Fibrous Arthropathy Associated With Etienne Merlin, MD, PhD,a​ Sylvain Breton, MD,b​ Sylvie Fraitag, MD, PhD,​c Jean-Louis Stéphan, MD, PhD,​d CarineMorphea: Wouters, MD, PhD,​e Christine A Bodemer,New MD, PhD, Cause​f Brigitte Bader-Meunier, of DiffuseMD, PhDg Acquired Joint Contractures abstract Etiologies for childhood-onset diffuse joint contractures encompass a “ ” large group of inherited disorders and acquired diseases, in particular a subtype of juvenile idiopathic arthritis called dry polyarthritis,​ aInserm CIC 1405, Centre Hospitalier Universitaire de dermatomyositis, and systemic sclerosis. We report on 2 boys, aged 5 and Clermont-Ferrand, Clermont-Ferrand, France; bRadiologie 8 years, who developed acquired symmetric painless joint contractures Pédiatrique, Hôpital Necker Enfants Malades, Assistance Publique – Hopitaux de Paris, Paris, France; cService preceding the development of superficial plaques of morphea by 7 to 13 d’Anatomie et de Cytologie Pathologiques, Hôpital Necker months. There was no other clinical involvement, biological inflammation, Enfants Malades, Assistance Publique – Hopitaux de Paris, d or autoantibodies. No urinary mucopolysaccharidosis was seen. In both Paris, France; Service d’hématologie immunologie et rhumatologie pédiatrique, Centre Hospitalier Universitaire patients, wrist MRI showed no joint effusion, no bone erosion, and no or de Saint-Etienne, Saint-Priest-en-Jarez, France; eDepartment mild synovial thickening with slight enhancement after gadolinium infusion. of Pediatric Rheumatology, University Hospital Leuven, Leuven, Belgium; fService de Dermatologie, Hôpital Necker One patient underwent a synovial biopsy, which showed dense fibrosis Enfants Malades, Institut IMAGINE, Assistance Publique with a sparse inflammatory infiltrate, similar to the pathologic pattern – Hopitaux de Paris, Paris, France; and gUnité d’Immuno- Hématologie et Rhumatologie Pédiatrique, Hôpital Necker observed in the skin biopsy. With methotrexate and systemic steroids, joint Enfants Malades, Institut IMAGINE, Assistance Publique – contractures slowly improved in the first patient and remained stable in the Hopitaux de Paris, Paris, France second. These 2 cases suggest that fibrous synovitis should be considered Dr Merlin drafted the initial manuscript; Dr Breton in children with acquired diffuse, symmetric, painless contractures and performed imaging studies and reviewed and without elevation of acute-phase reactants, even in the absence of cutaneous revised the manuscript; Dr Fraitag performed histological examination and reviewed and manifestations. Articular MRI with gadolinium and careful cutaneous revised the manuscript; Drs Stéphan and Wouters examination at onset and during follow-up should provide clues for participated in the care of the patients and diagnosing this entity. reviewed and revised the manuscript; Drs Bodemer and Bader-Meunier conceptualized the study and reviewed and revised the manuscript; and all the authors approved the final manuscript as submitted. Etiologies of childhood-onset diffuse joint capsule fibrosis. The skin and joint contractures encompass a subcutis in these patients is described DOI: https://​doi.​org/​10.​1542/​peds.​2016-​1899 “ ” large group of inherited disorders as hard and indurated and feels Accepted for publication Feb 14, 2017 and acquired diseases, in particular, tacked down. At times, involvement Address correspondence to Brigitte Bader- subgroups of patients within of deep connective tissue below the Meunier, MD, PhD, Unité d’Immuno-Hématologie et “ ” connective tissue diseases that skin may affect joint functioning Rhumatologie Pédiatrique, Hôpital Necker Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. demonstrate a dry synovitis,​ which slightly distal to the area. For example, E-mail: [email protected] is the presence of joint contractures an indurated linear patch of LS of the PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, or stiffness without obvious effusion upper arm may affect the functioning 1098-4275). or warmth of the joint. These include of the elbow, wrist, and fingers if the “ ” Copyright © 2017 by the American Academy of juvenile idiopathic arthritis (JIA), deeper tendons are involved, causing a Pediatrics dermatomyositis, systemic sclerosis, pulley effect. The forearm and hand and localized scleroderma (LS), will otherwise appear normal without To cite: Merlin E, Breton S, Fraitag S, et al. Fibrous typically the deep morphea and linear cutaneous findings in these instances. Arthropathy Associated With Morphea: A New morphea subtypes of LS affecting the Here we describe for the first time the Cause of Diffuse Acquired Joint Contractures. extremity. In LS and systemic sclerosis, cases of 2 patients who presented with Pediatrics. 2017;140(4):e20161899 the dry synovitis is associated with diffuse acquired joint contractures deep subcutis, fascial, tendon, and preceding distant superficial Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 140, number 4, October 2017:e20161899 Case Report

