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1 Lincolnshire Knowledge and Resource Service This search summary contains the results of a literature search undertaken by the Lincolnshire Knowledge and Resource Service librarians in; March 2014 All of the literature searches we complete are tailored to the specific needs of the individual requester. If you would like this search re-run with a different focus, or updated to accommodate papers published since the search was completed, please let us know. We hope that you find the information useful. If you would like the full text of any of the abstracts listed, please let us know. Alison Price Janet Badcock Alison.price@lincolnshire.gov.uk janet.badcock@lincolnshire.gov.uk Librarians, Lincolnshire Knowledge and Resource Service Lexicon House Stephenson Road North Hykeham Lincoln LN6 3QU

2 Lincolnshire Knowledge and Resource Service Please find below the results of your literature search request. If you would like the full text of any of the abstracts included, or would like a further search completed on this topic, please let us know. Google can bring you back 100,000 answers, a librarian can bring you back the right one. Neil Gaiman Literature Search Results Search request date: 24 th March 2014 Search completion date: Alison Price Search completed by: 24 th March 2014 Enquiry Details Rituximab for the Management of Dermatomyositis. Disclaimer Every effort has been made to ensure that this information is accurate, up-to-date, and complete. However it is possible that it is not representative of the whole body of evidence available. No responsibility can be accepted for any action taken on the basis of this information. It is the responsibility of the requester to determine the accuracy, validity and interpretation of the search results. All links from this resource are provided for information only. A link does not imply endorsement of that site and the Lincolnshire Knowledge and Resource Service does not accept responsibility for the information displayed there, or for the wording, content and accuracy of the information supplied which has been extracted in good faith from reputable sources.

3 Opening Internet Links The links to internet sites in this document are live and can be opened by holding down the CTRL key on your keyboard while clicking on the web address with your mouse Full Text Papers Links are given to full text resources where available. For some of the papers, you will need a free NHS Athens Account. If you do not have an account you can register by following the steps at: You can then access the papers by simply entering your username and password. If you do not have easy access to the internet to gain access, please let us know and we can download the papers for you. Guidance on Searching within Online Documents Links are provided to the full text of each of these documents. Relevant extracts have been copied and pasted into these Search Results. Rather than browse through often lengthy documents, you can search for specific words and phrases as follows: Portable Document Format / pdf. / Adobe Click on the Search button (illustrated with binoculars). This will open up a search window. Type in the term you need to find and links to all of the references to that term within the document will be displayed in the window. You can jump to each reference by clicking it. You can search for more terms by pressing search again. Word documents Select Edit from the menu, the Find and type in your term in the search box which is presented. The search function will locate the first use of the term in the document. By pressing next you will jump to further references.

4 Overview and Medication Summary from Medscape Dermatomyositis is an idiopathic inflammatory myopathy, with characteristic cutaneous findings, that occurs in children and adults. This systemic disorder most frequently affects the skin and muscles but may also affect the joints, the esophagus, the lungs, and, less commonly, the heart.[1, 2] Calcinosis is a complication of dermatomyositis that is observed most often in children and adolescents. Medication Summary The goals of pharmacotherapy are to reduce morbidity and to prevent complications. In addition to the agents listed below, colchicine, alendronate, and warfarin have been shown to be potentially beneficial for the treatment of calcinosis. Prednisone is a first-line therapy for dermatomyositis. The dose is altered according to the response of the patient s condition. Immunosuppressive/cytotoxic drugs are used as steroid-sparing agents for the muscle disease of dermatomyositis. Methotrexate has been demonstrated to be useful for skin disease, even in the absence of significant muscle disease. Mycophenolate mofetil may also be useful for cutaneous disease. Antimalarials, particularly hydroxychloroquine, may be useful for cutaneous disease. Patients with dermatomyositis may be at increased risk for drug eruptions. Intravenous immunoglobulin (IVIG) is used in patients in whom therapy with corticosteroids and immunosuppressants fails. This agent is useful for both the skin and the muscles. Biologic therapies, including rituximab and tumor necrosis factor (TNF) antagonists might be useful. However, their widespread use is discouraged until adequate, preferably controlled, studies demonstrate their efficacy and safety. A recent, small, double-blind, placebo-controlled study of etanercept has demonstrated a steroid-sparing effect among 5 of 11 etanercept-treated patients versus treatment failure in all 5 placebo-treated patients. The effects were mostly on muscle disease, but some positive effects on skin disease were noted, utilizing the CDASI as a measure. However, 2 patients developed rash in the treated group, and 2 developed antinuclear antibodies. One patient in the placebo group developed ovarian cancer, but none in the etanercept group developed cancer during the year-long treatment period. While this is a small study, it does suggest that etanercept might have a role in the treatment of dermatomyositis.[52]

