Handy Hints About Raynaud’s Phenomenon in Children: A Critical Review Donato Rigante, Ph.D., M.D.,* Michele Fastiggi, M.D.,* Francesco Ricci, M.D.,† Francesca D’Errico, M.D.,* Benedetta Bracci, M.D.,* and Cristina Guerriero, Ph.D., M.D.† *Institute of Pediatrics, †Institute of Dermatology, Universit a Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy Abstract: Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited episodes of skin pallor, cyanosis, and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes and can occur in any age group. Hands, feet, nose, ears, and nipples can be affected. The diagnosis is made clinically, assessing varying degrees of ischemia in the involved areas of skin, but this transient ischemia may also herald the onset of connective tissue disease. Investigation is recommended when RP starts in childhood to exclude an underlying autoimmune condition and close follow-up for its develop- ment. Management of RP in children includes conservative and pharma- cologic treatments. Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited epi- sodes of skin pallor, cyanosis and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes, which can occur at any age. The hands, feet, nose, ears, and nipples can be affected, even in the pediatric population. At a clinical level, pediatricians and dermatologists can assess varying degrees of ischemia in the involved areas of skin, and indeed this transient ischemia may also represent a sign of different connective tissue diseases (CTDs), which can start insidiously in young people (1). The general rules to manage RP can be summar- ized in four actions: prove the diagnosis, assess any risk factors of an underlying disease, distinguish whether it is primary or secondary RP, and consider either conservative or pharmacologic treatments. CONFIRM THE DIAGNOSIS OF RP Classically, RP is defined according to the occurrence of triphasic color changes in the fingers or toes, with blanching (white) followed by cyanosis (blue) and then reactive hyperemia (red) (2,3), although not every patient experiences these three color changes. Biphasic and triphasic color changes are less common than monophasic changes in primary and secondary RP, consisting of an isolated bluish discoloration of the digits (4). Despite the lack of large-scale popula- tion data, RP is considered to be rare in children. Address correspondence to Francesco Ricci, M.D., Institute of Dermatology, Universit a Cattolica Sacro Cuore, Largo A. Gemelli 8-00168 Rome, Italy, or e-mail: [email protected]. DOI: 10.1111/pde.13129 © 2017 Wiley Periodicals, Inc. 235 REVIEW ARTICLES Pediatric Dermatology Vol. 34 No. 3 235–239, 2017
Handy Hints About Raynaud’s Phenomenon in Children: A Critical Review
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Handy Hints About Raynaud's Phenomenon in Children: A Critical ReviewHandy Hints About Raynaud’s Phenomenon in Children: A Critical Review
Donato Rigante, Ph.D., M.D.,* Michele Fastiggi, M.D.,* Francesco Ricci, M.D.,† Francesca D’Errico, M.D.,* Benedetta Bracci, M.D.,* and Cristina Guerriero, Ph.D., M.D.†
*Institute of Pediatrics, †Institute of Dermatology, Universita Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
Abstract: Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited episodes of skin pallor, cyanosis, and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes and can occur in any age group. Hands, feet, nose, ears, and nipples can be affected. The diagnosis is made clinically, assessing varying degrees of ischemia in the involved areas of skin, but this transient ischemiamay also herald the onset of connective tissue disease. Investigation is recommended when RP starts in childhood to exclude an underlying autoimmune condition and close follow-up for its develop- ment. Management of RP in children includes conservative and pharma- cologic treatments.
Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited epi- sodes of skin pallor, cyanosis and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes, which can occur at any age. The hands, feet, nose, ears, and nipples can be affected, even in the pediatric population. At a clinical level, pediatricians and dermatologists can assess varying degrees of ischemia in the involved areas of skin, and indeed this transient ischemia may also represent a sign of different connective tissue diseases (CTDs), which can start insidiously in young people (1).
The general rules to manage RP can be summar- ized in four actions: prove the diagnosis, assess any risk factors of an underlying disease, distinguish
whether it is primary or secondary RP, and consider either conservative or pharmacologic treatments.