Merlin et al 2017 ROUGH GALLEY PROOF Fibrous Arthropathy Associated With https://doi.org/10.1542/peds.2016-1899 October 2017 Morphea: A New Cause of Diffuse Acquired Joint Contractures 4 140 Pediatrics TABLE 1 Characteristics of the Patients Patient 1 Patient 2 circumscribed morphea, without associated deep morphea. This report Age at onset of contractures/sex 8 y/male 5 y/male Joints involved Mild limitations of PIP, DIP, Moderate limitations of PIP, DIP, emphasizes that fibrosing synovitis wrists, elbows, hips, knees, wrists, hips, knees, ankles, should be considered in children with ankles cervical spine acquired contractures, even in the Time from onset of polyarthritis and 7 mo 13 mo absence of cutaneous manifestations. onset of morphea Type of morphea 3 superficial plaques (pubis, 5 superficial plaques (neck, Clinical Reports back, leg) axilla, pubis, groin) ESR/CRP Normal Normal Eosinophilia/elevated CPK No/no No/no Autoantibodies ANA, anti-SSA, anti-SSB, anti- ANA and RF: negative Two Caucasian boys, aged 5 and 8 RNP, anti-Scl70: negative years, were referred to a pediatric Wrist MRI with gadolinium infusion Mild synovial thickening with No synovial thickening, slight rheumatologist for the evaluation slight enhancement of enhancement of synovial of diffuse joint contracture that had synovial membrane after membrane after gadolinium gadolinium infusion infusion developed some months earlier. No joint effusion, sparse No joint effusion, no bone Their medical history was negative intraosseous edema abnormalities (Table 1). There was no noteworthy without bone erosion family history or consanguinity. Joint Skin biopsy Dermal fibrosis, mild Dermal fibrosis, sparse limitation was graduated from 1 to 3, lymphocytic infiltrate, inflammatory infiltrate horizontalization of as mild (1), moderate (2), or severe elastic fibers and adnexa P(3).atient 1 rarefaction Synovial biopsy Dense fibrosis with very Not done sparse inflammatory infiltrates An 8-year-old boy had diffuse ANA, antinuclear antibodies; CPK, creatinine phosphokinase; CRP, C reactive protein; DIP, distal interphalangeal joint; painless mild joint limitation of ESR, erythrocyte sedimentation rate; NSAID, nonsteroidal antiinflammatory drug; PIP, proximal interphalangeal joint; RF, motion that had developed 5 months rheumatoid factor; RNP, ribonucleoprotein; SSA and SSB, Sjögren syndrome A and B. earlier, involving the proximal and distal interphalangeal joints, wrists, hips, knees, and ankles. The severity of joint limitations was mild with the patient began treatment2 with <15 minutes. No other clinical no functional impact. Seven months methotrexate (10 mg/m /week) abnormalities were noted. Wrist after the onset of joint involvement, combined with corticosteroids x-rays, ophthalmologic examination 3 hyperpigmented superficial (1 mg/kg/day prednisone for 1 (including slit-lamp examination), cutaneous plaques suggestive of month then tapered to 5 mg/day) and echocardiography were normal, morphea had appeared on the pubis, for 6 months. In the absence of along with acute phase reactants. back, and leg. Laboratory tests found any articular improvement, a wrist Wrist MRI showed no joint effusion, normal complete blood cell count synovial biopsy was performed, no bone abnormalities, no synovial with differential and C-reactive which showed dense fibrosis with thickening, no subcutis/fascial protein level. Rheumatoid factor and a sparse inflammatory infiltrate edema, but mild enhancement of the antinuclear antibody were negative (Fig 2). Methotrexate and steroids carpal synovium after gadolinium (single-strand DNA and histone were stopped after 6 months, and infusion. Laboratory results are antibodies were not tested). Joint physiotherapy was pursued. Morphea given in Table 1. Nonsteroidal x-rays (hips, knees, ankles, wrists, remitted within the next 4 months, antiinflammatory drugs provided a leaving residual hyperpigmentation and spine), echocardiography, eye mild subjective improvement,2 and examination, and pulmonary function without induration. One year after methotrexate (15 mg/m /week) tests were normal. Ultrasonography the treatment discontinuation, the combined with steroids (10 mg/day and MRI showed no joint effusion or patient was well with stable mild prednisolone 6 weeks, then 7.5 mg/ bone erosions, but a mild synovial Pjointatient limitations. 2 day 6 weeks, then 5 mg/day 8 weeks, thickening slightly enhanced then 2.5 mg/day) and physiotherapy after gadolinium infusion with no was started. Three months later, the subcutis or fascial edema (Fig 1). A 5-year-old boy had symmetric parents noted 4 new small pigmented Skin biopsy was consistent with the diffuse painless moderate joint macules on the neck, pubis, and diagnosis of morphea (Table 1 and limitations identified 10 months leg, suggestive of superficial plaque ‍Fig 2). Four months of physiotherapy earlier (Table 1). His parents morphea. Biopsy of 1 of these lesions provided no valuable benefit, and reported morning stiffness lasting was consistent with the diagnosis of Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 Merlin et al