5 Immunosuppressive Agents Immunosuppressive agents are used early in the treatment course as steroid-sparing agents. They decrease the risk of steroid-related complications. Methotrexate (Trexall, Rheumatrex) Methotrexate has benefits in both muscle and skin disease. Its mechanism of action in treatment of inflammatory reactions is unknown. It may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). It is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. A satisfactory response is typically seen 3-6 weeks after administration. Adjust the dose gradually to attain satisfactory response. Azathioprine (Imuran, Azasan) Azathioprine is a purine analogue that inhibits purine synthesis, resulting in inhibition of DNA, RNA, and protein synthesis. It may decrease proliferation of immune cells, thereby leading to lower autoimmune activity. It has few, if any, effects on the skin. Mycophenolate (CellCept, Myfortic) Mycophenolate is useful for both skin and muscle disease. It inhibits purine synthesis and proliferation of human lymphocytes. Sirolimus (Rapamune) Sirolimus inhibits lymphocyte proliferation by interfering with signal transduction pathways. It binds to immunophilin FK506 binding protein (FKBP) to block the action of mammalian target of rapamycin (mtor). It is approved by the US Food and Drug Administration (FDA) for prophylaxis against organ rejection in patients receiving allogeneic renal allografts. A cyclosporine-sparing regimen has recently been FDA-approved for patients with low-tomoderate rejection risk at 2-4 months after transplantation. This regimen allows cyclosporine to be withdrawn, thus significantly decreasing renal toxicity while maintaining a similar antirejection effect. Rituximab (Rituxan) Rituximab is a third-line choice for the treatment of dermatomyositis. It is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. It is an IgG1-kappa immunoglobulin that contains murine light- and heavy-chain variable region sequences and human constant region sequences.

6 Systematic Reviews The effectiveness and safety of rituximab (anti-cd20) in neurologic autoimmune diseases Technology Assessment Unit of the McGill University Health Centre 2013 PRINCIPAL MESSAGES Rituximab, an anti-cd20 (white cell marker) antibody, has been used off-label for the treatment of four rare autoimmune diseases, myasthenia gravis (MG), neuromyelitis optica (NMO), dermatomyositis, and chronic inflammatory demyelinating polyneuropathy (CIDP). Although the evidence to support its use for these conditions is slender, their rarity indicates that better evidence will be hard to accumulate. The scanty evidence available is sufficient to justify conditional and temporary approval for use of rituximab in the MUHC for patients with MG and NMO who are refractory to or intolerant of standard therapy. Evidence is insufficient to support its use for dermatomyositis or CIDP. All relevant patient data should be collected and maintained in a regularly updated registry which should be examined at the latest in two years at which time the issue of approval should be reconsidered. The chapter on dermatomyositis is reproduced overleaf. Title: A systematic review of the off-label use of biological therapies in systemic autoimmune diseases Citation: Medicine, November 2008, vol./is. 87/6( ), (November 2008) Author(s): Ramos-Casals M., Brito-Zeron P., Munoz S., Soto M.-J. Abstract: In 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases (SAD). The information source is a periodic surveillance of reported cases by a MEDLINE search (last update before this writing: December 31, 2007). The analysis included a total of 19 SAD and 6 biological agents.by December 31, 2007, the Registry included 1370 patients with SAD who had been treated with biological agents (562 received infliximab, 463 rituximab, 285 etanercept, 42 anakinra, and 18 adalimumab). SAD included Sjogren syndrome (SS; 215 cases), Wegener granulomatosis (261 cases), sarcoidosis (219 cases), systemic lupus erythematosus (SLE; 172 cases), Behcet disease (173 cases), adult-onset Still disease (118 cases), cryoglobulinemia (88 cases), and other diseases (80 cases). The higher rate of therapeutic response was found for the use of rituximab in patients with SLE (90%), SS (91%), antiphospholipid syndrome (92%), and cryoglobulinemia (87%); infliximab in sarcoidosis (99%), adult-onset Still disease (90%), and polychondritis (86%); and etanercept in Behcet disease (96%). Results from controlled trials showed lack of efficacy for the use of infliximab in SS and etanercept in SS, Wegener granulomatosis, and sarcoidosis. In addition, an excess of side effects (>50% of reported cases) was observed for the use of infliximab in inflammatory myopathies and sarcoidosis, and for the use of etanercept in polymyositis. Sufficient data are not yet available to evaluate fully the efficacy and safety of adalimumab and anakinra in patients with SAD.In conclusion, current scientific evidence on the use of biological therapies in patients with SAD is mainly based on uncontrolled, observational data. The best results have been observed in the use of rituximab for SS, SLE, and cryoglobulinemia; infliximab for sarcoidosis and adult-onset Still disease; and etanercept for Behcet disease. Lack of efficacy was demonstrated for infliximab and etanercept in SS, for etanercept in Wegener granulomatosis and sarcoidosis, and for anti-tumor necrosis factor (TNF) in SS. Future controlled trials are needed to confirm the potential use of biological therapies in patients with SAD. Copyright 2008 by Lippincott Williams & Wilkins.