CONFIRM THE DIAGNOSIS OF RP
Classically, RP is defined according to the occurrence of triphasic color changes in the fingers or toes, with blanching (white) followed by cyanosis (blue) and then reactive hyperemia (red) (2,3), although not every patient experiences these three color changes. Biphasic and triphasic color changes are less common than monophasic changes in primary and secondary RP, consisting of an isolated bluish discoloration of the digits (4). Despite the lack of large-scale popula- tion data, RP is considered to be rare in children.
Address correspondence to Francesco Ricci, M.D., Institute of Dermatology, Universita Cattolica Sacro Cuore, Largo A. Gemelli 8-00168 Rome, Italy, or e-mail: [email protected].
DOI: 10.1111/pde.13129
REVIEW ARTICLES
Another condition that can mimic the hyperemic phase of RP is primary erythromelalgia, a rare autosomal dominant disorder characterized by recur- rent burning pain, warmth, and redness of the extremities. Warm temperatures worsen symptoms and cold exposure provides relief. These patients frequently ask to immerse their hands in ice-cold water for pain relief (12).
Chronic chilblains, also known as pernio, are painful localized inflammatory lesions of the skin resulting from an abnormal response to cold temper- atures and should be kept in mind for differential diagnosis of RP. They are usually characterized by a prolonged capillary refill time, an abnormal modified Allen test (to evaluate arterial blood flow), finger swelling, and even skin ulcerations (13). Moreover, simple excessive cold hypersensitivity can also be confused with RP. Some epidemiologic studies have shown that this sensitivity in the extremities can be found in 10% of healthy people, who do not report any skin color abnormalities (14,15).
ASSESSRISK FACTORS ANDCOMORBIDITIES
Risk factors for RP in children have not been completely elucidated, but there is general agreement that living in cold climates, female sex, positive family history, and any associated immune-mediated condi- tion may be associated with RP (16). Most rheuma- tologic disorders and many noninflammatory processes are associated with RP, and different case reports have shown that several diseases or drugs can trigger RP in children (Table 1) (17–23). RP may be the sentinel sign of various rheumatologic disorders, including progressive systemic sclerosis (scleroderma), systemic lupus erythematosus, rheumatoid arthritis
(or juvenile idiopathic arthritis in patients younger than 16 years), dermatomyositis, and mixed CTD (24). Pavlov et al (25) reported that 32 of 250 children with RP fulfilled criteria for the diagnosis of one specific CTD after 2 years of follow-up and that the mean time between the onset of RP and diagnosis of a rheumatologic disease was at least 2.4 years. Simi- larly, an Italian multicenter study revealed that 8% of children and adolescents with RP developed a rheumatologic disease over a 3-year period (26). Secondary RP has also been reported in the setting of autoinflammatory syndromes, a heterogeneous group of diseases characterized by inflammatory flares unrelated to autoimmune or infectious triggers (27), such as familial Mediterranean fever (FMF). In particular, Dinc et al (28) showed that individuals with FMF might manifest RP with tortuosity and enlargement of capillary loops on nailfold video capillaroscopy (NVC). New-onset RP apparently induced by parvovirus B19 infection was described in two previously healthy 13- and 14-year-old sisters. The pathogenesis was related to direct virus-induced endothelial damage leading to the activation of platelets and subsequent vasoconstrictive response.
TABLE 1. Medical Conditions and Medications Associated with Raynaud’s Phenomenon
Rheumatologic disorders Systemic sclerosis spectrum (scleroderma) Systemic lupus erythematosus Rheumatoid arthritis and juvenile idiopathic arthritis Dermatomyositis, polymyositis Mixed connective tissue disease Takayasu arthritis Giant cell arteritis (17) Primary biliary cirrhosis (18)
Mechanical injury Recurring trauma Thoracic outlet syndrome
Arterial disease: brachiocephalic atherosclerosis Vasospastic disease: migraine Hematologic disease Cryoglobulins Cold agglutinin disease Polycythemia Hyperhomocysteinemia (30)
Infection Parvovirus B19 (19,27) Helicobacter pylori (20)
Medication Beta blockers Bleomycin Vinblastine Fluorouracil Methysergide Interferon a (21) Interferon b (22) Methylphenidate (23)
Endocrinopathy: hypothyroidism Other: cold blood transfusion (27)
236 Pediatric Dermatology Vol. 34 No. 3 May/June 2017
Zhang and Cote (29) reported typical RP triggered by the transfusion of cold blood in a 2-year-old burn patient under general anesthesia.