Merlin et al 2017 ROUGH GALLEY PROOF Fibrous Arthropathy Associated With https://doi.org/10.1542/peds.2016-1899 October 2017 Morphea: A New Cause of Diffuse Acquired Joint Contractures 4 140 Pediatrics after gadolinium infusion and no bone erosion or synovial effusion. A synovial pathology study evidenced that this arthropathy resulted from synovial fibrosis with minimal “ ” inflammatory infiltrate, which may be considered an articular morphea. Morphea, also referred to as LS, is a fibrotic autoimmune disease of the skin and underlying tissues

that is equally1,2​ frequent in children and adults. ‍ The clinical subtypes (superficial circumscribed morphea,

generalized morphea, deep morphea,3 and linear and mixed scleroderma) share the same histologic features as systemic scleroderma: deep dermal infiltration by mononuclear cells with thickened collagen fibers, horizontalized fragmented elastic fibers, and adnexal rarefaction. Morphea is usually thought to be a self-limiting disease, but ∼ extracutaneous involvement is reported in 22% of patients, especially in the linear and

generalized subtypes4 in the series of Zulian et al. Extracutaneous 4,5​ involvement was mainly articular ‍ FIGURE 1 MRI patterns of inflammatory dry synovitis for comparison (A) and fibrotic arthropathy in morphea and presented as oligoarthritis or (B and C). A, For comparison, a patient cared for at our center, a 3-year-old girl with inflammatory polyarthritis, related to the skin painful diffuse dry polyarthritis (left wrist: T1-weighted frontal view, T2 fat-saturated (FS)-weighted lesion site in three-quarters of frontal and axial views and T1 gadolinium FS-weighted frontal view); B, patient 1 (right wrist, patients. However, the remaining T1-weighted frontal view, T2 FS-weighted frontal view and T1 gadolinium FS-weighted frontal and axial views); C, patient 2 (right wrist, T1-weighted frontal view, T2 FS-weighted frontal view and patients had arthritis completely T1 gadolinium FS-weighted frontal and axial views). Synovial thickening slightly enhanced after unrelated to the site of the skin gadolinium administered; no subcutis, fascia, tendon, or muscle edema was noted on the upper lesion, and 30% were positive for extremity MRI in either case. rheumatoid factors, raising the