7 Consensus Statement Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2011 The section on rituximab is attached. This makes no reference to use for dermatomyositis. Randomised Controlled Trials Title: Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Citation: Arthritis & Rheumatism, February 2013, vol./is. 65/2(314-24), ; Author(s): Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, FW, Rockette HE, RIM Study Group Abstract: OBJECTIVE: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients.methods: Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and >2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required >3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve >20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8.RESULTS: Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial.conclusion: Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design. Copyright 2013 by the American College of Rheumatology. in_tx_of_myosi tis_rim_study_with_editorial_2013.pdf

8 Trials Title: Biomarker and serologic predictors of clinical improvement after b cell depletion in refractory adult and juvenile dermatomyositis (DM) and adult polymyositis (PM)-the rim (rituximab in myositis) trial Citation: Arthritis and Rheumatism, October 2013, vol./is. 65/(S877-S878), Author(s): Reed A.M., Crowson C.S., Hein M.S., Lopez De Padilla C., Khun H., Aggarwal R., Abstract: Background/Purpose: The aim of this study was to examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoabs) as biomarkers of disease outcome in refractory myositis patients treated with B cell depletion (BCD). Methods: In the RIM Trial, all subjects received 1 gram of rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n=177) were analyzed at 0, 8, 16, and 24 weeks after BCD with multiplexed sandwich immunoassays (Meso Scale Discovery) to quantify type-1 IFNregulated and other pro-inflammatory chemokines and cytokines. Biomarker scores were generated based on a priori assignment from literature review for serum levels from the following pathways: type-1 IFN-inducible (IP-10, I-TAC, MCP1), Th1 (IFN, TNF, IL2), Th2 (IL4, IL5, IL10, IL12, IL13), Th17 (IL6, IL17, IL1b) and regulatory cytokines (IL10 and TNFa). Biomarker scores are defined as the normalized sum of cytokine/chemokine levels adjusted to a 100-point scale. Myositis autoabs (antisynthetase (anti-syn) n=28, TIF1-g n=19, Mi-2 n=25, SRP n=21, MJ n=18, nonmyositis associated (non-maa) n=24, unidentified autoantibody n=9, and no autoantibodies n=33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum test was used for comparisons. Results: The mean (SD) values for muscle disease and physician global disease activity VAS scores (0-100 mm) were 46 (22) and 49 (19). IFN scores (median values) were higher at baseline in patients with anti-syn; (43), TIF1-g (31) and Mi-2 (30) compared with other autoab groups (p<0.001). No significant improvement in biomarker scores was detected at 8 weeks. However, at 16 weeks after BCD anti-syn and Mi-2 autoab (+) patients and non-maa had a greater improvement in IFN scores (-6.7, -6.1 and -7.2 p<.001) while TIF1-g (+) patients worsened by 7.0. The change in IFN score at 16 weeks correlated with percent change in muscle (r=0.27, p<0.001) and physician VAS (r=0.16, p=0.06). High IFN scores at baseline (>30) demonstrated the greatest clinical improvement based on global and muscle VAS among patients in certain autoab groups (e.g., Mi-2, none and "undefined") (IFN score-autoab interaction p=0.075; Figure). Regulatory scores were higher at baseline in patients with anti-syn (31) and non- MAA (32) vs. other groups (p=0.01). Regulatory score improved at 16 weeks in anti-syn (- 5.8) and Mi-2 (-3.4) and non-maa (-7.2, p=0.028). Th1 scores decreased in the anti-syn, Mi- 2, non-maa and to a lesser extent in the TIF-g group at 16 weeks (p=0.039) with the greatest improvement at 24 weeks (p=0.014) suggesting a longer time to improvement if the Th1 score is elevated. Th17 remained unchanged. Conclusion: Biomarker signatures in conjunction with autoabs prior to treatment help guide response to BCD in refractory myositis. In addition, biomarker and clinical response is greatest at 16 weeks after BCD.