DISTINGUISH PRIMARY AND
SECONDARY RP
RP can be designated as primary (or Raynaud’s disease) if there is no known underlying illness to justify its occurrence and secondary (or Raynaud’s syndrome) if there is an associated disorder detected upon instrumental and laboratory assessments. This distinction is important because it can influence prognosis, severity, and treatment. LeRoy and Meds- ger (24) described the distinguishing clues in identify- ing primary RP: history of episodic peripheral pallor or cyanosis, absence of peripheral vascular disease, no evidence of tissue necrosis, normal nailfold capillaries, negative antinuclear antibody (ANA) test, and nor- mal erythrocyte sedimentation rate. Moreover, clini- cians should determine whether there is a family history of RP and whether the child has had digital ulcers or any other symptoms that might reveal an underlying autoimmune disorder, including oral ulcers, photosensitivity, alopecia, easy bruising, dys- pnea, headache or other neurologic symptoms, dry eyes or dry mouth, eye pain or redness, weight loss, and recurrent fevers. A drug history should also be taken (30).
Digital ulcers may be an indication of an underly- ing autoimmune disorder (31,32), and the detection of ANA and abnormal results of NVC are of paramount importance to reinforce the suspicion of rheumato- logic disorders. Several studies have illustrated the clinical utility of ANA testing to detect most rheuma- tologic disorders, although a positive ANA can be encountered in otherwise healthy children (33). A recent Italian study revealed that 63% of a cohort of children with RP who developed rheumatologic diseases over time had a ANA titer above 1:160 and that only 22% of the cohort with primary RP had this positivity (26). Similarly, in a retrospective study of 123 pediatric cases of RP, ANA positivity was present in 85% of patients with secondary RP and 25% of those with primary RP (2).
Children with RP might also have high S-homo- cysteine levels, suggesting that homocysteine plays a role in the development of vascular dysfunction, even in children (34). Antiphospholipid antibodies (aPL) were found in 21% of children with primary and secondary RP (2), but the association between aPL and RP was not found in 40 patients with systemic lupus erythematosus and RP. Thrombotic events may
complicate severe forms of digital vasospasms, and patients with RP unresponsive to conventional vasodilator treatments might also require long-term anticoagulation (35). With regard to confirmation of the diagnosis, skin examination using skin surface microscopy, known as dermoscopy or epilu- minoscopy may be helpful. Using a high-quality lens with 10 to 14 times magnification and a lighting system enables the visualization of subsurface struc- tures and patterns of capillaries in the fingers of patients with RP. However, NVC is the essential screening tool for children and adolescents with RP, mainly to specify any vascular abnormality eventually associated with CTDs (37). Pavlov-Dolijanovic et al (25) distinguished three capillaroscopic patterns: nor- mal (with a typical hairpin structure), nonspecific (with meandering and crossed capillaries, focal distri- bution of hemorrhages, edema, and capillary spasms), and sclerodermic (with low capillary density and the presence of dilated loops or avascular areas). In this study, which recruited 250 children and young adults 10 to 20 years of age, approximately 90% of subjects with RP and 65% of those with secondary RP maintained a primarily normal capillaroscopic frame- work. In addition, those with secondary RP had a nonspecific pattern in 18% of cases and a sclerodermic pattern in a minority. Another study of 123 children with primary RP showed that NVC was altered in only 23% of cases, in contrast to 68% of those with secondary RP (5). Although thermography (an infrared camera to determine skin temperature distri- butions by measuring thermal radiation) can help distinguish between patients with primary RP and RP secondary to scleroderma, this is an expensive tech- nique, available in only a few specialized centers (38). Additionally, when RP is present unilaterally, and especially if the peripheral pulse is difficult to perceive, investigation with Doppler ultrasonography and angiography should be performed (30).
