case of raynaud syndrome after the use of methimazole€¦ · raynaud syndrome, also known as...

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203 ReceivedAugust 14, 2017, RevisedNovember 3, 2017, AcceptedNovember 28, 2017 Corresponding toJeong-Hoon Kim http://orcid.org/0000-0001-5238-2256 Department of Surgery, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea. E-mail[email protected] Copyright 2018 by The Korean College of Rheumatology. 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. Case Report pISSN: 2093-940X, eISSN: 2233-4718 Journal of Rheumatic Diseases Vol. 25, No. 3, July, 2018 https://doi.org/10.4078/jrd.2018.25.3.203 Case of Raynaud Syndrome after the Use of Methimazole Yunkyung Kim 1 , Hee-Sang Tag 1 , Geun-Tae Kim 1 , Seung-Geun Lee 2 , Eun-Kyung Park 2 , Ji-Heh Park 2 , Seong-min Kweon 2 , Song-I Yang 3 , Jeong-Hoon Kim 3 1 Division of Rheumatology, Department of Internal Medicine, Kosin University Gospel Hospital, 2 Division of Rheumatology, Department of Internal Medicine, Pusan National University Hospital, 3 Department of Surgery, Kosin University Gospel Hospital, Busan, Korea Raynaud syndrome is a medical condition that causes pain, numbness, and changes in skin color at the distal extremities. Raynaud syndrome can be subdivided into primary Raynaud's and secondary Raynaud's. The former is diagnosed when the cause is unknown and the latter is caused by an underlying condition, such as connective tissue diseases, injury, smoking, or certain medications. Both cancer chemotherapy and β-blockers are relatively common causes of Raynaud syndrome but there are no reports of its association with methimazole administration. The authors encountered a 43-year old woman with hyper- thyroidism who developed digital ulcers associated with Raynaud syndrome after a methimazole treatment. Her digital ulcers and Raynaud syndrome were improved after methimazole was replaced with propylthiouracil and conventional therapy. This paper reports this case along with a review of the relevant literature. (J Rheum Dis 2018;25:203-206) Key Words. Methimazole, Raynaud syndrome, Ulcer INTRODUCTION Raynaud syndrome, also known as Raynaud's phenom- enon, was first described as a medical condition by Maurice Raynaud in 1862. In Raynaud syndrome, distal blood flow is blocked by vasospasm of small arteries re- sulting in skin color changes, pain, and sensory dis- turbances in the extremities [1]. The prevalence of Raynaud syndrome varies regionally and between the sexes. It is reported that 3%19% of the total population is affected, with higher rates in women than men [2,3]. Primary Raynaud’s (also called Raynaud's disease), which occurs without any other accompanying disease, ac- counts for about 80% of cases [4]. Secondary Raynaud’s (also called Raynaud's phenomenon), occurs with many other conditions including connective tissue disorders, such as scleroderma or lupus, trauma, smoking, and cer- tain medications [5]. Methimazole is a thionamide drug which is commonly used as a treatment for hyperthyroidism including Graves' disease [6]. Common side effects are urticaria, rash, ar- thritis, and indigestion. Possible life-threatening compli- cations of methimazole administration are agranulocy- tosis or toxic hepatitis [7]. In rare cases, drug-induced au- toimmunity, such as vasculitis or systemic lupus eryth- ematosus, occurs [8]. The incidence of Raynaud’s phenomenon due to the use of methimazole has not been reported. Here, we report a literature review and a case where methimazole triggered Raynaud syndrome and associated digital ulcers and small infarctions. These symptoms improved after dis- continuing methimazole in this case. CASE REPORT A 43-year old woman visited a tertiary hospital present- ing with pain and color change in two fingers. She had a history of hyperthyroidism and had been treated with propylthiouracil for 25 years. Her medication was changed to methimazole 7 months before visiting the

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Page 1: Case of Raynaud Syndrome after the Use of Methimazole€¦ · Raynaud syndrome, also known as Raynaud's phenom-enon, was first described as a medical condition by Maurice Raynaud

203

Received:August 14, 2017, Revised:November 3, 2017, Accepted:November 28, 2017

Corresponding to:Jeong-Hoon Kim http://orcid.org/0000-0001-5238-2256Department of Surgery, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea. E-mail:[email protected]

Copyright ⓒ 2018 by The Korean College of Rheumatology. 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.