9 Title: Real life experience suggests differential effects of rituximab on refractory dermatomyositis and polymyositis Citation: Annals of the Rheumatic Diseases, June 2013, vol./is. 72/, (June 2013) Author(s): Unger L., Kampf S., Luthke K., Aringer M. Abstract: Background Rituximab has been used for patients with refractory myositis in many centers, including ours. In a large double-blind trial on rituximab in inflammatory myopathies, no significant difference has been found between the two arms, where patients received rituximab at week 0 or week 8 (1). Nevertheless, the authors reporting on this trial argued that the data still suggested a rituximab effect. Objectives To investigate objective outcome parameters of off label therapies with rituximab in patients with severe dermatomyositis or polymyositis refractory to standard therapy. Methods In a historical prospective way, the charts of all our patients with dermatomyositis or polymyositis who received rituximab were analyzed for glucocorticoid dose, CPK, and lung function tests, where available, as well as for serious adverse events. Results A total of 19 patients were identified, one of whom died from aspiration three weeks after the first rituximab infusion. Charts of 18 patients (13 with polymyositis, 5 with dermatomyositis, age years (mean+sd), 17 female : 1 male) could be further analyzed. Rituximab was initiated in patients suffering from inflammatory myopathies with myositis (n=12), alveolitis (n=11), or arthritis (n=7) refractory to previous therapies (glucocorticoids in all, methotrexate in 67%, azathioprine in 39%, cyclophosphamide in 50%, intravenous immunoglobulin in 56%). In addition to the fatal aspiration pneumonia, six more severe infections (erysipelas (n=2), respiratory tract infection (n=1), urinary tract infection (n=1), herpes zoster (n=1), unclear focus (n=1)) were seen. One patient developed hypogammaglobulinaemia. Two patients had mild infusion reactions. Under rituximab, prednisolone was reduced from a median of 23.3 (range 7.5 to 523.5) mg q.d. to 8.8 ( ) mg q.d. by week 18 (+6) (p=0.0156, Wilcoxon signed rank test) and to 7.5 ( ) mg q.d. by week 30 (+6). At the same time, CPK decreased from a median of (range ) mumol/l*s to 3.27 (range ) mumol/l*s by week 18 (p=0.0024, Wilcoxon signed rank test) and to 1.77 ( ) mumol/l*s by week 30. Of 13 patients with elevated CPK, 8 had a decrease by at least 50%. In 8 patients with sufficient documentation of pathological lung function tests, an increase from a baseline % (mean+sd) to % of the expected value was seen at six months (p=0.0183, paired t-test), with 6/8 patients improving their total lung capacity (TLC) over time. Over all, of the 13 polymyositis patients, 9 were seen as responders, and 8/13 anti-synthetase syndrome patients had to be retreated because of flares. In contrast, all 5 dermatomyositis patients responded, and none had to be retreated. Conclusions In a real life population of patients with severe, refractory polymyositis or dermatomyositis, objective improvement was seen in the majority of patients with regard to CPK and lung function tests. At the same time, glucocorticoids could be reduced. In contrast to the subgroup with dermatomyositis, where one cycle of rituximab appeared sufficient, patients with anti-synthetase syndromes commonly experienced flares necessitating rituximab re-therapy.