suspicion of a systemic, rather5, 6​ than local, pathologic process. ‍ The clinical characteristics of morphea. Six months after initiation of superficial morphea. These polyarthritis associated with of treatment, the articular motion had contractures presented the same morphea were not described in improved slightly; after 12 months of clinical, biological, and radiologic this study, and extracutaneous therapy complete articular and active characteristics. Our 2 patients had manifestations occurred at the cutaneous remission was achieved. acquired painless, symmetrical same time or after the diagnosis of Macules turned hypochromic without polyarthritis of mild severity, morphea. induration. involving both peripheral and Discussion axial joints and associated with Although it is not uncommon to find normal acute phase reactants and joint contractures in the linear and no autoantibodies. Articular MRI generalized morphea subtypes, such We report here, to our knowledge provided clues for diagnosing this involvement seems infrequent in for the first time, that childhood- superficial morphea-associated superficial subtypes. Our patients onset diffuse joint contractures may fibrous arthropathy by showing had no subcutis induration, and result from fibrous arthropathy absent or moderate thickening of proximal MRI of the forearm and preceding the development synovium with mild enhancement upper arm showed no subcutis Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 140, number 4, October 2017 3

Merlin et al 2017 ROUGH GALLEY PROOF Fibrous Arthropathy Associated With https://doi.org/10.1542/peds.2016-1899 October 2017 Morphea: A New Cause of Diffuse Acquired Joint Contractures 4 140 Pediatrics distinguished from those observed in deep morphea. In patients with deep morphea, musculoskeletal involvement is frequently detected with MRI, but it is adjacent to the area of morphea and frequently associated with fascial thickening and increased fascial enhancement. Moreover, tenosynovitis, perifascial enhancement, myositis, enthesitis, and bone marrow involvement are

detected in7 addition to articular synovitis.

A careful evaluation of family history and clinical, biological, and radiologic features should allow exclusion of most differential diagnoses for childhood contractures. Causes of diffuse evolving contractures not present at birth include many conditions, both inherited (connective tissue disorders, neuromuscular diseases, mucopolysaccharidosis type I [MPS I]) and acquired

(JIA, dermatomyositis,8 systemic sclerosis). Most of these are associated with extra-articular FIGURE 2 manifestations, which promptly Articular (A) and cutaneous (B and C) histologic features of patient 1. A, Hematoxyline Eosine lead the physician to suspect the Safran coloration 200 wrist synovial biopsy: dense fibrosis with few inflammatory cells, mostly × cause of contractures. The more located around the capillaries (black arrow: fibrosis and white arrow lymphocytes). B, Hematoxyline “ ” Eosine Safran coloration ×100 cutaneous biopsy showing clear dermal fibrosis associated with relevant differential diagnoses are horizontalization of elastic fibers (black arrow) and scarce perivascular lymphocytes (white arrow). attenuated MPS I and dry arthritis. C, Same cutaneous biopsy. Immunostaining with anti-CD3 emphasizes this perivascular infiltrate Attenuated MPS I, unlike the ( 100). × severe Hurler form of the disease, is often revealed by painless joint contractures and no clinical or edema. This suggests that their symmetric contractures of unknown biological signs of inflammation8 or contractures resulted not from deep cause. This examination will search obvious physical abnormalities. “ However, almost all forms of MPS hidden fibrosis but rather from for superficial plaque morphea ” show dysplastic carpal and tarsal primary synovial fibrosis preceding associated with this newer articular “ ” bones, which are hypoplastic and cutaneous morphea. The present morphea,​ in addition to being on “ ” “ ” irregularly shaped, a sign that should findings thus argue for including the lookout for the more typical prompt the physician to perform a articular morphea among the dry synovitis in deep/linear scleroderma. urinary glycosaminoglycan analysis causes of childhood-onset diffuse (both quantitative and qualitative) contractures, even in the absence of Articular MRI provides clues for at a reputable laboratory. Joint cutaneous manifestations. Because diagnosing this superficial morphea- imaging shows prominent dysostosis morphea is usually asymptomatic associated fibrous arthropathy. It associated with9 thickening of and the development of lesions showed mild synovial enhancement soft tissues. Dry polyarthritis is – is typically insidious, a careful after gadolinium infusion with no considered an uncommon variant cutaneous examination is warranted joint effusion, and a mild bone edema of rheumatoid factor negative at onset and during follow-up of predominant in perivascular regions. JIA characterized by an absence patients who present with acquired This radiologic feature should be of joint effusions and synovial Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 Merlin et al