EVALUATE BOTH CONSERVATIVE AND
PHARMACOLOGIC TREATMENTS
Practical management of RP must be adapted to the level of discomfort and the eventual cause of the vasospastic disorder; the prescribing of drugs should be restricted to the most severe cases. Treatment of RP in children depends on the severity of digital ischemia, limitations on everyday life, and the pres- ence of underlying diseases (39,40). Treatment modal- ities are derived from clinical experience in adults since studies in children are limited. Starting with conservative lifestyle modifications, such as avoiding
Rigante et al: Handy Hints About Raynaud’s Phenomenon 237
cold exposure, moving to warmer climates, and protecting exposed skin areas during cool weather, is an appropriate way to manage all forms of noncomplicated RP in children. Minimizing exposure to cold and protecting the entire body, not just the fingers, with gloves, footwear, hats, scarves, and facemasks should be the criterion standard of treat- ment. In addition, all medications that might increase the risk of vasoconstriction, such as beta blockers, should be avoided (4). Therapeutic studies in adults who do not respond to nonpharmacologic measures have shown that calcium channel blockers are first- choice drugs for primary (41) and secondary (sclero- derma-related) RP (42). Conversely, there is little evidence related to children. The most used drugs for children with mild to moderate RP are calcium channel blockers, such as nifedipine or amlodipine (31), although Gargh et al (40) found that topical application of glyceryl trinitrate patches was effective and well tolerated in more than half of treated patients. Iloprost (a prostacyclin analogue given intravenously) is used in the most severe cases of RP, mostly when symptoms persist despite preventive measures or in children with underlying autoimmune diseases. In particular, iloprost has been proven to be a safe and effective treatment for digital ulcers in children with different underlying rheumatologic disorders, and the combination of iloprost and immunosuppressive drugs might have a role in preventing irreversible complications, such as digital gangrene and amputation (43).
CONCLUSION
In conclusion, although RP was first described more than 100 years ago, little is truly understood about this disorder in children, including its natural history and optimal treatment. Pediatric dermatologists and rheumatologists involved in the care of children should be somewhat confident with the classification, diagnostic assessment, and management strategies of RP given the current data. It is vital that children and adolescents with RP be followed over the long term to monitor for the development of any associated rheumatologic disorders.
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19. Harel L, Straussberg R, Rudich H et al. Raynaud’s phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes. Clin Infect Dis 2000;30:500–503.
20. Gasbarrini A, Massari I, Serricchio M et al. Helicobac- ter pylori eradication ameliorates primary Raynaud’s phenomenon. Dig Dis Sci 1998;43:1641–1645.
21. Kruit WH, Eggermont AM, Stoter G. Interferon- induced Raynaud’s syndrome. Ann Oncol 2000;11: 1501–1502.
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23. GoldmanW, Seltzer R, Reuman P. Association between treatment with central nervous system stimulants and Raynaud’s syndrome in children: a retrospective
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25. Pavlov-Dolijanovic S, Damjanov N, Ostojic P, et al. The prognostic value of nailfold capillary changes for the development of connective tissue disease in children and adolescents with primary Raynaud phenomenon: a follow-up study of 250 patients. Pediatr Dermatol 2006;23:437–442.
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35. Caccavo D, Del Porto F, Garzia P et al. Raynaud’s phenomenon and antiphospholipid antibodies in sys- temic lupus erythematosus: is there an association? Ann Rheum Dis 2003;62:1003–1005.
36. Hughes M, Moore T, O’Leary N et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis-spectrum disorders. Rheumatology (Oxford) 2015;54:1435–1442.
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38. Anderson ME, Moore TL, Lunt M, Herrick AL. The ‘distal-dorsal difference’: a thermographic parameter by which to differentiate between primary and secondary Raynaud’s phenomenon. Rheumatology (Oxford) 2007;46:533–538.
39. Bakst R, Merola JF, Franks AG Jr, Sanchez M. Raynaud’s phenomenon: pathogenesis and manage- ment. J Am Acad Dermatol 2008;59:633–653.
40. Gargh K, Baildam EM, Cleary GA et al. A retrospec- tive clinical analysis of pharmacological modalities used for symptomatic relief of Raynaud’s phenomenon in children treated in a UK paediatric rheumatology centre. Rheumatology (Oxford) 2010;49:193–194.
41. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis. Rheumatology (Oxford) 2005;44:145–150.