10 Title: Clinical and serologic predictors of response in rituximab-treated refractory adult and juvenile dermatomyositis (DM) and adult polymyositis (PM)-the rim study Citation: Arthritis and Rheumatism, October 2012, vol./is. 64/(S682-S683), Author(s): Aggarwal R., Reed A.M., Ascherman D.P., Barohn R.J., Feldman B.M., Miller Abstract: Background/Purpose: The Rituximab in Myositis (RIM) Study evaluated 200 refractory myositis patients treated with rituximab, 83% of whom met the definition of improvement (DOI). The aim of this study was to identify the clinical and laboratory predictors of response in this cohort. Methods: All patients failed corticosteroids and at least 1 other immunosuppressive (IS) agent and received rituximab at weeks 0/1 (Early) or 8/9 (Late). The 1degree endpoint in this 44-week trial was time to achieve DOI [>20% improvement in 3 of 6 core set measures (CSM) (includes manual muscle testing (MMT), muscle enzymes, HAQ, patient/parent global, physician global disease activity and extramuscular disease activity) with no >2 CSM worsening by >25% (excluding MMT)] at 2 consecutive visits. We analyzed the effect of the following baseline variables on the time to DOI: myositis subtype, demographics, laboratory [IgM, IgG, myositis-associated autoantibodies (MAA), CBC, creatinine], damage measures (global, muscle damage and atrophy and organ-related), disease activity and other clinical parameters (skeletal/gi/pulmonary/muscle disease activity, Raynaud, calcinosis, mechanic hands), CSM, medication (early vs. late rituximab, IS agents and corticosteroids) and MAA subset [anti-synthetase (anti-syn), Mi-2, SRP, TIF1->, MJ, other autoantibodies and those without an MAA]. The Wilcoxon test was used to univariately evaluate the association of baseline variables with the time to DOI. A multivariate time-dependent proportional hazard model was built using forward selection (>=0.05) based on univariate variables with p<0.1. Results: 200 randomized patients (76 PM/76 DM/48 JDM) were analyzed (96 Early/104 Late). Table 1 lists the baseline variables which predicted time to DOI univariately. The multivariate model included autoantibodies (anti-syn was the best DOI predictor followed by Mi-2 as compared to the 'no MAA' subset), and global damage (lower damage had a better response). The effects of global damage diminished by week 20. Myositis subtype (JDM had a better response than adult myositis) was not statistically significant univariately, however, final model was stratified by the subtypes due to their clinical relevance and post hoc had statistical significance in multivariate models. (Table presented) Conclusion: Anti-Syn and Mi-2 autoabs strongly predicted improvement in rituximab-treated refractory myositis patients. JDM and lower disease damage predicted more rapid improvement early in course of treatment. It is unclear whether this effect is due to a delayed beneficial effect of rituximab in patients with higher damage and adult PM/DM. These results suggest that early, more aggressive therapy could be considered in some clinical and serologic myositis subsets to achieve a better therapeutic response and to avoid disease-related damage.

11 Title: Efficacy and safety of rituximab in the treatment of refractory inflammatory myopathies in adults: Results from the AIR registry Rheumatology, December 2011, vol./is. 50/12( ). Sibilia J., Fain O., Hot A., Abstract: Objectives. To assess the efficacy and safety of rituximab (RTX) in patients with refractory idiopathic inflammatory myopathies (IIMs). Methods. RTX efficacy was based on improvement in three criteria: creatine phosphokinase (CPK) level, daily CS dose and physicians' opinion. A decrease in CPK level or CS dose was significant if it was >25%. Results. Thirty patients were studied (21 women; age 52.5 years, disease duration 6.1 years). All had previously received immunosuppressors (ISs). Twenty-five patients received 1 g of RTX twice 2 weeks apart and five received 4 weekly RTX infusions (375 mg/m²). RTX was given in association with IS in 21 patients. Twenty-eight patients received CS (mean dose 21.2 mg/day). Mean follow-up was 17.2 months. Thirteen adverse events were reported, including seven infections and one serious infection (pyelonephritis). RTX was effective in 16 patients. Duration of efficacy was 15.5 months. Of the 20 patients with baseline CPK level >2 x upper limit of normal (ULN), 11 (55%) improved. The main level fell from 20.7 to 11 xuln. CS decreased in 15 patients, stopped in 4, remained stable in 8 and increased in the remaining 3. The CS dose decreased from 21.2 to 9.9 mg/day. The physicians' opinion was favourable in 21 patients. Manual muscle testing was performed in only five patients: it increased from 87 to 91/100 at 6 months. Conclusions. RTX was well tolerated and had some beneficial effects on patients with IIM, the main limitation of this study resulted in a lack of manual muscle testing. The Author Title: Rituximab treatment in patients with refractory inflammatory myopathies. Citation: Rheumatology, December 2011, vol./is. 50/12( ), ; Author(s): Mahler EA, Blom M, Voermans NC, van Engelen BG, van Riel PL, Vonk MC Abstract: OBJECTIVE: To assess the efficacy of rituximab on disease activity and muscle strength in patients with inflammatory myopathies refractory to conventional therapy. METHODS; Thirteen patients were treated with rituximab 1000mg i.v., twice, with a 2-week interval and followed for a median of 27 months. Primary outcomes were disease activity measured by creatine phosphokinase (CPK), lactate dehydrogenase (LDH) levels and muscle strength measured by hand-held dynamometry and manual muscle testing (MMT). Secondary outcomes were improvement in secondary laboratory measures, global assessment of general health, disease activity and pain, CS dose, functional ability, healthrelated quality of life and safety. Retreatment with rituximab was conducted if disease activity relapsed. RESULTS; The median levels of CPK and LDH were significantly reduced by 93.2 and 39.8%, respectively, compared with baseline after 34.6 months. The median muscle strength measured by hand-held dynamometry was significantly improved by 21.5% after 24 months. The median increase in muscle strength measured with MMT was 7.0% after 24 months of follow-up, although this did not reach statistical significance. Secondary outcomes improved as well. CONCLUSION; Rituximab is an effective treatment in refractory inflammatory myopathies, showing a decrease in CPK and LDH, an increase in muscle strength and improvement in scores of disease activity, general health, functional ability and health related quality of life with sustained effect during a median of 27.1 months of followup. Editorial: Rituximab in myositis. This editorial refers to Rituximab treatment in patients with refractory inflammatory myopathies, by Elien A. M. Mahler et al above. in_tx_of_myositi s_rim_study_with_editorial_2013.pdf

