Introduction: Mixed connective tissue disease (MCTD) is an autoimmune disease that is rare in children. The disease is presented with complex clinical features, so early diagnosis is challenging. Herein we describe the management and outcome of a girl with MCTD associated with macrophage activation syndrome (MAS) and refractory Raynaudsâ�� phenomenon. Case report: A 13-year-old girl was admitted to the pediatric rheumatology ward with mild fever, reduced appetite, 6 kg weight loss (body mass index 15.8), digital ulcers, sclerodactyly, scleroderma, dysphagia, gastroesophageal reflux and arthralgia. She also had photosensitivity, Raynaud's phenomenon, painless oral ulcers, and malar rash. She developed arthritis of the knees and ankles with limited range of motion. Spirometry showed a restrictive pattern. There was speckled antinuclear antibodies (ANA; 1/1260) and positive Î²-2-glycoprotein, U1-ribonucleoprotein (U1-RNP), anti-Scl-70 and anti-Ro52 antibodies. Anti-double stranded deoxyribonucleic acid and anti-cyclic citrullinated protein antibodies were negative. Based on clinical and laboratory findings, MCTD was confirmed. The child was treated with steroid, vasodilators, and immunosuppressives. She had an attack of salmon pink rashes, spiky fevers, Koebner phenomenon, serositis, and organomegaly and the diagnosis of associated MAS was held. The patient was treated with pentoxifylline, prednisolone, methotrexate, low dose aspirin, nifedipine, and hydroxychloroquine. On follow up there was refractory digital ulcers and Raynaud's phenomenon; transthoracic endoscopic sympathectomy was performed and digital ulcers and coldness resolved. Conclusion: MCTD may present with a myriad of rheumatic manifestations and in association with MAS the diagnosis and management may be challenging. Refractory Raynaudsâ�� phenomenon may remarkably improve on transthoracic sympathectomy. Â© 201

Ghasemi, S.

Jari, M.

Parvaneh, V.J.

Rahmani, K.

Shiari, R.

