Background
Juvenile Idiopathic Inflammatory myopathies (JIIM) are a heterogeneous group of autoimmune diseases that were originally categorized by their clinical phenotypes. In recent years, it has become clear that there is scope for further sub classification using serological phenotypes defined by Myositis-Specific Antibodies (MSA’s) and Myositis-Associated Antibodies (MAA’s) [
1‐
8]. Anti-Signal Recognition Particle (anti-SRP) is an MSA which has been well described in the adult population but rarely in children. JIIM associated with anti-SRP antibodies has been characterized by severe, progressive proximal muscle weakness, minimal skin involvement, and markedly raised CK (usually more than 40 times greater than the upper limit of normal) with high levels of disability [
2].
Thus far, the paediatric literature has demonstrated a picture consistent with the adult population, however only a handful of cases have been reported [
9‐
15]. Currently the limited number of cases precludes definitive conclusions to guide clinicians in their management and thus a variety of therapies have been trialled on an individual basis, with variable success.
In this paper, we discuss three new cases of anti-SRP myositis and relate this to the published literature. Our report highlights the use of an aggressive induction regime where standard therapy failed, including combination of intravenous immunoglobulin (IVIG), cyclophosphamide and rituximab, with intensive physical therapy, which resulted in positive outcomes in each case.
Discussion
Our report highlights three paediatric cases of anti-SRP necrotising myositis presenting at a single centre during 2014–15. All 3 cases were initially identified with Immunoblot and subsequently confirmed by immunoprecipitation. All cases were negative for other myositis specific and myositis associated antibodies. Given the rarity of published paediatric cases, our report helps confirm the clinical and histological findings in the paediatric age group and importantly, identifies an induction regime that was effective in all 3 patients.
The original Bohan and Peter [
16] criteria for IIM have not been validated in the paediatric population and fail to specifically identify children with necrotising myopathies. From a clinical perspective, this distinction is essential as patients with anti-SRP myositis fail to respond to first line therapy for JDM and are at risk of poor outcomes.
Muscle biopsy histology alone is unlikely to accurately distinguish necrotising myopathies from JDM, as some cases of anti-synthetase associated myopathies can have necrotic features, and conversely anti-SRP biopsies may have an inflammatory infiltrate (Fig.
1, case 3). Interestingly, one of our cases had tubuloreticular inclusion bodies on electron microscopy – previously considered a characteristic feature of DM/JDM. All our patients were tested for anti-HMGCR by ELISA with no positive results [
17]. To ensure the correct diagnosis of anti-SRP myositis, we would recommend that all patients diagnosed with Juvenile IIM be tested for MSAs including anti-SRP.
In all 3 of our patients, standard treatment with methotrexate and steroids failed to significantly improve muscle strength. Each patient subsequently responded to combination therapy with rituximab, cyclophosphamide and IVIG, together with a longer duration of intensive daily physical therapy. Although 2 of the more severe cases took between 6 (case 1) and 12 (case 3) months to regain MMT > 70 all 3 were able to regain independent mobility. Recent data from the RIM study suggests that the median time to achieve a 20% improvement in MMT8 with rituximab is 20 weeks [
18]. The nature of our report precludes definitive conclusions on the comparison of combination therapy vs individual agents, however, it is notable that in all 3 of our cases an improvement in MMT8 occurred between 12 and 16 weeks, which is earlier than data for rituximab alone. Given that anti-SRP myositis is usually more resistant to therapy than other forms of adult and juvenile myositis, we suggest that our patient’s results reflect the combination of rituximab together with cyclophosphamide and IVIG rather than from one agent alone.
Currently there is a lack of data regarding long term outcomes of anti-SRP myositis. A recent large cohort study of 37 adult patients with anti-SRP myositis found that only 50% of their cohort reached near-full or full strength after 4 years of treatment and that most continued to have persistently elevated CK levels [
19]. This study also documented worse outcomes in their younger patients.
In spite of the good initial response to combination therapy, two of our patients (case 1 and 2) had rising CK levels 7–8 months after presentation, once the prednisolone dose had fallen below 10 mg and they remained on MTX and IVIG alone. In both patients CK levels responded to an escalation in corticosteroids and re-dosing with rituximab. Long term follow-up of paediatric patients is needed to monitor for evidence of ongoing active disease after treatment.
