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The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
Rejected
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Rejected
ATC codes: L04AC03
EMLc
Indication
Juvenile systemic arthritis ICD11 code: FA24.4
INN
Anakinra
Medicine type
Biological agent
List type
Complementary
Formulations
Parenteral > General injections > SC: 100 mg per 0.67 mL in pre-filled syringe
EML status history
Application rejected in 2021 (TRS 1035)
Sex
All
Age
Also recommended for children
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Main patents have expired but secondary patents might remain active in some jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPal.org
Wikipedia
DrugBank
Expert Committee recommendation
The Expert Committee noted that macrophage activation syndrome is a rare but serious condition involving excessive immune activation that can occur in children with systemic-onset juvenile idiopathic arthritis (JIA), and that it is associated with high short-term mortality, especially if untreated. The Committee noted anakinra has not been approved for this indication by the European Medicines Agency or the US Food and Drug Administration. However, anakinra is suggested as an initial therapeutic option for patients with suspected macrophage activation syndrome according to the 2013 JIA guideline of the American College of Rheumatology guidelines (weak recommendation). The Committee acknowledged that other treatments for systemic-onset JIA recommended in guidelines and used in clinical practice include corticosteroids and disease-modifying anti-rheumatic agents (DMARDs), such as methotrexate, antitumour necrosis factor alpha agents (e.g. etanercept, adalimumab), Janus kinase inhibitors (e.g. tofacitinib) and anti-interleukin-6 receptor antibodies (e.g. tocilizumab, canakinumab). The Committee acknowledged that management of systemic-onset JIA with DMARD treatment has the potential to minimize the severe side-effects of corticosteroids and noted that antitumour necrosis factor agents were included on the EML and EMLc for juvenile idiopathic arthritis in 2019. The Committee noted that the application reported data only from uncontrolled cohort studies or case series, most enrolling a small number of patients. The Committee agreed that extrapolating clinical benefits and potential harms of anakinra and comparing anakinra to other potentially relevant therapeutic alternatives based on this type of evidence was difficult. The Committee accepted that there may not be alternatives to quasi-experimental studies on macrophage activation syndrome given the rarity of the disease, but that this was not the case for systemic-onset JIA. The Committee also noted that anakinra is often a highly priced medicine, with potentially important limitations in accessibility and affordability at the country level. The Committee also acknowledged the limitations in availability of specialist paediatric rheumatologists in some lower-resource settings. The Expert Committee therefore did not recommend the listing of anakinra for the treatment of systemic-onset JIA and macrophage activation syndrome because of the uncertainty in the estimates of clinical benefit and concerns about affordability and access to specialist medical services.
Background
Anakinra had not previously been considered for inclusion on the Model Lists. In 2007, acetylsalicylic acid (aspirin) was included on the first EMLc for the treatment of juvenile arthritis (1). In 2019, the Expert Committee considered an application requesting inclusion of antitumour necrosis factor biological agents on the Model Lists for treatment of severe chronic inflammatory autoimmune disorders, including JIA (2). The Committee recognized that autoimmune disorders are highly debilitating and that there is a public health need for effective treatments for patients who do not respond to first-line treatments (e.g. methotrexate). On the basis of the evidence presented and a positive benefit-to-harm profile of the medicines, the Committee recommended the addition of the antitumour necrosis factor antibody adalimumab, with a square box, with therapeutically equivalent alternatives limited to etanercept and infliximab for children (EMLc), and etanercept, infliximab, certolizumab pegol and golimumab for adults (EML). The Committee also recognized that these medicines have a substantial impact on the budget of health systems. However, the availability of several therapeutically equivalent alternatives and the increasing availability of biosimilar products could lead to more market competition.