eprints Iran University of Medical Sciences

The Egyptian Rheumatologist 41 (2019) 323–325Contents lists available at ScienceDirectThe Egyptian Rheumatologistjournal homepage: www.elsevier .com/locate /e j rJuvenile-onset mixed connective tissue disease associated withmacrophage activation syndrome: A case with refractory Raynaud’sphenomenonhttps://doi.org/10.1016/j.ejr.2019.04.0011110-1164/ 2019 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Peer review under responsibility of Egyptian Society of Rheumatic Diseases.⇑ Corresponding author at: Shahid Beheshti University of Medical Sciences,Faculty of Medicine, Mofid Children’s Hospital, Shariati Avenu, Tehran, Iran.E-mail address: shiareza@yahoo.com (R. Shiari).Vadood J. Parvaneh a, Mohsen Jari a,b, Saeideh Ghasemi c, Khosro Rahmani a, Reza Shiari a,⇑aDepartment of Pediatric Rheumatology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IranbDepartment of Pediatrics, Imam Hossein children’s Hospital, Isfahan University of Medical Sciences, Isfahan, IrancDepartment of Pediatrics, Ali-asghar Children’s Hospital, Iran University of Medical Sciences, Tehran, Irana r t i c l e i n f o a b s t r a c tArticle history:Received 30 March 2019Accepted 2 April 2019Available online 15 April 2019Keywords:Mixed connective tissue diseaseSystemic lupus erythematosusRaynaud’s phenomenonMacrophage activation syndromeSympathectomyIntroduction: Mixed connective tissue disease (MCTD) is an autoimmune disease that is rare in children.The disease is presented with complex clinical features, so early diagnosis is challenging. Herein wedescribe the management and outcome of a girl with MCTD associated with macrophage activation syn-drome (MAS) and refractory Raynauds’ phenomenon.Case report: A 13-year-old girl was admitted to the pediatric rheumatology ward with mild fever, reducedappetite, 6 kg weight loss (body mass index 15.8), digital ulcers, sclerodactyly, scleroderma, dysphagia,gastroesophageal reflux and arthralgia. She also had photosensitivity, Raynaud’s phenomenon, painlessoral ulcers, and malar rash. She developed arthritis of the knees and ankles with limited range of motion.Spirometry showed a restrictive pattern. There was speckled antinuclear antibodies (ANA; 1/1260) andpositive b-2-glycoprotein, U1-ribonucleoprotein (U1-RNP), anti-Scl-70 and anti-Ro52 antibodies. Anti-double stranded deoxyribonucleic acid and anti-cyclic citrullinated protein antibodies were negative.Based on clinical and laboratory findings, MCTD was confirmed. The child was treated with steroid,vasodilators, and immunosuppressives. She had an attack of salmon pink rashes, spiky fevers, Koebnerphenomenon, serositis, and organomegaly and the diagnosis of associated MAS was held. The patientwas treated with pentoxifylline, prednisolone, methotrexate, low dose aspirin, nifedipine, and hydroxy-chloroquine. On follow up there was refractory digital ulcers and Raynaud’s phenomenon; transthoracicendoscopic sympathectomy was performed and digital ulcers and coldness resolved.Conclusion: MCTD may present with a myriad of rheumatic manifestations and in association with MASthe diagnosis and management may be challenging. Refractory Raynauds’ phenomenon may remarkablyimprove on transthoracic sympathectomy. 2019 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).1. IntroductionJuvenile mixed connective tissue disease (MCTD) is a rareautoimmune disease characterized by various overlapping featuressuch as juvenile idiopathic arthritis (JIA), polymyositis, cutaneousscleroderma, systemic lupus erythematosus (SLE), and systemicsclerosis (SSc) [1,2]. Fatigue, mild fever, cold fingers, paresthesias,puffiness of the hands and fingers, arthritis, myositis, and skin rashare main features of the disease [3]. The heart, lungs, and kidneyscan also be affected in the later stages of the disease [4]. MCTD isan autoimmune disease with unknown underlying mechanism,yet genetic factors may play a key role in its etiology [5]. Addition-ally, certain viruses and chemicals may also contribute. It is note-worthy that MCTD is very rare in children [6]. The diseasepresents with features of more than one, usually two, connectivetissue diseases. Herein, we describe a 13-year-oldgirl admitted tohospital with sequential complaints and findings compatible