12 Title: Safety and efficacy of rituximab in severe juvenile dermatomyositis: Results from 9 patients from the French autoimmunity and rituximab registry Citation: Journal of Rheumatology, July 2011, vol./is. 38/7( ), X;1499- Author(s): Bader-Meunier B., Decaluwe H., Barnerias C., Gherardi R., Quartier P., Faye A., Abstract: Objective. To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients. Methods.We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry. Results. Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients. Conclusion. This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with severe JDM. The Journal of Rheumatology Copyright Title: Safety and efficiency of rituximab in juvenile dermatomyositis: A series of eight cases from the French AIR registry Citation: Arthritis and Rheumatism, 2010, vol./is. 62/(1693), (2010) Author(s): Bader-Meunier B., Decaluwe H., Quartier P., Faye A., Guigonis V., Pagnier A., Abstract: Background: Juvenile dermatomyositis (JDM) is a rare vasculopathic condition of presumably autoimmune etiology. No data are available regarding the safety and efficacy of anti-cd20 treatment in patients with JDM refractory to conventional treatments except for six case reports with conflicting results. Aim: To describe the efficacy and safety of rituximab (RTX) in JDM patients. Methods: French multicenter retrospective study of patients with JDM diagnosed according to the criteria of Bohan and Peter treated with RTX and included in the French Autoimmunity and Rituximab (AIR) registry. Complete remission was defined by the normalization of manual muscle testing (MMT) and child myositis assessment scale (CMAS) for muscular involvement and by the disappearance of active skin lesions and abdominal pain for cutaneous and abdominal involvement. Results: Eight patients (7 girls and 1 boy) were included. Age at diagnosis of JDM ranged from 2,5 to 10 years, and JDM duration at onset of rituximab therapy from 0,15 to 11 years. All the patients had been previously treated with immunosuppressive agents, and received rituximab because of the lack of efficiency of these treatments. The main indication for rituximab treatment was refractory muscle, skin and/or gastrointestinal involvement (6 patients) (group 1) and chronic complications consisting of severe calcinosis and severe abdominal pain associated with abdominal lipomatosis (2 patients) (group 2). The number of rituximab infusions ( mg/m²/infusion) ranged from 2 to 5. RTX was associated with corticosteroids and with immunosuppressive drugs in 8/8 and 4/8 patients respectively. The first RTX infusion had to be stopped in 1 patient (group 1) because of an infusion-related event. Clinical muscular, cutaneous and abdominal remission was achieved in 3/5 evaluable patients in group 1, including one patient with severe JDM who received plasmapheresis before and during the RTX course; MMT and CMAS returned to normal values within 3 to 12

13 months; normal values of serum CPK level were observed before and after RTX. In these responders steroid therapy was stopped in 1 patient 1,5 years after the first infusion of RTX, and was tapered at 10 and 15% of the baseline dosage respectively in the two others; the mean follow-up was 1,5 to 4 years, and complete remission lasted in 2 patients, while 1 patient has a relapse occurring 16 months after the start of the first course, successfully retreated with a second course of rituximab. RTX was ineffective in four patients (2 patients in each group). Calcinosis did not improve in two responders as well as in one non responder. Two patients presented localized bacterial infection of the calcinosis sites 2 and 11 months after RTX, and 1 patient died from non-related DM cause. Effective depletion of peripheral blood B cells was observed in all the patients and lasted more than 7 months in all patients except in one non responder. Conclusion: This small series suggests that rituximab may be an effective and safe co-therapy for treating muscular and skin involvement in a subset of children with refractory JDM, but had no effect on calcinosis.

