Horizon Scanning Centre May 2014 Tabalumab for systemic lupus erythematosus SUMMARY NIHR HSC ID: 5581 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Tabalumab (LY-2127399) is intended to be used as second line therapy for the treatment of systemic lupus erythematosus (SLE). If licensed, it would offer an additional treatment option for patients who have active moderate to severe SLE despite treatment with glucocorticoids, anti-malarials, and/or immunosuppressants; a group who currently have few effective therapies available. Tabalumab is a human anti-b-cell activating factor (BAFF or B lymphocyte stimulator [BLyS]) monoclonal antibody. It is administered subcutaneously, in contrast to the only existing licensed BAFF antagonist, which is administered via IV infusion. The annual incidence of SLE in the UK is between 3 and 4 cases per 100,000 population, which equates to approximately 1,600 and 2,100 new cases in England per year. The estimated prevalence of SLE is 25-28 per 100,000 population, commensurate with around 15,000 people in England with the disease. SLE is associated with considerable morbidity and mortality, with 10-year survival rates ranging from 70% to 92%. Around 40 70% of SLE patients develop renal involvement which confers a worse prognosis for survival; and approximately 10% of patients with lupus nephritis develop end-stage renal failure requiring dialysis or transplantation. Neuropsychiatric involvement occurs in 27% of people with SLE, and SLE is also characterised by haematological features and cardiovascular complications. Treatment strategies for SLE depend on the severity of disease and organ involvement. Antimalarials (especially hydroxychloroquine) and non-steroidal anti-inflammatory drugs, all in combination with glucocorticoids, are standard therapy for those with mild to moderate skin and joint disease. Immunosuppressive agents such as azathioprine, methotrexate, IV cyclophosphamide or mycophenolate mofetil are considered for refractory moderate skin and joint disease. Biological disease-modifying anti-rheumatic drugs are used in patients with refractory severe disease. Belimumab (Benlysta) is currently the only licensed treatment for active autoantibodypositive SLE which is refractory to standard therapy. Tabalumab is currently in phase III clinical trials comparing its effect on disease activity against treatment with placebo. The first trial is expected to complete in July 2015. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham Email: nihrhsc@contacts.bham.ac.uk Web: http://www.hsc.nihr.ac.uk
TARGET GROUP Systemic lupus erythematosus (SLE): moderate to severe; active; without active lupus nephritis or active central nervous system (CNS) lupus second line; in combination with standard of care (SOC) treatment. TECHNOLOGY DESCRIPTION Tabalumab (LY-2127399) is a human anti-b-cell activating factor (BAFF or B lymphocyte stimulator [BLyS]) monoclonal antibody. Tabalumab is an antagonist of both soluble- and membrane-bound forms of BAFF, which binds to receptors expressed on B cells. BAFF over-expression may contribute to autoimmune diseases, including SLE, via effects on autoreactive B-lymphocyte activation, proliferation, survival and immunoglobulin (autoantibody) production 1,2. Belimumab (Benlysta) is currently the only licensed treatment for active autoantibody-positive SLE which is refractory to standard therapy 3. However, many SLE patients fail to clinically improve on belimumab therapy, which targets only soluble BAFF and requires intravenous (IV) administration 2. Tabalumab in combination with SOC is intended for the treatment of patients with active moderate to severe SLE (without active lupus nephritis or active CNS lupus) which is refractory to treatment. It is administered by subcutaneous (SC) injection at a loading dose of 240mg, followed by 120mg every 2 weeks or 4 weeks in combination with SOC. Tabalumab has completed a phase II clinical trial in end-stage renal failure and is in a phase II clinical trial for the treatment of multiple myeloma. INNOVATION and/or ADVANTAGES If licensed, tabalumab will offer an additional treatment option for patients who have active moderate to severe SLE despite treatment with glucocorticoids, anti-malarials, and/or immunosuppressants; a group who currently have few effective therapies available. Tabalumab is administered SC in contrast to the only existing licensed BAFF antagonist, which is administered via IV infusion. DEVELOPER Eli Lilly and Company Limited. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND SLE is a chronic, autoimmune, inflammatory disease which affects the skin, joints, internal organs and serous membranes 1. The cause of SLE is unknown, though a combination of genetic, environmental and hormonal factors is thought to play a role in disease 2