withfeatures of four rheumatologic disorders: SSc, SLE, JIA, and macro-phage activation syndrome (MAS) which eventually, lead to thefinal diagnosis of MCTD.324 V.J. Parvaneh et al. / The Egyptian Rheumatologist 41 (2019) 323–3252. Case reportA 13-year-old girl was admitted to the pediatric rheumatologicward, Mofid Children’s Hospital, Shahid Beheshti University ofMedical Sciences, Tehran, Iran with arthralgia of the knees andwrists with back pain for 2 weeks duration and mild fever for2 days. She also complained of reduced appetite, 6 kg weight loss(weight: 40 kg; height: 150 cm; and BMI: 15.8 kg/m2), gastroe-sophageal reflux, and upper painless dysphagia to solids, as wellas coldness, pain and peripheral cyanosis of fingers following con-tact with water and cold weather from 2 months ago. Also, shecomplained of muscle weakness. On physical examination, shehad restricted active and passive range of motion (ROM) of theknees and ankles, swelling and warmness of the joints (arthritis),sclerodactyly, and digital ulcers, as well as tenderness of sacroiliacjoints. The Patrick’s test for Flexion, ABduction, and External Rota-tion (FABER) test was also positive. She also had malar rash, photo-sensitivity, Raynaud’s phenomenon, and painless oral ulcers. Themuscle power of the upper and lower extremities was normal.The informed consent has been obtained from parents of the girl.Complete blood count (CBC) showed a white blood cell count of5200  103/mm3 with absolute lymphopenia (624  103/mm3).The erythrocyte sedimentation rate (ESR), C-reactive protein(CRP), Immunoglobulins (Igs), muscle enzymes and complementslevel were within normal limits. Serological tests for hepatitis,infectious mononucleosis, cytomegalovirus (CMV), and parvovirusB19 were negative. Antinuclear antibodies (ANA) were highly pos-itive (ANA:1/1260) with speckled pattern. U1-ribonucleoproteinautoantibody (U1-RNP) was increased (3+). The anti-doublestranded deoxyribonucleic acid (anti-ds-DNA) and also anti-cycliccitrullinated protein antibodies (anti-CCP) were negative. b-2-glycoprotein (b-2GP) antibodies (IgM and IgG) were three timesmore than normal concentration. Topoisomerase I (Scl-70) and antiRo antibodies (Ro52) had been increased (2+ and >200 U/mlrespectively).Her chest X-ray, echocardiography, abdominal and pelvic ultra-sound were normal. Lung high-resolution computed tomography(HRCT) was normal; however, a restrictive pattern was observedin her lung on Spirometry test analysis. Bone mineral densitometryrevealed low bone mineral content (with Z score 3.3). MCTD waseventually diagnosed according to the increased levels of ANA,b-2GP antibodies, U1-RNP, Scl-70 and Ro52, as well as the presenceof SSc and SLE according to the classification and diagnosticcriteria [7].The patient had received prednisolone (0.5 mg/kg/day),methotrexate (MTX) (10 mg/m2/w), hydroxychloroquine (HCQ)(6 mg/kg/day), naproxen (15 mg/kg/ day) and nifedipine(0.25 mg/kg/day). Pamidronate (1 mg/kg/day) was also infusedfor 3 days every three months. On monthly follow-up, arthritiswas resolved after 3 months. Furthermore, photosensitivity wasresolved. Malar rash and oral ulcers were negative and her weighthad been increased by 2 kg after 3 months. At the end of 4thmonth, the patient developed deep pain on the right hand from fin-gers tip to the clavicle besides digital ulcers and puffiness. Then shewas admitted to hospital and started treatment with alprostadil(10 mg/kg/day for 5 days) and heparin. Furthermore, she receivedrituximab (500 mg/m2/day) two times biweekly. After discharge,pentoxifylline, antiplatelet dose of acetylsalicylic acid (ASA) andwarfarin were added.Three months later, the case was re-admitted with high-gradefever, headache, vomiting and lethargy. Laboratory investigationsrevealed leukocytosis, neutrophilia, and increased levels of ESRand CRP. Lumbar puncture (LP) was performed to examine thecerebrospinal fluid (CSF) analysis and revealed a normal result.CSF and blood cultures, urinalysis, and viral serologic markers werealso negative. Chest x-ray, echocardiography, abdominal and pelvicultrasound results were normal. During hospitalization, she devel-oped high fever spikes (>39 C) along with the salmon-coloredrash. Koebner’s phenomenon was positive. On the 5th day afteradmission, the