. J Musculoskeletal Med 2003;20:124-31.
Bakst R, Merola JF, Franks AG Jr., Sanchez M. Raynaud's phenomenon: Pathogenesis and management. J Am Acad Dermatol 2008;59:633-53.
Prete M, Fatone MC, Favoino E, Perosa F. Raynaud's phenomenon: From molecular pathogenesis to therapy. Autoimmun Rev 2014;13:655-67.
Spencer-Green G. Outcomes in primary Raynaud phenomenon: A meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med 1998;158:595-600.
O'connor CM. Raynaud's phenomenon. J Vasc Nurs 2001;19:87-92.
Varga J. Etiology and pathogenesis of scleroderma A2. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell JR, editors. Kelley and Firestein's Textbook of Rheumatology. 10th
ed., Ch. 83. London Elsevier; 2017. p. 1400-40.e3.
Hirschl M, Hirschl K, Lenz M, Katzenschlager R, Hutter HP, Kundi M, et al.
Transition from primary Raynaud's phenomenon to secondary Raynaud's phenomenon identified by diagnosis of an associated disease: Results of ten years of prospective surveillance. Arthritis Rheum 2006;54:1974-81.
Maverakis E, Patel F, Kronenberg DG, Chung L, Fiorentino D, Allanore Y, et al.
International consensus criteria for the diagnosis of Raynaud's phenomenon. J Autoimmun 2014;48-49:60-5.
Nagy Z, Czirják L. Nailfold digital capillaroscopy in 447 patients with connective tissue disease and Raynaud's disease. J Eur Acad Dermatol Venereol 2004;18:62-8.
Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol 2011;40:78-83.
Eger T, Thompson A, Leduc M, Krajnak K, Goggins K, Godwin A, et al.
Vibration induced white-feet: Overview and field study of vibration exposure and reported symptoms in workers. Work 2014;47:101-10.
Haimovici H, Steinman C, Caplan LH. Role of arteriovenous anastomoses in vascular diseases of the lower extremity. Ann Surg 1966;164:990-1002.
Hamilton WF, Moore JW, Kinsman J, Spurling R. Studies on the circulation: IV. Further analysis of the injection method, and of changes in hemodynamics under physiological and pathological conditions. Am J Physiol Leg Content 1932;99:534-51.
Norton WL, Nardo JM. Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 1970;73:317-24.
Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S, et al.
The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 2015;18:433-48.
Mørk C, Kvernebo K, Asker CL, Salerud EG. Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism. J Invest Dermatol 2002;119:949-53.
Walløe L. Arterio-venous anastomoses in the human skin and their role in temperature control. Temperature (Austin) 2016;3:92-103.
Rychlik-Golema W, Mastej K, Adamiec R. The role of endothelin-1 and selected cytokines in the pathogenesis of Raynaud's phenomenon associated with systemic connective tissue diseases. Int Angiol 2006;25:221-7.
Khouri C, Blaise S, Carpentier P, Villier C, Cracowski JL, Roustit M, et al.
Drug-induced Raynaud's phenomenon: Beyond β-adrenoceptor blockers. Br J Clin Pharmacol 2016;82:6-16.
Wigley FM. Vascular disease in scleroderma. Clin Rev Allergy Immunol 2009;36:150-75.
Greenberg SA. Dermatomyositis and type 1 interferons. Curr Rheumatol Rep 2010;12:198-203.
Houman MH, Bel Feki N. Pathophysiology of Behçet's disease. Rev Med Interne 2014;35:90-6.
Charles ED, Dustin LB. Hepatitis C virus-induced cryoglobulinemia. Kidney Int 2009;76:818-24.
Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al.
Experimental and clinical observations on frostbite. Ann Emerg Med 1987;16:1056-62.
Arkkila PE, Gautier JF. Musculoskeletal disorders in diabetes mellitus: An update. Best Pract Res Clin Rheumatol 2003;17:945-70.
Kobayashi M, Ito M, Nakagawa A, Nishikimi N, Nimura Y. Immunohistochemical analysis of arterial wall cellular infiltration in Buerger's disease (endarteritis obliterans). J Vasc Surg 1999;29:451-8.
Simone B, De Stefano V, Leoncini E, Zacho J, Martinelli I, Emmerich J, et al.
Risk of venous thromboembolism associated with single and combined effects of factor V leiden, prothrombin 20210A and methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013;28:621-47.
Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK, et al.
Polycythemia vera: An appraisal of the biology and management 10 years after the discovery of JAK2 V617F. J Clin Oncol 2015;33:3953-60.
Doll DC, Ringenberg QS, Yarbro JW. Vascular toxicity associated with antineoplastic agents. J Clin Oncol 1986;4:1405-17.
Waller DG, Dathan JR. Raynaud's syndrome and carpal tunnel syndrome. Postgrad Med J 1985;61:161-2.
Urschel HC, Kourlis H. Thoracic outlet syndrome: A 50-year experience at Baylor university medical center. Proc (Bayl Univ Med Cent) 2007;20:125-35.
Ichiki T. Thyroid hormone and vascular remodeling. J Atheroscler Thromb 2016;23:266-75.
Goundry B, Bell L, Langtree M, Moorthy A. Diagnosis and management of Raynaud's phenomenon. BMJ 2012;344:e289.
Dasgupta C, Zhang L. Angiotensin II receptors and drug discovery in cardiovascular disease. Drug Discov Today 2011;16:22-34.
Flavahan NA. A vascular mechanistic approach to understanding Raynaud phenomenon. Nat Rev Rheumatol 2015;11:146-58.
Pancera P, Sansone S, Secchi S, Covi G, Lechi A. The effects of thromboxane A2 inhibition (picotamide) and angiotensin II receptor blockade (losartan) in primary Raynaud's phenomenon. J Intern Med 1997;242:373-6.
Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, et al.
Losartan therapy for Raynaud's phenomenon and scleroderma: Clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 1999;42:2646-55.
Block JA, Sequeira W. Raynaud's phenomenon. Lancet 2001;357:2042-8.
Wood HM, Ernst ME. Renin-angiotensin system mediators and Raynaud's phenomenon. Ann Pharmacother 2006;40:1998-2002.
Herrick AL. Pathogenesis of Raynaud's phenomenon, Rheumatology 2005;44:587-96.
Pollack MH, Rosenbaum JF, Hyman SE. Calcium channel blockers in psychiatry: Potential for a growing role in pharmacotherapy. Psychosomatics 1987;28:356-60.
Rey J, Cretel E, Jean R, Pastor MJ, Durand JM. Serotonin reuptake inhibitors, Raynaud's phenomenon and erythromelalgia. Rheumatology (Oxford) 2003;42:601-2.
Bell C, Coupland N, Creamer P. Digital infarction in a patient with Raynaud's phenomenon associated with treatment with a specific serotonin reuptake inhibitor. A case report. Angiology 1996;47:901-3.
Garcia-Porrua C, Margarinos CC, Gonzalez-Gay MA. Raynaud's phenomenon and serotonin reuptake inhibitors. J Rheumatol 2004;31:2090.
Buecking A, Rougemont E, Fabio Zullino D. Treatment of raynaud's phenomenon with escitalopram. Int J Neuropsychopharmacol 2005;8:307-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]