Overview of Juvenile Dermatomyositis Pediatric Rheumatology Red Team Resident Teaching Series

What is Juvenile Dermatomyositis? “A multisystem disease of uncertain origin that results in chronic inflammation of striated muscle and skin.” (Cassidy and Petty, 2011) A rare pediatric autoimmune disease, but the most common inflammatory myopathy in children Average annual incidence rate: 3.2 cases per 1 million children (Mendez, EP, et al. 2003) 16-20% of all dermatomyositis patients have onset in childhood Girls > boys (2.2:1) Peak age of onset: 7.6 years old, peak range: 5-14 years of age No difference in incidence in different ethnicities

What is Juvenile Dermatomyositis? Systemic small vessel vasculopathy Mainly muscle and skin involvement, but can involve other organ systems Presentation: insidious onset malaise, fever, fatigue, rash, muscle weakness/pain Don’t always have skin AND muscle manifestations at the same time Amyopathic JDM = JDM without evidence of muscle involvement

Differential Diagnosis of Juvenile Idiopathic Inflammatory Myopathies Feldman et al, Lancet 2008; 371, 2201-12

JDM - Etiology & Pathogenesis Cause unknown Likely autoimmune angiopathy Environmental and genetic factors implicated A history of infection prior to onset is common 65- 70% of patients have a history of a significant infection during the three months prior to first onset of symptoms Proposed triggers include various infectious agents, vaccines, medications, UV light Cellular and humoral immunity implicated Complement-mediated injury important Innate immune response: type I interferons and dendritic cells

Cellular and Humoral Immunity Autoimmunity ~70-80% JDM patients have positive ANA ~10% children have classic myositis specific antibodies (MSA) compared to >50% adults Some auto-antibodies that you might see positive in these patients: anti-Jo1, anti-SSA, anti-SSB, anti-topoisomerase, anti-U1RNP Abnormalities of cell-mediated immunity MHC class I antigens strongly expressed by muscle cells of JDM patients but not normal controls Association with immunodeficiency Occurrence in children with hypogammaglobulinemia, selective IgA deficiency, & C2 deficiency

Clinical Features of JDM Patients Constitutional Fever: 16-65% Adenopathy: 20% Lethargy: 10% Musculoskeletal Weakness: 95% Myalgia or arthralgia: 25-73% Arthritis: 23-58% Contractures: 26-27% Raynaud’s disease: 9-14% Cutaneous Gottron’s papules: 57-100% Heliotrope rash: 66-100% Nailfold capillary changes: 91% Malar or facial rash: 42-73% Mouth ulcers: 35% Skin ulcers: 23-30% Limb edema: 11-32% Calcinosis: 6-30% Lipodystrophy: 10-14% Pulmonary Dyspnea: 7-43% Gastrointestinal Dysphonia or dysphagia: 18-44% Gastrointestinal symptoms: 22-37% Feldman et al, Lancet 2008; 371, 2201-12

Dermatomyositis – other organ involvement Gastrointestinal vasculitis- gut wall perforation Arthritis - common but usually early and mild, non-erosive Cardiac - inflammation, fibrosis, conduction defects Renal - glomerular hypercellularity Pulmonary - fibrosis, pneumothorax Central nervous system - behavior changes, seizures Alopecia Eyes - exudative vasculitis of retina Derm – calcinosis, subcutaneous nodules, ulcerations Lipodystrophy

The Pictures of Juvenile Dermatomyositis Heliotrope Rash with periorbital edema Malar rash Rash on extensor surfaces Gottron’s Papules V Sign Shawl Sign Calcinoses

Heliotrope: The flower for which the rash is named!

Periorbital edema and heliotrope rash The heliotrope rash occur over the upper eyelids and is violaceous, reddish-purple in coloration (see last slide). It is often associated with periorbital edema, and is often accompanied by a malar rash (see next slide). It is one of the most common rashes seen in JDM.

Facial and extremity rash The facial rash of JDM appears in a malar-distribution (bilateral cheeks, extending across the nasal bridge, sparing the nasolabial folds), similar to the malar rash seen in lupus but usually less well-demarcated. The chin and forehead can also be involved. This tends to be a photosensitive rash. This patient also has rash on her bilateral elbows, consistent with Gottron’s papules (see next slide).

Gottron’s papules Gottron’s papules are shiny, erythematous, scaly plaques seen in a symmetrical distribution on the extensor surfaces of the upper and lower extremities (often over the MCPs, PIPs, and DIPs of the hands, also occur on the elbows, knees, and sometimes on the malleoli of the ankles). They can start initially as flat erythematous lesions. It is one of the most common rashes seen in JDM. Note also the erythema around the nailbeds, reflecting nailbed capillary abnormalities, another common finding (see next slide).

Nailbed Capillary Abnormalities A common finding in JDM, this reflects active vasculitis of the nailbed capillaries. Upper left, a normal nailfold capillary pattern. Upper right, shows dilation of capillary loops, with loss of surrounding loop structures (“drop-out”). Lower right, dilated capillary loops are present with areas of arborized clusters of loops. Lower left, dilated and prominent capillary loops.