Case ReportpISSN: 2093-940X, eISSN: 2233-4718Journal of Rheumatic Diseases Vol. 25, No. 3, July, 2018https://doi.org/10.4078/jrd.2018.25.3.203

Case of Raynaud Syndrome after the Use of Methimazole

Yunkyung Kim1, Hee-Sang Tag1, Geun-Tae Kim1, Seung-Geun Lee2, Eun-Kyung Park2, Ji-Heh Park2, Seong-min Kweon2, Song-I Yang3, Jeong-Hoon Kim3

1Division of Rheumatology, Department of Internal Medicine, Kosin University Gospel Hospital, 2Division of Rheumatology, Department of Internal Medicine, Pusan National University Hospital, 3Department of Surgery, Kosin University Gospel Hospital, Busan, Korea

Raynaud syndrome is a medical condition that causes pain, numbness, and changes in skin color at the distal extremities. Raynaud syndrome can be subdivided into primary Raynaud's and secondary Raynaud's. The former is diagnosed when the cause is unknown and the latter is caused by an underlying condition, such as connective tissue diseases, injury, smoking, or certain medications. Both cancer chemotherapy and β-blockers are relatively common causes of Raynaud syndrome but there are no reports of its association with methimazole administration. The authors encountered a 43-year old woman with hyper-thyroidism who developed digital ulcers associated with Raynaud syndrome after a methimazole treatment. Her digital ulcers and Raynaud syndrome were improved after methimazole was replaced with propylthiouracil and conventional therapy. This paper reports this case along with a review of the relevant literature. (J Rheum Dis 2018;25:203-206)

Key Words. Methimazole, Raynaud syndrome, Ulcer

INTRODUCTION

Raynaud syndrome, also known as Raynaud's phenom-enon, was first described as a medical condition by Maurice Raynaud in 1862. In Raynaud syndrome, distal blood flow is blocked by vasospasm of small arteries re-sulting in skin color changes, pain, and sensory dis-turbances in the extremities [1]. The prevalence of Raynaud syndrome varies regionally and between the sexes. It is reported that 3%∼19% of the total population is affected, with higher rates in women than men [2,3]. Primary Raynaud’s (also called Raynaud's disease), which occurs without any other accompanying disease, ac-counts for about 80% of cases [4]. Secondary Raynaud’s (also called Raynaud's phenomenon), occurs with many other conditions including connective tissue disorders, such as scleroderma or lupus, trauma, smoking, and cer-tain medications [5].Methimazole is a thionamide drug which is commonly

used as a treatment for hyperthyroidism including Graves'

disease [6]. Common side effects are urticaria, rash, ar-thritis, and indigestion. Possible life-threatening compli-cations of methimazole administration are agranulocy-tosis or toxic hepatitis [7]. In rare cases, drug-induced au-toimmunity, such as vasculitis or systemic lupus eryth-ematosus, occurs [8].The incidence of Raynaud’s phenomenon due to the use

of methimazole has not been reported. Here, we report a literature review and a case where methimazole triggered Raynaud syndrome and associated digital ulcers and small infarctions. These symptoms improved after dis-continuing methimazole in this case.

CASE REPORT

A 43-year old woman visited a tertiary hospital present-ing with pain and color change in two fingers. She had a history of hyperthyroidism and had been treated with propylthiouracil for 25 years. Her medication was changed to methimazole 7 months before visiting the

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Yunkyung Kim et al.