development and progression 1. Disease activity varies over time and, at the onset, symptoms can be non-specific and include pyrexia, extreme fatigue, myalgia, arthralgia, and skin rash 1. Active SLE involves frequent flares and more severe symptoms compared with inactive disease (when the disease is in remission) 1. SLE can lead to arthritis, kidney failure, heart and lung inflammation, CNS abnormalities and blood disorders 1. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The National Service Framework for Long Term Conditions (2005). The National Service Framework for Renal Services (2004). NHS England. 2013/14 NHS Standard Contract for Specialised Rheumatology Services (Adult). A13/S/a. NHS England. 2013/14 interim Clinical Commissioning Policy Statement: Rituximab for the Treatment of Systemic Lupus Erythematosus in Adults. A13/PS/a. CLINICAL NEED and BURDEN OF DISEASE The annual incidence of SLE in the UK is between 3 and 4 cases per 100,000 population 4, which equates to approximately 1,600 and 2,100 new cases in England per year. The estimated prevalence of SLE is 25-28 per 100,000 population, commensurate with around 15,000 people in England with the disease 4. Although the severity of SLE is greater in men, it is 8-10 times more common in women, and mainly affects women aged 15-40 years 1,5. The majority of people with SLE are of working age and the disease results in most being unable to work a. The prevalence of SLE is significantly higher in African-Caribbean, South Asian and Chinese populations compared with European white populations 1. SLE is associated with considerable morbidity and mortality, with 10-year survival rates ranging from 70% to 92% 6. Long-term damage accrues as a result of persistent disease activity and the cumulative effects of glucocorticoids 1. Various studies have estimated that 40 70% of SLE patients develop renal involvement 7, which confers a worse prognosis for survival b. The prevalence of biopsy-proven lupus nephritis in the northwest of England in 2001 was 4.4 per 100,000 7. Approximately 10% of patients with lupus nephritis develop endstage renal failure requiring dialysis or transplantation 8. Neuropsychiatric involvement occurs in 27% of people with SLE and has a wide variety of clinical presentations, including seizures, chronic headache, transverse myelitis, vascular brain disease, psychosis, and neural cognitive dysfunction. SLE is also characterised by haematological features, such as haemolytic anaemia (8%), thrombocytopenia (22%) and lymphadenopathy (12%), and cardiovascular complications, such as thrombosis (14%) and Raynaud's phenomenon (34%) 9. Approximately 20-30% of patients with SLE continue to have high disease activity despite standard therapies or have organ involvement particularly associated with a worse prognosis, e.g. renal, neuropsychiatric or haematological involvement 8. SLE can lead to a poor quality of life (QoL) and associated psychological disorders b. In one study comparing SLE with rheumatoid arthritis and non-inflammatory rheumatic disorders, physical function was better but general health and mental component QoL summary scores (vitality, social function, role-emotional and mental health) were more impaired in SLE 10. In 2012-13 there were 4,038 admissions for SLE (ICD-10 M32) in England, resulting in 9,595 bed days and 4,574 finished consultant episodes 11. There were 164 deaths (150 deaths in women) due to SLE (ICD-10 code M32) registered in England and Wales during 2012 12. a Expert personal communication. b Expert personal communication. 3
PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Systemic lupus erythematosus (autoantibody-positive) - belimumab (ID416). Expected date of issue to be confirmed. NICE clinical guideline. Chronic kidney disease: Early identification and management of chronic kidney disease in adults in primary and secondary care (CG73). September 2008. NICE quality standard. Chronic kidney disease (QS5). March 2011. Other Guidance Arthritis Research UK. Overview of the management of systemic lupus erythematosus. 2013 13. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. 2012 14. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. 2012 15. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. 2010 16. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. 2007 17. Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. 1999 18. CURRENT TREATMENT OPTIONS The aim of drug therapy in SLE is to reduce disease activity and prevent disease flares 8. Treatment strategies depend on the severity of disease and organ involvement. Antimalarials (especially hydroxychloroquine) and non-steroidal anti-inflammatory drugs, all in combination with glucocorticoids, are standard therapy for those with mild to moderate skin and joint disease 8. In non-responsive patients or patients not able to reduce glucocorticoids below doses acceptable for chronic use, immunosuppressive agents such as azathioprine and methotrexate should also be considered for moderate skin and joint disease 16. Those refractory to this treatment require more potent immunosuppression therapy, such as IV cyclophosphamide or mycophenolate mofetil 8. Biological diseasemodifying anti-rheumatic drugs (DMARDS) are used in patients with severe disease who do not respond to conventional treatments or require unacceptably high doses of glucocorticoids 8,12,19. Treatment options for SLE may include 1,20,21 : Non-steroidal anti-inflammatory drugs (NSAIDs) Antimalarial hydroxychloroquine sulphate (licensed) 4
Glucocorticoids (licensed): o Topical and low-dose oral: for mild SLE o Oral, intramuscular or intra-articular: for moderate SLE o Intravenous high-dose: for serious, life- or organ-threatening SLE Immunosuppressive/cytotoxic agents: o Non-biological DMARDS (unlicensed for this indication) azathioprine, methotrexate, mycophenolate mofetil, ciclosporin, tacrolimus, cyclophosphamide o Biological DMARDS belimumab (licensed), rituximab (unlicensed for this indication) Additional treatment options that are considered for severe SLE with or without renal involvement may include: Plasmapheresis: for antiphospholipid syndrome, thrombotic thrombocytopenic purpura and pulmonary haemorrhage c Immunoglobulin IV d Dapsone (unlicensed for this indication): for cutaneous lupus not responding to antimalarials d Gonadotrophin inhibitor danazol (unlicensed for this indication): to protect against cyclophosphamide induced ovarian toxicity d SLE patients who develop chronic kidney disease or end-stage renal failure may receive dialysis and renal transplantation as indication of end-stage renal failure from any cause d. EFFICACY and SAFETY Trial ILLUMINATE-1, NCT01196091, 13656, H9B-MC BCDS; LY-2127399 vs placebo; phase III. ILLUMINATE-2, NCT01205438, 13653, H9B-MC-BCDT; LY-2127399 vs placebo; phase III. Sponsor Eli Lilly and Company. Eli Lilly and Company. Status Ongoing. Ongoing. Source of Trial registry 22, manufacturer. Trial registry 23, manufacturer. information Location EU (not UK), USA, Canada and other countries. EU (incl UK), USA, Canada and other countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=1,161; aged 18 years; SLE (by American College of Rheumatology [ACR] criteria); positive antinuclear antibodies (ANA); appropriate SELENA- SLEDAI d score at screening; no severe lupus kidney disease, active CNS or peripheral neurologic disease; no receipt of IV immunoglobulin (IVIg) within 180 days, 40mg prednisolone within 30 days, changed dose of antimalarial drug within 30 days, changed dose of immunosuppressive drug within 90 days, or previous rituximab treatment. n=1,121; aged 18 years; SLE (by ACR criteria); positive ANA; appropriate SELENA-SLEDAI score at screening; no severe lupus kidney disease, active CNS or peripheral neurologic disease; no receipt of IVIg within 180 days, 40mg prednisolone within 30 days, changed dose of antimalarial drug within 30 days, changed dose of immunosuppressive drug within 90 days, or previous rituximab treatment. c Expert personal communication. d SELENA-SLEDAI: Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index. It measures 24 descriptors of disease activity with a weighted score (up to 8) given to any one that is present. The more serious manifestations (such as renal, neurologic, and vasculitis) are weighted more than others (such as cutaneous manifestations). The maximum possible score is 105. 5
