pISSN: 2093-940X, eISSN: 2233-4718 Journal of Rheumatic Vol. 25, No. 1, January, 2018 https://doi.org/10.4078/jrd.2018.25.1.69 Case Report

Coexistence of and Raynaud’s Phenomenon in a Systemic Erythematosus Patient

Yong-Yon Won1, Eun-Jae Shin2, Ki-Heon Jeong2, Min Kyung Shin2 1Department of Dermatology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 2Department of Dermatology, Kyung Hee University School of Medicine, Seoul, Korea

Erythromelalgia (EM) is an uncommon disorder characterized by redness, heat, and painful extremities with intense burning sensation. Attacks of EM may be worsened by limb warming, exercise, or dependency of the affected extremity. Although the coexistence of EM and Raynaud’s phenomenon (RP) may appear to be opposites in symptomatology and clinical presentation, recent studies provide an explanation based on a dysfunction of the regulation of vasomotor tone. Here, we report a case of EM in a patient with RP. (J Rheum Dis 2018;25:69-72)

Key Words. Erythromelalgia, Raynaud’s phenomenon, Systemic lupus erythematosus

INTRODUCTION some patients with RP, the greatest discomfort occurs with warming the affected limb—a feature it shares with Erythromelalgia (EM), an uncommon disorder first de- EM [5]. Although both RP and EM can occur in patients scribed by Mitchell in 1878, is characterized by redness, with SLE, only a few cases of both conditions coexisting in heat, pain, and an intense burning sensation in the ex- the same patient have been reported [5-8]. We present a tremities. Exacerbation of symptoms may occur follow- case of a patient with SLE showing coexistence of RP and ing warming of a limb, exercise, or placing the affected ex- EM. tremity in a dependent position [1]. It usually occurs in the lower extremities and less commonly affects the up- CASE REPORT per extremities, as well as the face and ears [2]. Primary EM, usually showing symptoms in childhood, is a rare au- A 59-year-old woman was referred to our Dermatology tosomal dominant inherited caused by mutations Department due to a burning sensation accompanied by in the SCN9A gene that encodes a voltage-dependent so- and redness on her palms and soles. Her symp- dium channel α-subunit [3]. Secondary EM is related to toms first occurred 15 days prior to her presentation and various disorders, viz., thrombocythemia, myeloprolifer- were usually exacerbated by warm temperatures and re- ative disorders, arterial , , and sys- lieved by cooling. Her past medical history included is- temic lupus erythematosus (SLE) [4]. chemic dilated cardiomyopathy and a 20-year history of Compared to EM, the most prominent symptom of RP. Her family history was negative for EM, RP, or other Raynaud phenomenon (RP) is whiteness of digits occur- diseases. Although the history of her medication was not ring as a result of cold-induced , some- clear, there was no change of the medication in recent times followed by and rubor of . However, years. Physical examination showed symmetrical eryth- RP and EM are similar in some respects. Sometimes in ematous patches with bean- to pinpoint-sized violaceous

Received：March 22, 2017, Revised：June 26, 2017, Accepted：July 8, 2017 Corresponding to：Yong-Yon Won, Department of Dermatology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. E-mail：[email protected]

Copyright ⓒ 2018 by The Korean College of . All rights reserved. This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

69 Yong-Yon Won et al.

Figure 1. (A) Diffuse redness with mild swelling on the both sole. (B) Grouped bean sized violaceous macules on the medial side of right heel. (C) Bluish cyanotic changes on the left 2nd, 4th, and 5th fingers.