14 Pilot Studies Title: A pilot trial of rituximab in the treatment of patients with dermatomyositis Citation: Archives of Dermatology, June 2007, vol./is. 143/6( ), X;0003- Author(s): Chung L., Genovese M.C., Fiorentino D.F. Abstract: Background: Dermatomyositis is an autoimmune disease that is associated with muscle and skin inflammation. Using quantitative scales, we sought to evaluate the effects of rituximab therapy on muscle strength and skin disease in patients with dermatomyositis. Observations: An open-label trial of rituximab therapy was conducted in 8 adult patients with dermatomyositis. Patients received 2 infusions of rituximab (1 g each) 2 weeks apart without peri-infusional steroids. The primary outcome was partial remission at week 24 (prespecified reduction in elevated creatine phosphokinase levels, muscle strength deficit (Manual Muscle Test), or skin disease (Dermatomyositis Skin Severity Index). After the first infusion of rituximab, all patients achieved sustained depletion of peripheral B cells. One patient withdrew at week 16 owing to a lack of treatment efficacy. Three patients (38%) achieved partial remission at week 24, in each case by improvement in muscle strength. Muscle enzyme levels and skin scores at week 24 were not significantly changed from those at baseline. Rituximab infusions were well tolerated, with no serious infectious complications. One patient died of metastatic cancer 9 months after his last infusion. Conclusion: Depletion of peripheral B cells had modest effects on muscle disease and limited effects on skin disease in our cohort of patients with dermatomyositis American Medical Association. Title: Rituximab in the treatment of dermatomyositis: An open-label pilot study Citation: Arthritis and Rheumatism, February 2005, vol./is. 52/2( ), Author(s): Levine T.D. Abstract: Objective. To test the hypothesis that B cells play a role in the pathophysiology of dermatomyositis (DM) by examining the effect of B cell depletion in patients with symptomatic DM. Patients were treated with rituximab, a CD20+ B cell-depleting monoclonal antibody. Methods. This was an open-label uncontrolled pilot trial in 7 adult patients with DM, 6 of whom had longstanding illness that was responding inadequately to a number of currently available immunosuppressive agents. All patients received 4 intravenous infusions of rituximab given at weekly intervals. Patients were followed up for up to 1 year without further treatment with rituximab. One patient was lost to followup. The principal efficacy outcome was muscle strength, measured by quantitative dynomometry. Results. All 6 evaluable patients exhibited major clinical improvement, with muscle strength increasing over baseline by %. Maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab. CD20+ B cells were effectively depleted in all patients by 12 weeks. Four patients experienced a return of symptoms that coincided with the return of B cells before the 52-week end point. Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells. Other symptoms of DM, including rash, alopecia, and reduced forced vital capacity, improved markedly in patients with these symptoms. Rituximab was well tolerated, with no treatment-related severe or serious adverse events during the observation period of this study. Conclusion. This small open-label study of DM patients treated with rituximab provided sufficiently encouraging results to justify a more formal evaluation of the value of B cell depletion therapy in the treatment of DM.

15 Literature Reviews Title: Juvenile dermatomyositis: Immunopathogenesis, role of myositis-specific autoantibodies, and review of rituximab use Citation: Pediatric Dermatology, July 2011, vol./is. 28/4( ), ; Author(s): Chiu Y.E., Co D.O. Abstract: Juvenile dermatomyositis (JDM) is an autoimmune disease of the skin and muscle that affects children. The etiology is poorly understood, but genetic susceptibility, environmental triggers, and abnormal immune responses are each thought to play a part. T cells have traditionally been implicated in the immunopathogenesis of JDM, but dendritic cells, B cells, and microchimerism are increasingly associated. Additionally, myositis-specific autoantibodies (MSA) can be present in the sera of affected patients and may correlate with distinct clinical phenotypes. Given the role of humoral immunity and MSA, there has been recent interest in the use of rituximab to treat JDM. Early results are mixed, but it is hoped that a prospective clinical trial will shed light on the issue in the near future Wiley Title: Juvenile-onset clinically amyopathic dermatomyositis: an overview of recent progress in diagnosis and management. Citation: Paediatric Drugs, 2010, vol./is. 12/1(23-34), ; (2010) Author(s): Walling HW, Gerami P, Sontheimer RD Abstract: Juvenile-onset amyopathic dermatomyositis is an uncommon variant of juvenileonset dermatomyositis (JDM), characterized by the hallmark cutaneous features of dermatomyositis for at least 6 months without clinical or laboratory evidence of muscle disease. Cutaneous calcinosis, vasculopathy, and interstitial lung disease frequently complicate the course of classic JDM (typical JDM with myositis) but are infrequent in amyopathic JDM. Recent literature suggests that approximately 75% of amyopathic JDM patients will remain free from muscle disease after years of follow-up, while approximately 25% of patients will evolve to having classic JDM. No clinical, laboratory, or ancillary parameters have been found to be predictive for this transition to muscle disease. Treatment of the cutaneous disease of amyopathic JDM centers on photoprotection and topical therapies directed against inflammation. Oral antimalarials are effective for cutaneous disease not adequately controlled with topical care. Systemic corticosteroids, while central to the treatment of classic JDM, are controversial in the treatment of amyopathic JDM. Randomized controlled trials are not available to guide the management of this disease. Proponents for early aggressive systemic corticosteroid therapy for amyopathic JDM advocate that this intervention may decrease the likelihood of progression to classic JDM, and/or prevent disease-specific complications of JDM such as calcinosis. Opponents of early intervention with systemic corticosteroids favor expectant management directed toward controlling skin disease, citing the predictable adverse effects of systemic corticosteroids in the face of uncertain benefit. Other therapeutic options for severe and recalcitrant cutaneous disease, including methotrexate, intravenous immunoglobulin, and rituximab, are reviewed, as are treatment options for calcinosis cutis. In weighing the available evidence, the authors conclude that early aggressive treatment of amyopathic JDM with systemic immunosuppressant agents should be avoided in most cases as the risk of these medications will outweigh the measurable benefit. The reported literature suggests a good prognosis for amyopathic JDM. Ongoing clinical follow-up is recommended in all cases to allow early detection of subtle signs of muscle disease.