204 J Rheum Dis Vol. 25, No. 3, July, 2018

Figure 1. Change in patient’s finger lesion. (A∼C) First visit, (D∼F) after 3 months, (G∼I) after 8 months. Arrow: digital ulcer, Arrow head: small infarction.

hospital. The Raynaud’s phenomenon occurred 6 months after the change in medication.She was a kindergarten caregiver and there were no oth-

er notable findings in her social, past medical, and family histories. She was 166 cm tall and weighed 56 kg. Her blood pres-

sure, pulse rate, respiratory rate, and body temperature were 133/81 mmHg, 94 beats/minute, 20 breathes/mi-nute and 36.5°C, respectively. Color changes and small digital ulcers with infarctions were observed in two fin-gers (Figure 1A∼C). There was no skin thickening or calcification. Laboratory findings revealed the following: normal white blood cell count 4.13×103/μL (neutrophil 61%, lymphocyte 27.3%, monocyte 7.5%, eosinophil 3.8%, basophil 0.4%), hemoglobin 13 g/dL, hematocrit 39.8%, and platelets 184×103/μL. C-reactive protein was 0.104 mg/dL and erythrocyte sedimentation rate was 17 mm/hour. Liver function, renal function, and uri-

nalysis tests were normal. The thyroid function test pro-file indicated euthyroid function with a serum Free T4 of 0.83 ng/dL, T3 of 83.46 ng/dL, and thyroid-stimulating hormone of 1.722 μIU/mL. Antinuclear antibody, an-ti-double-stranded DNA antibody, anti-Smith antibody, anti-centromere antibody, anti-topoisomerase I, anti- Cardiolipin antibody, lupus anticoagulant, anti-neutrophil cytoplasmic antibodies (ANCA), and cryoglobulin were all negative. Complements were within the normal range. Chest and hand X-rays were normal.We considered the possibility of secondary Raynaud's

associated with methimazole. We replaced methimazole with propylthiouracil and used beraprost 40 mg/day, pen-toxifylline 400 mg/day and losartan 50 mg/day. There was no further deterioration after methimazole was dis-continued, but the digital ulcers persisted (Figure 1D∼

F). Thereafter, progressive improvement of the skin le-sions was observed after 8 months of treatment (Figure

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Case of Raynaud Syndrome after the Use of Methimazole

www.jrd.or.kr 205

1G∼I). The patient currently takes only propylthiouracil and there has been no recurrence of her lesions.

DISCUSSION

Although the cause and pathophysiology of Raynaud syndrome have not yet been clearly established, it is pre-sumed that various factors are associated with its onset. The syndrome is clinically classified into primary Raynaud's and secondary Raynaud's [9].Primary Raynaud's follows a benign course with no dam-

age to the blood vessels. However, in secondary Raynaud's, tissue damage due to the remodeling of capillary vessels may be accompanied by ulcers and gangrene [1,10,11]. If secondary Raynaud’s is suspected, confirmation of con-comitant connective tissue disease or other causes should be confirmed by testing skin sclerosis, skin calcification, antinuclear antibodies, and nail capillary microscopy [5,11].In this case, there was digital ulceration with necrosis

which is not observed in primary Raynaud's. There was no evidence of connective tissue disease in the patient’s history, physical examination, or autoantibody tests. However, six months before the onset of Raynaud syn-drome, the patient’s anti-thyroid medication, propylth-iouracil, was replaced with methimazole.Drugs that reduce peripheral microcirculation can cause

Raynaud’s phenomenon. Cisplatin, bleomycin, and β- adrenoceptor blockers are known to be the most common causes of Raynaud syndrome. Others are clonidine, ergot alkaloids, dopaminergic agonists, selective serotonin re-uptake inhibitors, sympathomimetic drugs, cyclosporine, vinyl chloride, interferons, and tyrosine kinase inhibitors [12].No case of methimazole-induced Raynaud syndrome

has been previously reported, but several cases showed methimazole related Raynaud syndrome as part of other autoimmune disease it. Thong and Ajaz reported [13,14] the incidence of ANCA positive vasculitis with Raynaud syndrome in a 29-year-old woman after 3 weeks of methi-mazole at a dose of 10 mg and in an 18-year-old woman after 1 week of methimazole at a dose of 15 mg. Hosoi et al. [15] reported a case of cryofibrinogenemia with sub-sequent Raynaud syndrome, acral ulcer, and multiple ar-thritic joints in an 18-year-old woman who used 30 mg of methimazole.Here, we present a case of Raynaud syndrome present-