42. Thompson AE, Shea B, Welch V et al. Calcium channel blockers for Raynaud’s phenomenon in systemic scle- rosis. Arthritis Rheum 2001;44:1841–1847.
43. Zulian F, Corona F, Gerloni V et al. Safety and efficacy of iloprost for the treatment of ischaemic digits in paediatric connective tissue diseases. Rheumatology (Oxford) 2004;43:229–233.
Donato Rigante, Ph.D., M.D.,* Michele Fastiggi, M.D.,* Francesco Ricci, M.D.,† Francesca D’Errico, M.D.,* Benedetta Bracci, M.D.,* and Cristina Guerriero, Ph.D., M.D.†
*Institute of Pediatrics, †Institute of Dermatology, Universita Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
Abstract: Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited episodes of skin pallor, cyanosis, and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes and can occur in any age group. Hands, feet, nose, ears, and nipples can be affected. The diagnosis is made clinically, assessing varying degrees of ischemia in the involved areas of skin, but this transient ischemiamay also herald the onset of connective tissue disease. Investigation is recommended when RP starts in childhood to exclude an underlying autoimmune condition and close follow-up for its develop- ment. Management of RP in children includes conservative and pharma- cologic treatments.
Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by recurrent self-limited epi- sodes of skin pallor, cyanosis and hyperemia caused by paroxysmal spasms in the small arteries of the fingers and toes, which can occur at any age. The hands, feet, nose, ears, and nipples can be affected, even in the pediatric population. At a clinical level, pediatricians and dermatologists can assess varying degrees of ischemia in the involved areas of skin, and indeed this transient ischemia may also represent a sign of different connective tissue diseases (CTDs), which can start insidiously in young people (1).
The general rules to manage RP can be summar- ized in four actions: prove the diagnosis, assess any risk factors of an underlying disease, distinguish
whether it is primary or secondary RP, and consider either conservative or pharmacologic treatments.
CONFIRM THE DIAGNOSIS OF RP
Classically, RP is defined according to the occurrence of triphasic color changes in the fingers or toes, with blanching (white) followed by cyanosis (blue) and then reactive hyperemia (red) (2,3), although not every patient experiences these three color changes. Biphasic and triphasic color changes are less common than monophasic changes in primary and secondary RP, consisting of an isolated bluish discoloration of the digits (4). Despite the lack of large-scale popula- tion data, RP is considered to be rare in children.
Address correspondence to Francesco Ricci, M.D., Institute of Dermatology, Universita Cattolica Sacro Cuore, Largo A. Gemelli 8-00168 Rome, Italy, or e-mail: [email protected].
DOI: 10.1111/pde.13129
REVIEW ARTICLES
Another condition that can mimic the hyperemic phase of RP is primary erythromelalgia, a rare autosomal dominant disorder characterized by recur- rent burning pain, warmth, and redness of the extremities. Warm temperatures worsen symptoms and cold exposure provides relief. These patients frequently ask to immerse their hands in ice-cold water for pain relief (12).
Chronic chilblains, also known as pernio, are painful localized inflammatory lesions of the skin resulting from an abnormal response to cold temper- atures and should be kept in mind for differential diagnosis of RP. They are usually characterized by a prolonged capillary refill time, an abnormal modified Allen test (to evaluate arterial blood flow), finger swelling, and even skin ulcerations (13). Moreover, simple excessive cold hypersensitivity can also be confused with RP. Some epidemiologic studies have shown that this sensitivity in the extremities can be found in 10% of healthy people, who do not report any skin color abnormalities (14,15).