Acknowledgements
The Juvenile Dermatomyositis Research Group would like to thank all of the patients and their families who contributed to the Juvenile Dermatomyositis Cohort & Biomarker Study & Repository. We thank all local research coordinators and principal investigators who have made this research possible. The JDRG members were as follows:
Dr. Kate Armon, Mr. Joe Ellis-Gage, Ms. Holly Roper, Ms. Vanja Briggs and Ms. Joanna Watts (Norfolk and Norwich University Hospitals), Dr. Liza McCann, Mr. Ian Roberts, Dr. Eileen Baildam, Ms. Louise Hanna, Ms. Olivia Lloyd and Susan Wadeson (The Royal Liverpool Children’s Hospital, Alder Hey, Liverpool), Dr. Phil Riley and Ms. Ann McGovern (Royal Manchester Children’s Hospital, Manchester), Dr. Clive Ryder, Mrs. Janis Scott, Mrs. Beverley Thomas, Professor Taunton Southwood, Dr. Eslam Al-Abadi (Birmingham Children’s Hospital, Birmingham), Dr. Sue Wyatt, Mrs. Gillian Jackson, Dr. Tania Amin, Dr. Mark Wood, Dr. Vanessa VanRooyen and Ms. Deborah Burton (Leeds General Infirmary, Leeds), Dr. Joyce Davidson, Dr. Janet Gardner-Medwin, Dr. Neil Martin, Ms. Sue Ferguson, Ms. Liz Waxman and Mr. Michael Browne (The Royal Hospital for Sick Children, Yorkhill, Glasgow), Dr. Mark Friswell, Professor Helen Foster, Mrs. Alison Swift, Dr. Sharmila Jandial, Ms. Vicky Stevenson, Ms. Debbie Wade, Dr. Ethan Sen, Dr. Eve Smith, Ms. Lisa Qiao, Mr. Stuart Watson and Ms. Claire Duong (Great North Children’s Hospital, Newcastle), Dr. Helen Venning, Dr. Rangaraj Satyapal, Mrs. Elizabeth Stretton, Ms. Mary Jordan, Dr. Ellen Mosley, Ms. Anna Frost, Ms. Lindsay Crate, Dr. Kishore Warrier and Stefanie Stafford (Queens Medical Centre, Nottingham), Professor Lucy Wedderburn, Dr. Clarissa Pilkington, Dr. Nathan Hasson, Mrs. Sue Maillard, Ms. Elizabeth Halkon, Ms. Virginia Brown, Ms. Audrey Juggins, Dr. Sally Smith, Mrs. Sian Lunt, Ms. Elli Enayat, Mrs. Hemlata Varsani, Miss Laura Kassoumeri, Miss Laura Beard, Miss Katie Arnold, Mrs. Yvonne Glackin, Ms. Stephanie Simou, Dr. Beverley Almeida, Dr. Kiran Nistala, Dr. Raquel Marques, Dr. Claire Deakin, Ms. Stefanie Dowle, Ms. Charis Papadopoulou, Mrs. Cerise Johnson-Moore, Ms. Emily Robinson (Great Ormond Street Hospital, London), Dr. Kevin Murray (Princess Margaret Hospital, Perth, Western Australia) Dr. John Ioannou and Ms. Linda Suffield (University College London Hospital, London) Dr. Muthana Al-Obaidi, Ms. Helen Lee, Ms. Sam Leach, Ms. Helen Smith, Dr. Anne-Marie McMahon, Ms. Heather Chisem and Ruth Kingshott (Sheffield’s Children’s Hospital, Sheffield); Dr. Nick Wilkinson, Ms. Emma Inness, Ms. Eunice Kendall, Mr. David Mayers, Ruth Etherton, Danielle Miller and Dr. Kathryn Bailey (Oxford University Hospitals, Oxford); Dr. Jacqui Clinch, Ms. Natalie Fineman and Ms. Helen Pluess-Hall (Bristol Royal Hospital for Children, Bristol); Ms. Lindsay Vallance (Royal Aberdeen Children’s Hospital); Ms. Louise Akeroyd (Bradford Teaching Hospitals); Dr. Alice Leahy, Amy Collier, Rebecca Cutts, Emma Macleod, Dr. Hans De Graaf, Dr. Brian Davidson, Sarah Hartfree, Danny Pratt (University Hospital Southampton).