patient presented respiratory distress and pul-monary hemorrhage. She also had persistent fever, hep-atosplenomegaly, serositis, cytopenia and a normal ESR.The patient was then transferred to pediatric intensive care unit(PICU) and received intravenous immunoglobulin (2 g/kg over12 h), pulse methylprednisolone (30 mg/kg/day for three days),and intravenous cyclophosphamide (CYC) (500 mg/m2) being diag-nosed as systemic-onset JIA with macrophage activation syndrome(MAS) according to international league against rheumatism (ILAR)criteria for systemic JIA as well as the 2016 classification guidelinesfor MAS complicating systemic JIA [8,9]. Elevated liver enzymes,high triglycerides, hypofibrinogenemia, and the marked increasedserum ferritin level (6500 ng/ml) were revealed two days later.Treatment with pentoxifylline, prednisolone, MTX, ASA, nifedipine,and HCQ was also continued. Intravenous pulse CYC (500 mg/m2)was continued till 6 months and then every 3 months. Duringthese periods, she developed fingers wounds several times and alsocomplained from pain and peripheral cyanosis of fingers; refrac-tory Raynaud’s phenomenon. A right side transthoracic endoscopicsympathectomy was performed which showed a good response.Ten months later the same surgery was also done for left sideand the patient ulcers and coldness significantly resolved.3. DiscussionA 13-year-old girl with MCTD presenting by multiple manifes-tations including muscle weakness, fever, Raynaud’s phenomenonand arthritis has been reported. She had also malar rash, photosen-sitivity and painless oral ulcers and gradually developed manifes-tations of systemic JIA and MAS. Increased levels of b-2GPantibodies, Scl-70, Ro52, ANA, and U1-RNP pointed to the possiblediagnosis of systemic-onset JIA, SSc and SLE making the MCTD apotentially challenging diagnosis as the manifestations usuallyoccur sequentially over time. The common features of other rheu-matic diseases add to the difficulty in defining the disease. Thepatient was diagnosed as a case of MCTD in line with the variousclassification criteria [7,10]. Although MCTD occurs worldwideand affects people of all ages, it is rare in children [1,2]. Severalstudies reported MCTD in children [11–15]. Yang et al. reportedtwo girls (10- and 13-year-old) with MCTD initially presentingwith JIA, muscle weakness, Raynaud’s, elevated creatine kinaseand liver enzymes, sclerodactyly, arthralgia, lymphadenopathy,pericardial effusion, and paralytic ileus. Both had high serum titersof ANA and were seropositive for anti-RNP [16]. In another study,Latuśkiewicz-Potemska et al reported a 10-year-old girl with MCTDpresented with sclerodactyly and trophic damages of fingersaccompanied by Raynaud’s [14]. High levels of ANA and U1-RNP,which present in most MCTD patients, were found reliable testsfor the diagnosis of the disease [2]. Nevertheless, these antibodiesmay present in healthy people and in other disorders.Treatment of MCTD is similar to that of SLE, autoimmunemyositis, and SSc; however, it depends on the severity of diseasesymptoms. Some patients require continuous treatment, whileothers need treatment only during periods of heightened diseaseactivity. Non-steroidal anti-inflammatory drugs (NSAIDs),corticosteroids, HCQ, and immunosuppressive drugs (e.g. MTXand azathioprine) are usually used for these patients [5]. Immuno-suppressive drugs are usually used in moderate to severe cases.V.J. Parvaneh et al. / The Egyptian Rheumatologist 41 (2019) 323–325 325Several studies have shown the beneficial effect of sympathectomyin patients with Raynaud’s phenomenon [17–19]. MTX and CYChave been used as immunosuppressives in the present case. Shereceived maintenance treatment with pentoxifylline, prednisolone,MTX, ASA, nifedipine, pulse CYC, and HCQ. However, after treat-ment with these drugs, she still suffered with a refractory Ray-naud’s phenomenon. Eventually, right and left handstransthoracic endoscopic sympathectomy was performed and thepatient’s symptoms resolved. The role of sympathectomy in refrac-tory Raynaud’s phenomenon in adolescents has been reported [19].Different approaches have been used including local (digital orwrist block) or regional (cervical or lumbar) chemical, localizeddigital microsurgery and transthoracic endoscopic