ASSESSRISK FACTORS ANDCOMORBIDITIES
Risk factors for RP in children have not been completely elucidated, but there is general agreement that living in cold climates, female sex, positive family history, and any associated immune-mediated condi- tion may be associated with RP (16). Most rheuma- tologic disorders and many noninflammatory processes are associated with RP, and different case reports have shown that several diseases or drugs can trigger RP in children (Table 1) (17–23). RP may be the sentinel sign of various rheumatologic disorders, including progressive systemic sclerosis (scleroderma), systemic lupus erythematosus, rheumatoid arthritis
(or juvenile idiopathic arthritis in patients younger than 16 years), dermatomyositis, and mixed CTD (24). Pavlov et al (25) reported that 32 of 250 children with RP fulfilled criteria for the diagnosis of one specific CTD after 2 years of follow-up and that the mean time between the onset of RP and diagnosis of a rheumatologic disease was at least 2.4 years. Simi- larly, an Italian multicenter study revealed that 8% of children and adolescents with RP developed a rheumatologic disease over a 3-year period (26). Secondary RP has also been reported in the setting of autoinflammatory syndromes, a heterogeneous group of diseases characterized by inflammatory flares unrelated to autoimmune or infectious triggers (27), such as familial Mediterranean fever (FMF). In particular, Dinc et al (28) showed that individuals with FMF might manifest RP with tortuosity and enlargement of capillary loops on nailfold video capillaroscopy (NVC). New-onset RP apparently induced by parvovirus B19 infection was described in two previously healthy 13- and 14-year-old sisters. The pathogenesis was related to direct virus-induced endothelial damage leading to the activation of platelets and subsequent vasoconstrictive response.
TABLE 1. Medical Conditions and Medications Associated with Raynaud’s Phenomenon
Rheumatologic disorders Systemic sclerosis spectrum (scleroderma) Systemic lupus erythematosus Rheumatoid arthritis and juvenile idiopathic arthritis Dermatomyositis, polymyositis Mixed connective tissue disease Takayasu arthritis Giant cell arteritis (17) Primary biliary cirrhosis (18)
Mechanical injury Recurring trauma Thoracic outlet syndrome
Arterial disease: brachiocephalic atherosclerosis Vasospastic disease: migraine Hematologic disease Cryoglobulins Cold agglutinin disease Polycythemia Hyperhomocysteinemia (30)
Infection Parvovirus B19 (19,27) Helicobacter pylori (20)
Medication Beta blockers Bleomycin Vinblastine Fluorouracil Methysergide Interferon a (21) Interferon b (22) Methylphenidate (23)
Endocrinopathy: hypothyroidism Other: cold blood transfusion (27)
236 Pediatric Dermatology Vol. 34 No. 3 May/June 2017
Zhang and Cote (29) reported typical RP triggered by the transfusion of cold blood in a 2-year-old burn patient under general anesthesia.
DISTINGUISH PRIMARY AND
SECONDARY RP
RP can be designated as primary (or Raynaud’s disease) if there is no known underlying illness to justify its occurrence and secondary (or Raynaud’s syndrome) if there is an associated disorder detected upon instrumental and laboratory assessments. This distinction is important because it can influence prognosis, severity, and treatment. LeRoy and Meds- ger (24) described the distinguishing clues in identify- ing primary RP: history of episodic peripheral pallor or cyanosis, absence of peripheral vascular disease, no evidence of tissue necrosis, normal nailfold capillaries, negative antinuclear antibody (ANA) test, and nor- mal erythrocyte sedimentation rate. Moreover, clini- cians should determine whether there is a family history of RP and whether the child has had digital ulcers or any other symptoms that might reveal an underlying autoimmune disorder, including oral ulcers, photosensitivity, alopecia, easy bruising, dys- pnea, headache or other neurologic symptoms, dry eyes or dry mouth, eye pain or redness, weight loss, and recurrent fevers. A drug history should also be taken (30).
Digital ulcers may be an indication of an underly- ing autoimmune disorder (31,32), and the detection of ANA and abnormal results of NVC are of paramount importance to reinforce the suspicion of rheumato- logic disorders. Several studies have illustrated the clinical utility of ANA testing to detect most rheuma- tologic disorders, although a positive ANA can be encountered in otherwise healthy children (33). A recent Italian study revealed that 63% of a cohort of children with RP who developed rheumatologic diseases over time had a ANA titer above 1:160 and that only 22% of the cohort with primary RP had this positivity (26). Similarly, in a retrospective study of 123 pediatric cases of RP, ANA positivity was present in 85% of patients with secondary RP and 25% of those with primary RP (2).