Schedule Follow-up Primary outcome Secondary outcomes Expected reporting date Randomised to LY-2127399 240mg SC loading dose followed by 120mg SC every 2 weeks; or LY-2127399 240mg SC loading dose followed by 120mg SC every 4 weeks; or placebo SC every 2 weeks; or placebo every 4 weeks; all given with or without SOC treatment. Active treatment for 52 weeks, with option to continue in extension study NCT01488708. There is a 24-48 week B cell safety follow up for those that terminate early or do not enter extension study NCT01488708. SLE Responder Index (SRI). Change in prednisolone or equivalent glucocorticoid dose; change in antidsdna level; SLEDAI2K e score; time to first severe SLE flare; PGA f score; BFI g scores; LupusQoL h composite and domain scores; time to first new BILAG i A or 2 new BILAG B SLE flares; SELENA- SLEDAI disease activity score; modified SRI with no BILAG A or 1 BILAG B organ domain flares; BILAG numeric scores. Study completion date reported as Jul 2015. Randomised to LY-2127399 240mg SC loading dose followed by 120mg SC every 4 weeks; or LY-2127399 240mg SC loading dose followed by 120mg SC every 2 weeks; or placebo SC every 2 weeks; or placebo every 4 weeks; all given with or without SOC treatment. Active treatment for 52 weeks, with option to continue in extension study NCT01488708. There is a 24-48 week B cell safety follow up for those that terminate early or do not enter extension study NCT01488708. SRI. Change in prednisolone or equivalent glucocorticoid dose; change in antidsdna level; SLEDAI2K score; time to first severe SLE flare; PGA score; BFI scores; LupusQoL composite and domain scores; time to first new BILAG A or 2 new BILAG B SLE flares; SELENA- SLEDAI disease activity score; modified SRI with no BILAG A or 1 BILAG B organ domain flares; BILAG numeric scores. Study completion date reported as Aug 2015. Trial ILLUMINATE-X; NCT01488708, 13811, H9B-MC-BCDX; LY-2127399; phase IIIb extension. NCT02041091, 15193, H9B-MC-BCEI; LY-2127399; phase III. Sponsor Eli Lilly and Company. Eli Lilly and Company. Status Ongoing. Ongoing. Source of Trial registry 24, manufacturer. Trial registry 25, manufacturer. information Location EU (incl UK), USA, Canada and other countries. USA, Republic of Korea, Mexico and Puerto Rico. Design Non-randomised, crossover. Randomised. Participants n=1,276 (planned); completed clinical trials NCT01196091 or NCT01205438. n=216 (planned); aged 18 years; SLE (by ACR criteria); no severe lupus kidney disease, active CNS or peripheral neurologic disease; no receipt of 40mg prednisolone within 1 month, started or changed dose of immunosuppressive drug within 1 month, or receipt of B-cell targeted therapies (including rituximab) within the last year. e SLEDAI2K: Systemic Lupus Erythematosus Disease Activity Index 2000 f PGA: Physician Global Assessment g BFI: Brief Fatigue Inventory h LupusQoL: Lupus Quality of Life i BILAG: British Isles Lupus Assessment Group 6
Schedule Arm 1 - participants who previously received LY-2127399 every 2 weeks: LY-2127399 120mg SC at week 0, then LY-2127399 120mg SC every 2 weeks. Arm 2 - participants who previously received placebo every 2 weeks: LY-2127399 240mg SC at week 0, then LY-2127399 120mg SC every 2 weeks or LY2127399 120mg SC every 4 weeks all. Arm 3 - participants who previously received LY-2127399 every 4 weeks: LY-2127399 120mg SC at week 0, then LY-2127399 120mg SC every 4 weeks. Arm 4 - participants who previously received placebo every 4 weeks: LY-2127399 240mg SC at week 0, then LY-2127399 120mg SC every 2 weeks or LY2127399 120mg SC every 4 weeks. Follow-up Active treatment for 216 weeks, 24-48 week B cell safety follow up for those who complete or discontinue. Primary outcome Secondary outcomes Expected reporting date Adverse events. SRI response; change in glucocorticoid dose; SLEDAI; new severe SLE flares; LupusQoL; anti-dsdna level. Study completion date reported as Aug 2019. Randomised to LY-2127399 240mg SC (auto-injector) at week 0, then LY- 2127399 120mg SC every 2 weeks for 12-52 weeks; or LY-2127399 240mg SC (prefilled syringe) at week 0, then LY- 2127399 120mg SC every 2 weeks for 12-52 weeks. Active treatment for 12 weeks followed by an optional 40 weeks of treatment. There is a 24-48 week B cell safety follow up for those who complete or discontinue. Pharmacokinetics. Completeness of tabalumab dose