Merlin et al 2017 ROUGH GALLEY PROOF Fibrous Arthropathy Associated With https://doi.org/10.1542/peds.2016-1899 October 2017 Morphea: A New Cause of Diffuse Acquired Joint Contractures 4 140 Pediatrics 10 hypertrophy. It thus also presents A distinct interleukin-17 isoform immunosuppressive15 and antifibrotic as joint contractures but differs expression identifying a profibrotic12 effects. It therefore appears from fibrosing synovitis by the motif was recently described. adequate in patients with diffuse occurrence of joint pain and stiffness, Skin dysregulation of regulatory fibrosing synovitis associated with associated with laboratory indicators T-cell function has also been shown morphea. of inflammation. In addition, the to be involved13 in the triggering In light of these findings, physicians articular MRI pattern of dry JIA also of fibrosis. Thus, the imbalance should consider the diagnosis of differs from that observed in our between Th1/Th2/Th17-cell fibrosing synovitis in children with patients in showing a higher intensity subsets should drive inflammation acquired diffuse, symmetrical, of synovial enhancement, a more in the early stages of disease painless contractures and no prominent synovial thickening, and and fibrosis in11 the later stages of elevation of acute phase reactants. sometimes the presence of bone scleroderma. Our observations Articular MRI with gadolinium and erosions and tenosynovitis (Fig 1A). prompt us to hypothesize that careful cutaneous examination at Morphea involves autoimmune joint involvement follows the same onset and during follow-up are clues lesions that follow an initial evolution as morphea, with a first for diagnosis. mild inflammatory phase followed by inflammatory pattern1 and Abbreviations subsequent fibrosis. The primary a fibrotic process. lymphocytic infiltrate is mainly Current recommendations composed of T lymphocytes, for treating morphea include ’ JIA: juvenile idiopathic arthritis the cytokine secretion of which methotrexate combined with oral 14 LS: localized scleroderma stimulates fibroblasts and endothelial prednisone. Methotrexate s β MPS I: mucopolysaccharidosis cells to produce profibrotic factors mechanism of action in morphea is 11 type I such as tumor growth factor . still unclear but probably combines FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Merlin et al 2017 ROUGH GALLEY PROOF Fibrous Arthropathy Associated With https://doi.org/10.1542/peds.2016-1899 October 2017 Morphea: A New Cause of Diffuse Acquired Joint Contractures 4 140 Pediatrics juvenile localized scleroderma: Res (Hoboken). 2012;64(8): the expression of MMP-1 and type 1 a roadmap toward comparative 1175–1185 collagen in dermal fibroblast. effectiveness studies in juvenile 15. Nabai L, Kilani RT, Aminuddin F, Li Y, Mol Cell Biochem. 2015;409(1–2): localized scleroderma. Arthritis Care Ghahary A. Methotrexate modulates 213–224

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Merlin et al 2017 ROUGH GALLEY PROOF Fibrous Arthropathy Associated With https://doi.org/10.1542/peds.2016-1899 October 2017 Morphea: A New Cause of Diffuse Acquired Joint Contractures 4 140 Pediatrics Fibrous Arthropathy Associated With Morphea: A New Cause of Diffuse Acquired Joint Contractures Etienne Merlin, Sylvain Breton, Sylvie Fraitag, Jean-Louis Stéphan, Carine Wouters, Christine Bodemer and Brigitte Bader-Meunier Pediatrics 2017;140; DOI: 10.1542/peds.2016-1899 originally published online September 27, 2017;

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Fibrous Arthropathy Associated With Morphea: A New Cause of Diffuse Acquired Joint Contractures Etienne Merlin, Sylvain Breton, Sylvie Fraitag, Jean-Louis Stéphan, Carine Wouters, Christine Bodemer and Brigitte Bader-Meunier Pediatrics 2017;140; DOI: 10.1542/peds.2016-1899 originally published online September 27, 2017;

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