Children with RP might also have high S-homo- cysteine levels, suggesting that homocysteine plays a role in the development of vascular dysfunction, even in children (34). Antiphospholipid antibodies (aPL) were found in 21% of children with primary and secondary RP (2), but the association between aPL and RP was not found in 40 patients with systemic lupus erythematosus and RP. Thrombotic events may
complicate severe forms of digital vasospasms, and patients with RP unresponsive to conventional vasodilator treatments might also require long-term anticoagulation (35). With regard to confirmation of the diagnosis, skin examination using skin surface microscopy, known as dermoscopy or epilu- minoscopy may be helpful. Using a high-quality lens with 10 to 14 times magnification and a lighting system enables the visualization of subsurface struc- tures and patterns of capillaries in the fingers of patients with RP. However, NVC is the essential screening tool for children and adolescents with RP, mainly to specify any vascular abnormality eventually associated with CTDs (37). Pavlov-Dolijanovic et al (25) distinguished three capillaroscopic patterns: nor- mal (with a typical hairpin structure), nonspecific (with meandering and crossed capillaries, focal distri- bution of hemorrhages, edema, and capillary spasms), and sclerodermic (with low capillary density and the presence of dilated loops or avascular areas). In this study, which recruited 250 children and young adults 10 to 20 years of age, approximately 90% of subjects with RP and 65% of those with secondary RP maintained a primarily normal capillaroscopic frame- work. In addition, those with secondary RP had a nonspecific pattern in 18% of cases and a sclerodermic pattern in a minority. Another study of 123 children with primary RP showed that NVC was altered in only 23% of cases, in contrast to 68% of those with secondary RP (5). Although thermography (an infrared camera to determine skin temperature distri- butions by measuring thermal radiation) can help distinguish between patients with primary RP and RP secondary to scleroderma, this is an expensive tech- nique, available in only a few specialized centers (38). Additionally, when RP is present unilaterally, and especially if the peripheral pulse is difficult to perceive, investigation with Doppler ultrasonography and angiography should be performed (30).
EVALUATE BOTH CONSERVATIVE AND
PHARMACOLOGIC TREATMENTS
Practical management of RP must be adapted to the level of discomfort and the eventual cause of the vasospastic disorder; the prescribing of drugs should be restricted to the most severe cases. Treatment of RP in children depends on the severity of digital ischemia, limitations on everyday life, and the pres- ence of underlying diseases (39,40). Treatment modal- ities are derived from clinical experience in adults since studies in children are limited. Starting with conservative lifestyle modifications, such as avoiding
Rigante et al: Handy Hints About Raynaud’s Phenomenon 237
cold exposure, moving to warmer climates, and protecting exposed skin areas during cool weather, is an appropriate way to manage all forms of noncomplicated RP in children. Minimizing exposure to cold and protecting the entire body, not just the fingers, with gloves, footwear, hats, scarves, and facemasks should be the criterion standard of treat- ment. In addition, all medications that might increase the risk of vasoconstriction, such as beta blockers, should be avoided (4). Therapeutic studies in adults who do not respond to nonpharmacologic measures have shown that calcium channel blockers are first- choice drugs for primary (41) and secondary (sclero- derma-related) RP (42). Conversely, there is little evidence related to children. The most used drugs for children with mild to moderate RP are calcium channel blockers, such as nifedipine or amlodipine (31), although Gargh et al (40) found that topical application of glyceryl trinitrate patches was effective and well tolerated in more than half of treated patients. Iloprost (a prostacyclin analogue given intravenously) is used in the most severe cases of RP, mostly when symptoms persist despite preventive measures or in children with underlying autoimmune diseases. In particular, iloprost has been proven to be a safe and effective treatment for digital ulcers in children with different underlying rheumatologic disorders, and the combination of iloprost and immunosuppressive drugs might have a role in preventing irreversible complications, such as digital gangrene and amputation (43).
CONCLUSION
In conclusion, although RP was first described more than 100 years ago, little is truly understood about this disorder in children, including its natural history and optimal treatment. Pediatric dermatologists and rheumatologists involved in the care of children should be somewhat confident with the classification, diagnostic assessment, and management strategies of RP given the current data. It is vital that children and adolescents with RP be followed over the long term to monitor for the development of any associated rheumatologic disorders.
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