Other Skin Manifestations Photosensitive rash can also occur on the chest, neck, extremities, scalp (this is the V-sign and shawl sign seen on Slide #7) May evolve into poikiloderma (hyper or hypopigmentation with atrophy and telangiectasia) Mechanic’s hands Pruritis, psoriasiform scalp dermatitis Poikiloderma: Confluent violaceous papules with mottled dyspigmentation and telangiectasias Mechanic’s hands: Scaly, fissured, hyperkeratotic skin suggestive of manual labor

Other Skin Manifestations Lipodystrophy (below): reported in ~ 20% of JDM patients . Can be generalized, partial, or localized; characterized by a progressive, slow, and symmetrical loss of subcutaneous fatty tissue, which is often most noticeable over the face and the limbs. Calcinosis (above): seen in 12-43% of JDM patients, this tends to be a sign of chronic disease and rarely presents at diagnosis. These are calcium salt deposits from muscle inflammation that deposit in subcutaneous tissues, often over pressure-bearing surfaces. These can be superficial and can open to the environment, expressing calcium material, and can become superinfected. These can self-resolve, lessen in size, or remain unchanged. Trauma can be associated with formation. If they occur over joints they can cause joint contractures.

Muscle Weakness Probably affects all muscle groups, but proximal > distal Most obvious in limb-girdle, neck flexors, and trunk muscles May be tender, edematous, indurated Respiratory weakness In one report, ~ ¼ patients had involvement of pharyngeal, hypopharyngeal, and palatal muscles Difficulty swallowing, dysphonia, nasal speech, regurgitation of liquids through nose Aspiration risk May have Gowers’ or Trendelenberg’s sign

Gowers’ Sign Trendelenberg’s Sign

How is it diagnosed? Symmetrical weakness of the proximal musculature Characteristic cutaneous changes consisting of heliotrope discoloration of the eyelids, which may be accompanied by periorbital edema and erythematous papules over the extensor surfaces of joints, including the dorsal aspects of the metacarpophalangeal and proximal interphalangeal joints, elbows, knees, or ankles (i.e. Gottron papules) Elevation of the serum level of one or more of the following skeletal muscle enzymes: CK, AST, LDH, Aldolase EMG demonstration of the characteristics of myopathy and denervation Muscle biopsy documenting histological evidence of necrosis *** MRI of thigh muscles is preferred modality to establish presence of myositis in many centers (symmetrical muscle edema on fat-suppressed T2-weighted or STIR sequences), but is not specific for myositis as edema associated with other myopathies can appear similar on MRI. Definite JDM: rash + 3 other criteria Probable JDM: rash + 2 other criteria Criteria from Bohan and Peter: Polymyositis and dermatomyositis, N Engl J Med 292: 344-347, 403-407, 1975.

Revisiting the Criteria for JDM Although criteria used for JDM, sensitivity and specificity not validated in children (estimated 45-90% & 90%) For JDM diagnosis, require rash and 2 of 4 other criteria for diagnosis Most institutions don’t do EMG or biopsy if diagnosis is clear. MRI often being used in difficult cases, less painful and invasive than EMG or biopsy

Typical Laboratory Findings: Elevated muscle enzymes: Creatinine Kinase, Aldolase, LDH, AST, ALT Elevated inflammatory markers: ESR, CRP May have lymphopenia, but leukopenia and anemia are uncommon at onset of disease Positive ANA in ~ 70-80% of patients Other autoantibodies commonly tested that might be positive in JDM patients: Anti-Jo1 – 2-5% Anti-Ro (SSA) – 2-8% Anti-La (SSB) – 1% Anti-U1RNP – 5-6%

So what happens to these kids? Prior to steroids: 1/3 self-resolved, 1/3 would resolve but develop significant morbidity, 1/3 would die Morbidity and mortality rates have improved with the use of steroids and DMARDs Mortality < 3%, 28-41% with functional disability, 37-41% with monocyclical course Some patients do continue to have persistent chronic skin changes

Treatment: First line: Additional treatment options: Prednisone/Methylprednisone Methotrexate Additional treatment options: IVIG Cyclosporine Tacrolimus Mycophenolate Mofetil Azathioprine Cyclophosphamide Adjunctive therapies: Physical therapy Hydroxycholorquine Sun protection Calcium/Vitamin D

Board Review Question A 7 year old girl has a 2 month history of generalized weakness and a rash. Findings on exam include a violaceous discoloration of the malar regions, erythematous papules over the interphalangeal joints, and nailfold telangiectasias. Proximal muscle strength is 3/5. Of the following, the MOST appropriate intial step in evaluating this patient’s symptoms is to obtain a(n): a. antinuclear antibody titer b. creatine kinase concentration c. electromyogram d. magnetic resonance image of muscle e. muscle biopsy