administration; development of antitabalumab antibodies; subcutaneous administration assessment questionnaire (SQAAQ) score. Study completion date reported as Jan 2016. ESTIMATED COST and IMPACT COST The cost of tabalumab is not yet known. Belimumab (Benlysta) costs 405 for a 400mg vial, and treatment with 10mg/kg every 2 weeks for 6 months would cost 10,530 26. IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: potential for reduced cumulative glucocorticoid dose, limiting risk of long term adverse events. Impact on Health and Social Care Services Increased use of existing services Re-organisation of existing services Other: Reduced symptoms or disability No impact identified Decreased use of existing services: SC administration and reduced hospitalisation. Need for new services None identified 7
Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: Other: uncertain unit cost compared to existing treatments Reduced drug treatment costs Other reduction in costs: None identified Other Issues Clinical uncertainty or other research question identified: Expert opinion states that longer term data for belimumab indicates improved disease control and reduced toxic drug burden for some patients over several years; however it is unclear for tabalumab and other B cell targeted therapies in lupus, which patients are likely to benefit and which will not. There is also uncertainty as to where these drugs should appear in the treatment pathway; should they have failed anti-malarials, steroids and a DMARD or not? In addition, the most frequent severe manifestations, nephritis and CNS disease, are excluded from the trials. If biologics are used, what level of disease activity should trigger their use? Which tool should be used to measure response (e.g. SLEDAI or BILAG), and how should a response be defined? If there is a response, for how long should the treatments be continued? j There are a large number of patients with lupus who have refractory arthritis, skin disease, serositis and other manifestations in combination, the measurement of which would be relevant to the results of these trials. Indeed, for moderate to severe active lupus, it is this population with ongoing disease activity that tend to suffer long term damage and irreversible changes from their SLE (including joint deformities, cutaneous scarring, etc.). This population is often exposed to chronic low to moderate dose glucocorticoids, which are strongly associated with future harm from osteoporotic fractures, atherosclerotic complications, development of diabetes, skin thinning and cataract formation. All of these are significant long-term consequences of chronic lupus and one important benefit of any future agent would be its ability to provide steroid-sparing therapy. However, from the trials described, future steroid-sparing may need to be extrapolated from longterm extension studies or new trials formally assessing the steroid-sparing capabilities of this agent k. As for the current NHS policy on rituximab, the use of this agent would be best suited for collaboration with specialised centres managing SLE. Subcutaneous administration would facilitate this approach, as the specialist centre may help confirm that the drug is indicated, but patients can then receive treatment through homecare arrangements. Finally, for long term safety and audit purposes, follow-up of patients through a long term observational register would allow aggregated safety data to be provided. In addition, the health economics of SLE are not well developed. Therefore, it would be useful to consider tracking patients to determine the impact on health care usage and other costs to better understand the health economic benefits of drugs such as this n. REFERENCES 1 National Institute for Health and Clinical Excellence. Final scope for the appraisal of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus. February 2011. http://www.nice.org.uk/nicemedia/live/13307/53177/53177.pdf 2 Stohl, W. Biologic differences between various inhibitors of the BLyS/BAFF pathway: should we expect differences between belimumab and other inhibitors in development? Current Rheumatology Reports 2012;14:303-309. 3 The electronic Medicine Compendium (emc) Summary product characteristics, Benlysta GlaxoSmithKline UK, January 2014. j Expert personal communication. k Expert personal communication. 8