ing with digital ulcers in a hyperthyroid patient treated

with methimazole. Through clinical history, physical ex-amination, and laboratory tests, including autoantibody tests, we excluded other causes and made a diagnosis of secondary Raynaud's. After discontinuation of methima-zole, her digital ulcers and Raynaud syndrome gradually improved during conventional treatment with pentoxifyl-line, beraprost, and losartan. We did not perform a chal-lenge test, but we determined that methimazole was the cause of the Raynaud syndrome for the following reasons: first, there were no symptoms before the use of methima-zole; second, gradual improvement was observed after discontinuing methimazole; and third, there was no re-currence of Raynaud syndrome even after discontinuing the conventional treatments.

SUMMARY

We present the case of a patient with hyperthyroidism that developed digital ulcers associated with Raynaud syndrome induced by methimazole. The digital ulcers and Raynaud syndrome improved after methimazole was replaced with propylthiouracil. Although its exact patho-physiologic mechanism is not known, methimazole use should be included in the differential diagnosis of secon-dary Raynaud’s.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Herrick AL. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol 2012;8:469-79.

2. Silman A, Holligan S, Brennan P, Maddison P. Prevalence of symptoms of Raynaud's phenomenon in general practice. BMJ 1990;301:590-2.

3. Suter LG, Murabito JM, Felson DT, Fraenkel L. The in-cidence and natural history of Raynaud's phenomenon in the community. Arthritis Rheum 2005;52:1259-63.

4. Wigley FM, Herrick AL, Flavahan NA. Raynaud's Phenomenon: A Guide to Pathogenesis and Treatment. New York, NY, Springer New York, 2015, p. 21.

5. Kim HS. The efficacy of nailfold capillaroscopy in patients with Raynaud's phenomenon. J Rheum Dis 2015;22:69-75.

6. Davidson B, Soodak M, Neary JT, Strout HV, Kieffer JD, Mover H, et al. The irreversible inactivation of thyroid per-oxidase by methylmercaptoimidazole, thiouracil, and pro-pylthiouracil in vitro and its relationship to in vivo findings. Endocrinology 1978;103:871-82.

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7. Kwak MK, Kim SR, Park JW, Han SJ, Kim MJ, Jin SY, et al. Methimazole-induced acute cholestatic hepatitis in a pa-tient with history of simvastatin-induced liver injury. Soonchunhyang Med Sci 2014;20:163-7.

8. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352: 905-17.

9. Block JA, Sequeira W. Raynaud's phenomenon. Lancet 2001;357:2042-8.

10. LeRoy EC, Medsger TA Jr. Raynaud's phenomenon: a pro-posal for classification. Clin Exp Rheumatol 1992;10:485-8.

11. 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.

12. Khouri C, Blaise S, Carpentier P, Villier C, Cracowski JL,

Roustit M. Drug-induced Raynaud's phenomenon: beyond β-adrenoceptor blockers. Br J Clin Pharmacol 2016;82: 6-16.

13. Thong HY, Chu CY, Chiu HC. Methimazole-induced anti-neutrophil cytoplasmic antibody (ANCA)-associated vascu-litis and lupus-like syndrome with a cutaneous feature of vesiculo-bullous systemic lupus erythematosus. Acta Derm Venereol 2002;82:206-8.

14. Ajaz Y, Matto S. Carbimazole induced ANCA positive vasculitis. BJMP 2014;7:e712.

15. Hosoi K, Makino S, Yamano Y, Sasaki M, Takeuchi T, Sakane S, et al. Cryofibrinogenemia with polyarthralgia, Raynaud's phenomenon and acral ulcer in a patient with Graves' disease treated with methimazole. Intern Med 1997;36:439-42.