Figure 2. (A) Compact hyperkeratosis, irregular rete ridge, dilated vessels in the papillary dermis and small sized vessels with fibrin thrombi in the mid-dermis (H&E, ×40). (B) High-power view showing vessel dilatation with vessel endothelial hyperplasia, fibrin thrombi, fibrinous necrosis and mild perivascular and vascular lymphocytic infiltration (H&E, ×100). macules on both soles and palms (Figure 1A and 1B), and only dermal ectatic vessels (Figure 3). Laboratory inves- ulceration with atrophie blanche lesions on bilateral mal- tigations revealed: hemoglobin (8.7 g/dL), platelet count leolar areas. She sometimes noticed cyanotic changes in (78×103/μL), C3 (28.1 mg/dL), and C4 (15.3 mg/dL) her fingers consistent with a history of known RP (Figure were decreased while antinuclear antibodies (1:320), per- 1C). A punch biopsy obtained from a violaceous macule inuclear anti-neutrophil cytoplasmic antibodies, anti-dou- on her right second revealed vascular dilatation ble-stranded DNA antibodies, and direct Coombs test with endothelial hyperplasia, fibrin thrombi, fibrinous were positive. Peripheral blood smear (PBS) revealed nor- necrosis, and positive immunoglobulin G (IgG), and IgM mochromic normocytic red blood cell. C-reactive protein in the vessel walls noted on immunofluorescence stain- (5.93 mg/dL) and 24 hour urine protein (2,048 mg/day) ing—findings consistent with (Figure were also elevated. These findings met two clinical cri- 2). Another skin biopsy performed on an erythematous teria (renal, thrombocytopenia) and four immunological swollen patch on her sole revealed histological findings of criteria (anti-nuclear antibodies, anti-DNA, low comple-

70 J Rheum Dis Vol. 25, No. 1, January, 2018 Coexistence of Erythromelalgia and Raynaud’s Phenomenon

comfort by elevation or cooling of the affected extremity. EM may be primary or secondary in nature. Primary EM usually affects younger patients and is more often bilateral. Secondary EM is related to various disorders, such as thrombocythemia, myeloproliferative disorders, arterial hypertension, vasculitis, and SLE [4], and admin- istration of calcium channel blockers or [13,14]. A negative family history, late onset at the age of 59 years, and clinical symptoms of SLE indicated the pres- ence of secondary EM in the patient we reported in our study. In this case, hematologic disease could be ruled out as a cause of EM because normochromic normocytic red blood cell was revealed in PBS and any disease increasing Figure 3. Scattered dilated vessels in the upper dermis (H&E, blood viscosity, such as thrombocythemia or polycythe- ×100). mia vera, was not observed. She had a long history of di- lated myocardiopathy, so or beta ment, direct Coombs test) based on the 2012 systemic lu- blocker medication should also be taken into consideration. pus international collaborating clinics diagnostic criteria However, since there was no history of medication for SLE. Finally, we made a diagnosis of secondary EM and change in recent years, the medication could be ruled out secondary RP with SLE accompanying livedoid vasculitis, as a possible cause of EM. which is one of the non-specific skin symptoms indicating Similar to EM, RP maybe (i) primary (formerly known as systemic activity of SLE. Raynaud’s disease), or (ii) secondary (formerly known as In rheumatology, for the treatment of SLE, she was pre- Raynaud’s syndrome). Primary RP most typically affects scribed 400 mg hydroxychloroquine per day and 50 mg female patients in the first and second decades, often with prednisolone per day, which led to an improvement of a family history of the disease and is always symmetric. livedoid vasculitis and erythromelalgia. Secondary RP is most commonly associated with con- nective tissue disorders and less frequently with throm- DISCUSSION boangiitis obliterans, , paraneo- plastic syndrome, , administration of be- Lupus erythematosus is classified as acute, subacute, or ta blockers or , and exposure to vibrating ma- chronic cutaneous lupus erythematosus based on distinc- chinery [5]. Our patient related no family history and tive histological findings, and as a non-specific skin dis- showed an asymmetric pattern of RP; thus, she was more ease when no characteristic histological findings are ob- likely to have secondary rather than primary RP. served [9]. Non-specific skin symptoms associated with Although RP and EM are both vascular acrosyndromes, lupus erythematosus are mainly observed in SLE and are EM is a rare painful disorder of the extremities charac- important symptoms from a dermatologist’s viewpoint terized by redness, a burning sensation, and increase in because they are critical indicators of disease activity. exacerbated by exposure to heat [15]. Cutaneous manifestations related to, but not specific to Unlike EM, in patients having RP, the characteristic symp- SLE, include cutaneous vasculitis, periungual telangi- toms of or cyanosis are aggravated by cold. ectasia, , reticularis, atrophie Therefore, some authors believe that the coexistence of blanche, and bullous lesions [10]. RP is also seen in 15% RP and EM is simply coincidental [8]. However, recent to 30% of patients [11] and EM is rarely observed [12]. studies provide an explanation for the rare instances in Based on criteria proposed by Kurzrock and Cohen [1], which EM and RP are seen to coexist. Berlin and Pehr [5] EM is clinically diagnosed in patients showing: (i) Severe have postulated that both syndromes have a common ba- burning discomfort, warmth, and erythema of the feet sis in that in both conditions, there is a dysfunctional reg- and/or hands. (ii) Exacerbation and aggravation of symp- ulation of the vasomotor tone. In both, EM and RP, the in- toms upon exposure to heat or placing the involved ex- itial event seems to be . Subsequent to vaso- tremity in a dependent position. (iii) Amelioration of dis- constriction, reactive hyperemia may occur in both con-