https://www.medicines.org.uk/emc/medicine/24769/spc/benlysta+120+mg+and+400+mg+powde r+for+concentrate+for+solution+for+infusion/ 4 Nightingale AL, Farmer RDT and de Vries CS. Systemic lupus erythematosus prevalence in the UK: methodological issues when using the general practice research database to estimate frequency of chronic relapsing-remitting disease. Pharmacoepidemiology and Drug Safety 2007; 16:144-151. 5 Lee SJ and Kavanaugh A. Autoimmunity, vasculitis, and autoantibodies. Journal of Allergy and Clinical Immunology 2006;117(suppl.2):S445-S450. 6 Grech P and Khamashta M. Targeted therapies in systemic lupus erythematosus. Lupus 2013;22(10):978-986. 7 Patel M, Clarke AM, Bruce I N et al. The prevalence and incidence of biopsy-proven lupus nephritis in the UK: Evidence of an ethnic gradient. Arthritis & Rheumatism 2006;54(9):2963-2969 8 NHS England. NHS England clinical reference group for rheumatology. Interim clinical commissioning policy statement: rituximab for the treatment of systemic lupus erythematosus in adults. September 2013. A13/PS/a. http://www.england.nhs.uk/wp-content/uploads/2013/09/a13- psa.pdf 9 British Medical Journal. Clinical Evidence. Systemic lupus erythematosus. July 2009. http://clinicalevidence.bmj.com/x/systematic-review/1123/overview.html 10 Wolfe F, Michaud K, Li T et al. EQ-5D and SF-36 quality of life measures in systemic lupus erythematosus: comparisons with rheumatoid arthritis, noninflammatory rheumatic disorders, and fibromyalgia. The Journal of Rheumatology 2010;37(2):296-304. 11 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk 12 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2012. http://www.ons.gov.uk 13 Reynolds J A and Bruce I N. Overview of the management of systemic lupus erythematosus. Arthritis Research UK. Topical reviews Spring 2013;Issue 2:Series 7. http://www.arthritisresearchuk.org/health-professionals-and-students/reports/topicalreviews/topical-reviews-spring-2013.aspx#sthash.9jgtnfgf.dpuf 14 Bertsias GK, Tektonidou M, Amoura Z et al. Joint European League Against Rheumatism and European Renal Association European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Annals of the Rheumatic Diseases 2012;71(11):1771-1782. 15 Hahn BH, McMahon M, Wilkinson A et al. American College of Rheumatology Guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care & Research 2012;64(6):797-808. 16 Bertsias GK, Ioannidis JP, Aringer M et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Annals of the Rheumatic Diseases 2010;69(12):2074-2082. 17 Bertsias G, Ioannidis J P A, Boletis J et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics. Annals of the Rheumatic Diseases 2008;67:195-205. 18 Guidelines for referral and management of systemic lupus erythematosus in adults. American college of rheumatology ad hoc committee on systemic lupus erythematosus guidelines. Arthritis and Rheumatism 1999;42(9):1785-1796. 19 Orphanet. Systemic lupus erythematosus. March 2006. http://www.orpha.net/consor/cgibin/disease_search.php?lng=en&data_id=124&disease_disease_search_diseasegroup=syste mic-lupus-erythematosus&disease_disease_search_diseasetype=pat&disease(s)/group of diseases=systemic-lupus-erythematosus&title=systemic-lupuserythematosus&search=disease_search_simple 20 NHS. Map of medicine. Systemic lupus erythematosus (SLE) suspected. http://app.mapofmedicine.com/mom/1/page.html?department-id=4&specialty-id=1013&pathwayid=3343&page-id=13808&history=clear Accessed 20 May 2014. 21 Medscape. Bartels C M. Systemic Lupus Erythematosus (SLE). February 2014. http://emedicine.medscape.com/article/332244-overview#showall 9
22 ClinicalTrials.gov. A study of LY2127399 in patients with systemic lupus erythematosus. http://www.clinicaltrials.gov/ct2/show/nct01196091 Accessed 28th March 2014. 23 ClinicalTrials.gov. A study of LY2127399 in patients with systemic lupus erythematosus. http://www.clinicaltrials.gov/ct2/show/nct01205438 Accessed 28th March 2014. 24 ClinicalTrials.gov. On open-label study in participants with systemic lupus erythematosus (Illuminate-X) http://www.clinicaltrials.gov/ct2/show/study/nct01488708 Accessed 28th March 2014. 25 ClinicalTrials.gov. A study of tabalumab (LY2127399) using two different injection methods in participants with lupus. http://www.clinicaltrials.gov/ct2/show/nct02041091 Accessed 31st March 2014. 26 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 66. London: BMJ Group and RPS Publishing, September 2013. 10