16 Title: Rituximab: A review of dermatological applications Journal of Clinical and Aesthetic Dermatology, 2009, vol./is. 2/5(29-37) Author(s): Emer J.J., Abstract: The treatment of many dermatological disorders, such as autoimmune and immune-mediated diseases, consists of the use of systemic corticosteroids alone or in combination with other steroid-sparing immunosuppressants. Often, these treatment regimens are sufficient to control disease activity with relatively few side effects if monitored by a diligent physician. Some patients, however, may be refractory to treatment or develop intolerable side effects from therapy. For these patients, alternative treatment modalities with less toxicity and greater efficacy are required. Rituximab is a genetically engineered, chimeric monoclonal antibody directed against the B-cell lineage specific CD20 antigen. Originally developed for the treatment of B-cell non-hodgkin's lymphoma, rituximab has increasingly been used to treat a variety of autoimmune and immune-mediated disorders, such as rheumatoid arthritis, pemphigus diseases, systemic lupus erythematosus, dermatomyositis, and idiopathic thrombocytopenic purpura to name a few. Since very few randomized, controlled, clinical trials exist regarding the use of rituximab in the treatment of dermatological disorders, guidelines for the off-label use of this medication come from anecdotal case reports and cohort studies. Further clinical studies are needed to validate the safety and efficacy of rituximab therapy in dermatological disorders. Until then, we present a literature review of the emerging use of this B-cell depletion therapy. Title: Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature Citation: Clinical and Experimental Rheumatology, 2009, vol./is. 27/6( ), Author(s): Fernandez R.R., Rubio J.-L.C., Cano D.S., Moreno J.-A.S., Centeno N.O. Abstract: Objective. Rituximab is an anti-cd20 monoclonal antibody targeting B cells, which has been used with success in a wide variety of autoimmune diseases. The experience with this drug in patients with inflammatory myopathies (IM), nonetheless, is still limited. We review the literature and highlight several aspects in relation to therapy with rituximab in IM. Methods. We performed a research in the MEDLINE DATABASE. All cases identified from the literature research and cases diagnosed in our Unit were included in the analysis. Results. We identified 49 patients with IM treated with rituximab in the review of the literature carried out (31 female; 18 male), including our patients. Dermatomyositis (DM) was the most common disorder for which rituximab treatment was administered (69.4%). The other diseases treated included polymyositis (PM) 16.3%, antisynthetase syndrome (AS) 8.2%, one case with anti-srp-syndrome and other with juvenile dermatomyositis. The median time to diagnosis was 48 ( ) months. Sixty-five per cent (65.3%) of patients presented with skin manifestations, 89.8% with muscle weakness, 7.3% with arthritis, 16.3% with interstitial lung disease, and 7.3% with cardiomyopathy. Seventy-one (71.4%) of the patients received only one course of rituximab, 18.4% two courses, 4.1 % three, 2% four and only 4.1% five. We have observed both among our patients and those reported in the literature a high rate of response to rituximab, 75% of our patients and 72.5% of those described in the literature showed a good response. The median time free of symptoms between two courses was 12 (6-19) months. Rituximab was generally well tolerated by all patients, with no serious adverse events. Most of the adverse events reported were mainly infections, particularly respiratory tract infections. Conclusions. It is our belief that rituximab may be an optimal therapeutic choice for inflammatory myopathies. Nevertheless, there is a need for additional studies in order to assess the optimal regimen of treatment in the different subsets, as well as the initial dose, combination of treatments and re-treatment schedule.