www.jrd.or.kr 71 Yong-Yon Won et al. ditions, although it is more apparent and longer lasting in 3. Drenth JP, te Morsche RH, Michiels JJ. From gene to dis- EM. In this case, the patient had livedoid vasculitis with ease; primary erythermalgia--a neuropathic disease as a consequence of mutations in a sodium pump gene. Ned histologic findings of fibrin thrombi and vasculitis. It is Tijdschr Geneeskd 2006;150:194-6. thought that this vascular obstructive condition caused 4. Paira S, Cassano G, Korol V, Ortiz A, Roverano S. vasospasm associated with the development of RP and Erythromelalgia with subsequent digital necrosis, glomer- ulonephritis, and antiphospholipid antibodies. J Clin EM. Rheumatol 2005;11:209-12. 5. Berlin AL, Pehr K. Coexistence of erythromelalgia and SUMMARY Raynaud's phenomenon. J Am Acad Dermatol 2004;50:4 56-60. 6. Sunahara JF, Gora-Harper ML, Nash KS. Possible eryth- In summary, we report a case of EM in a patient with RP, romelalgia-like syndrome associated with in a which is supposed to be in the same spectrum of diseases patient with Raynaud's phenomenon. Ann Pharmacother involving a dysfunctional vasomotor tone like EM. 1996;30:484-6. Pathophysiological mechanisms underlying both, RP and 7. Slutsker GE. Coexistence of Raynaud's syndrome and erythromelalgia. Lancet 1990;335:853. EM are not yet clearly understood, and further studies 8. Kalgaard OM, Seem E, Kvernebo K. Erythromelalgia: a clin- may be helpful in understanding the pathophysiology of ical study of 87 cases. J Intern Med 1997;242:191-7. the two diseases. 9. Werth VP. Clinical manifestations of cutaneous lupus ery- thematosus. Autoimmun Rev 2005;4:296-302. 10. Uva L, Miguel D, Pinheiro C, Freitas JP, Marques Gomes M, CONFLICT OF INTEREST Filipe P. Cutaneous manifestations of systemic lupus ery- thematosus. Autoimmune Dis 2012;2012:834291. No potential conflict of interest relevant to this article 11. Kammer GM, Soter NA, Schur PH. Circulating immune complexes in patients with necrotizing vasculitis. Clin was reported. Immunol Immunopathol 1980;15:658-72. 12. Badeloe S, Henquet CJ, Nieuwhof CM, Frank J. Secondary erythromelalgia involving the ears probably preceding lupus REFERENCES erythematosus. Int J Dermatol 2007;46 Suppl 3:6-8. 13. Brodmerkel GJ Jr. Nifedipine and erythromelalgia. Ann 1. Kurzrock R, Cohen PR. Erythromelalgia: review of clinical Intern Med 1983;99:415. characteristics and pathophysiology. Am J Med 1991;91: 14. Eisler T, Hall RP, Kalavar KA, Calne DB. Erythromelalgia- 416-22. like eruption in parkinsonian patients treated with bro- 2. Chadachan V, Dean SM, Eberhardt RT. Cutaneous changes mocriptine. Neurology 1981;31:1368-70. in peripheral arterial . In: Goldsmith LA, 15. Davis MD, O'Fallon WM, Rogers RS 3rd, Rooke TW. Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Natural history of erythromelalgia: presentation and out- Fitzpatrick's dermatology in general medicine. 8th ed. New come in 168 patients. Arch Dermatol 2000;136:330-6. York, McGraw-Hill, 2012, p. 2108-9.

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