sympathectomy[18,20]. Sympathectomy should be reserved for patients withrefractory digital ischemia and ulcers.In conclusion, MCTD may present with a myriad of rheumaticmanifestations and in association with MAS the diagnosis andmanagement may be challenging. Refractory Raynauds’ phe-nomenon may remarkably improve on transthoracicsympathectomy.FundingThis research did not receive any specific grant from fundingagencies in the public, commercial, or not-for-profit sectors.Conflict of interestThe authors declare no conflict of interest.References[1] Deepak S, Warrier KC. Mixed connective tissue disease in children - case series.Rheumatol Orthop Med 2017;2:1–7.[2] Jovancevic B, Lindholm C, Pullerits R. Anti B-cell therapy against refractorythrombocytopenia in SLE and MCTD patients: long-term follow-up and reviewof the literature. Lupus 2013;22:664–74.[3] Katewa R, Jakhar RS, Barala GL. Mixed connective tissue disorder: a case report.Int J Case Rep Images 2014;5:650–5.[4] Gunnarsson R, Molberg O, Gilboe IM, Gran JT. PAHNOR1 Study Group. Theprevalence and incidence of mixed connective tissue disease: a nationalmulticentre survey of Norwegian patients. Ann Rheum Dis 2011;70:1047–51.[5] Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: anoverview of clinical manifestations, diagnosis and treatment. Best Pract ResClin Rheumatol 2012;26:61–72.[6] Knight A, Pamela FW, Morales K, Keren R. Depression, anxiety and suicidalthoughts in a cohort of pediatric lupus and mixed connective tissue diseasepatients. Abstract number 1252013 ACR/ARHP Annual Meeting.[7] Alarcon-Segovia D, Villarreal M. Classification and diagnostic criteria for mixedconnective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connectivetissue disease and anti-nuclear antibodies. Amsterdam: Elsevier; 1987. p.33–40.[8] Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. 2016 Classificationcriteria for macrophage activation syndrome complicating systemic juvenileidiopathic arthritis: a European league against rheumatism/American Collegeof Rheumatology/Paediatric Rheumatology International Trials OrganisationCollaborative Initiative. Arthritis Rheumatol 2016;68(3):566–76.[9] Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis iskey. Open Access Rheumatol 2018;10:117–28.[10] Amigues JM, Cantagrel A, Abbal M, Mazieres B. Comparative study of4diagnosis criteria sets for mixed connective tissue disease in patientswithanti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse.J Rheumatol 1996;23:2055–62.[11] Berard RA, Laxer RM. Pediatric mixed connective tissue disease. CurrRheumatol Rep 2016;18:28.[12] Michels H. Course of mixed connective tissue disease in children. Ann Med1997;29:359–64.[13] Tsai YY, Yang YH, Yu HH, Wang LC, Lee JH, Chiang BL. Fifteen-year experienceof pediatric-onset mixed connective tissue disease. Clin Rheumatol2010;29:53–8.[14] Latuśkiewicz-Potemska J, Zygmunt A, Biernacka-Zielińska M, Stańczyk J,Smolewska E. Mixed connective tissue disease presenting with progressivescleroderma symptoms in a 10-year-old girl. Postepy Dermatol Alergol2013;30:329–36.[15] Mier RJ, Shishov M, Higgins GC, Rennebohm RM,Wortmann DW, Jerath R, et al.Pediatric-onset mixed connectivetissue disease. Rheum Dis Clin North Am2005;31:483–96.[16] Yang YH, Tsai MJ, Lin SC, Lin MT, Chiang BL. Childhood mixed connective tissuedisease. J Formos Med Assoc 2000;99:158–61.[17] Jeon SB, Ahn HC, Ahn YS, Choi MS. Two-step incision for periarterialsympathectomy of the hand. Arch Plast Surg 2015;42:761–8.[18] Kotsis SV, Chung KC. A systematic review of the outcomes of digitalsympathectomy for treatment of chronic digital ischemia. J Rheumatol2003;30(8):1788–92.[19] Drake DB, Kesler RW, Morgan RF. Digital sympathectomy for refractoryRaynaud’s phenomenon in an adolescent. J Rheumatol 1992;19(8):1286–8.[20] Hartzell TL, Makhni EC, Sampson C. Long-term results of periarterialsympathectomy. J Hand Surg Am 2009;34(8):1454–60.

Juvenile-onset mixed connective tissue disease associated with macrophage activation syndrome: A case with refractory Raynaud's phenomenon

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Juvenile-onset mixed connective tissue disease associated with macrophage activation syndrome: A case with refractory Raynaud's phenomenon

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