Public health relevance
JIA is the most common chronic rheumatic disease of childhood, estimated to affect one in 1000 children (3). JIA is characterized by joint inflammation of more than 6 weeks’ duration, with onset before the age of 16 years and absence of another underlying cause (4,5). It is an autoimmune, inflammatory joint disease, the cause of which remains poorly understood; both genetic and environmental factors are thought to contribute to its development (6). The age at onset is typically young, with a peak incidence between 1 and 3 years of age. The disease persists into adulthood in about 50% of cases (7). Worldwide, more than 2 million children are estimated to have JIA, with the greatest prevalence in Africa and Asia (8) where access to specialist care and treatment is limited (9) resulting in worse clinical outcomes (10). Untreated, JIA causes pain, joint damage and functional disability, and affects quality of life (5,11,12). JIA also results in children missing school, affects social and peer interactions which may cause long-term psychosocial difficulties and mental ill-health, and leads to higher unemployment in people with the condition than their healthy peers (11,12). The International League of Associations for Rheumatology recognizes seven distinct subtypes of JIA (4,13). Systemic-onset JIA subtype is characterized by arthritis, fever, rash and systemic inflammation. Unlike other JIA subtypes, systemic-onset JIA is considered an autoinflammatory syndrome (14,15). The proportion of children with JIA who have systemic-onset JIA ranges from less than 10% to about 50% depending on the population, with higher rates reported in low-resource settings such as India (16). The condition is typically a chronic illness affecting young children – the age at onset is typically 1–5 years (17). Uncontrolled inflammation in systemic-onset JIA carries significant risk of high morbidity and potential mortality from macrophage activation syndrome, an uncontrolled cytokine storm (15,18,19). Death rates for children with systemic-onset JIA are higher than for children with other JIA forms in the United Kingdom (standardized mortality ratio 8.3, 95% confidence interval (CI) 2.7 to 19.4 versus 1.7, 95% CI 0.5 to 4.0) (20). The social implications are also important; 36% of caregivers reported that they had reduced their hours of work or stopped working due to their child’s systemic-onset JIA, and they lost on average 25 days of work a year (21). To prevent joint destruction, chronic pain and disability, as well as extra-articular complications such as blindness from uveitis (as a complication of JIA), the treatment paradigm for JIA has changed: earlier, more aggressive therapy is now the standard of care with early introduction of disease-modifying anti-rheumatic drugs (DMARDs) and, in many cases, biological agents (5,22). Notably, initial treatment of polyarticular disease in JIA with non-steroidal anti-inflammatory drugs alone is no longer recommended (23). Corticosteroids play a role in the early management of most forms of JIA, but their use in long-term health conditions is limited because of their side-effects (24), including growth failure, cataracts and osteoporosis (12).
Benefits
The application presented a review of the available evidence on the use of anakinra for systemic-onset JIA and macrophage activation syndrome in systemic-onset JIA, asserting that the most important way to treat macrophage activation syndrome in systemic-onset JIA is to control the underlying inflammation caused by systemic-onset JIA. Anakinra in systemic-onset JIA A single-centre prospective study in the Netherlands evaluated anakinra as first-line monotherapy in 42 patients (age range 3.9–11.8 years) with active systemic-onset JIA (25). The median time to achieve clinically inactive disease was 33 days. For children who had inactive disease at 3 months, anakinra was tapered and ultimately stopped. At 1 year, 76% of all the children had inactive disease, and 52% who had stopped receiving medication earlier continued to have inactive disease. Factors positively associated with inactive disease at 1 year included high neutrophil count at baseline and complete response after 1 month of anakinra treatment. After 5 years of follow-up, 96% of all the patients had inactive disease, and 75% continued to have inactive disease while not receiving medication. Articular or extra-articular damage was reported in < 5% of patients and only 33% received glucocorticoids. Treatment with anakinra was equally effective in systemic-onset JIA patients without arthritis at disease onset. The authors concluded that “treatment to target” (where disease activity is accurately monitored and clinical remission is actively pursued by regular adjustment of therapy (26), starting with first-line, short-course monotherapy with anakinra, is a highly effective strategy to induce and sustain inactive disease and to prevent damage from the disease and glucocorticoids. A single-centre retrospective study in Italy evaluated 25 patients with systemic-onset JIA treated with anakinra for at least 6 months (27). The median age at disease onset was 5.8 years and the median age at start of treatment was 7.3 years. Of note, 14 patients were receiving concomitant glucocorticoids, nine patients were receiving concomitant disease modifying antirheumatic drugs (methotrexate or ciclosporin), and six patients had previously received biological agents (etanercept, abatacept, infliximab). After 6 months of anakinra treatment, 14 patients (56%) had clinically inactive disease, reached at a median of 2.1 months after the start of treatment. Clinically inactive disease was maintained in all 14 patients at median follow up of 2.8 years. Nine patients were able to withdraw from anakinra and five continued with anakinra monotherapy. No cases of macrophage activation syndrome were observed during anakinra treatment. An international multicentre series analysed the use of anakinra as first-line disease-modifying therapy in 46 children with systemic-onset JIA (28). Of 46 patients meeting the inclusion criteria, anakinra monotherapy was used in 10 patients (22%), 21 received anakinra plus corticosteroids, five received anakinra plus DMARDs and 10 received anakinra plus corticosteroids and DMARDs. Outcomes were evaluated after a median follow-up of 14.5 months. Fever and rash resolved within 1 month in more than 95% of patients, while C-reactive protein and ferritin normalized within this time in more than 80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27% and at more than 6 months of follow-up in 11% of patients. About 60% of patients, including eight of 10 receiving anakinra monotherapy, attained a complete response without escalating therapy. Eleven episodes of macrophage activation syndrome (in nine patients) were observed, six episodes at presentation and five episodes after starting anakinra during the study. Anakinra effectively managed five out of the six cases of macrophage activation syndrome at presentation; increasing doses of anakinra and additional agents such as steroids and ciclosporin A were used to control these episodes. A retrospective case series from the United States of America (USA) evaluated the effect of anakinra on disease activity and corticosteroid dose in 33 patients with systemic-onset JIA (29). The median duration of systemic-onset JIA before treatment was 29 months and most patients had used more than one other medication before starting anakinra: prednisone (94%), methotrexate (76%), tumour necrosis factor inhibitors (61%), ciclosporin (36%) and cyclophosphamide (6%). Anakinra treatment was associated with reduction in corticosteroid dosage and erythrocyte sedimentation rate, and increases in haemoglobin and albumin, all indicators of response to therapy. Large joint arthritis counts decreased but not small joint counts after 3–4 months. More significant decreases in erythrocyte sedimentation rates from pre- to post-treatment (1–2 months) were seen in patients on high doses of anakinra than those on low doses, implying a dose–response effect. Fever and rash, present in seven cases before treatment, resolved in all cases. Eight patients had periods of arthritis, one developed macrophage activation syndrome and another Epstein–Barr virus infection. A single-centre series study reported on four patients who received anakinra as first-line therapy for systemic-onset JIA (30). The median age of the patients was 4.6 years (range 2.75–9.25 years). The mean follow-up time was 13.5 months (range 2–50 months). Anakinra was started at doses from 1.5 to 4 mg/kg for a median duration of 3 (range: 3–18) months. Two patients responded to anakinra monotherapy; two cases required corticosteroids. Normalized body temperature and the absence of evanescent rashes were achieved after a median of 4 (range: 2–10) days. The data suggest rapid efficacy of anakinra in early systemic-onset JIA with reduced treatment-related side-effects. Macrophage activation syndrome in systemic-onset JIA A single-centre study evaluated the use of anakinra to treat macrophage activation syndrome in 15 paediatric patients (31), 13 with systemic-onset JIA and two with other autoinflammatory diseases. Nineteen episodes of macrophage activation syndrome were observed in the 15 patients. Anakinra (2 mg/kg a day) was started within a median of 1 day of admission. Clinical symptoms resolved within a median (minimum–maximum) of 2 (1–4) days of the introduction of anakinra and laboratory findings normalized within a median of 6 (4–9) days. Steroid treatment was stopped within a median of 10 (4–13) weeks of starting anakinra. Patients were followed for a median of 13 (6–24) months. Two patients developed recurrent macrophage activation syndrome episodes when the anakinra dose was reduced, while the other patients achieved remission. A retrospective case series reported on 12 children with macrophage activation syndrome (eight due to systemic-onset JIA) in whom steroids, ciclosporin A and intravenous immunoglobulin were not working (32). Five patients required intensive care. All patients achieved remission of macrophage activation syndrome after addition of anakinra within a median of 13 (range 2–19) days. Corticosteroids were discontinued by 6 weeks in seven patients. Patients were followed for a median of 22 (2–40) months and all were in remission for macrophage activation syndrome at the final follow-up with excellent control of the underlying rheumatic disease.
Harms
Anakinra is used in systemic-onset JIA, macrophage activation syndrome and other autoinflammatory diseases such as cryopyrin-associated periodic fever syndrome (CAPS), rheumatoid arthritis and gout. In general, anakinra has a satisfactory safety profile. An international multicentre series described the use of anakinra to treat 46 children with systemic-onset JIA (28). Adverse events observed included injection site reactions (20 cases), serious infections (three cases), elevation of liver enzymes (two cases), hepatitis (one case), and mild asymptomatic neutropenia (one case). A prospective, open-label, single-centre, clinical cohort study investigated the efficacy and safety of anakinra treatment for up to 5 years in 43 patients with cryopyrin-associated periodic fever syndrome. Safety was evaluated using adverse-event reports, laboratory assessments, vital signs and diary reports (33). In total, 1233 adverse events were reported during the study, with a yearly rate of 7.7 adverse events per patient. The event rate decreased over time, and dose escalation during the study did not affect the frequency of adverse events. The most frequently reported adverse events were the typical disease symptoms of cryopyrin-associated periodic fever syndrome such as headache and arthralgia. Injection site reactions occurred mainly during the first month of anakinra treatment. In total, 14 patients experienced 24 severe adverse events, all of which resolved during the study period. The most commonly reported serious adverse events were infections (13 events in seven patients; seven events in three patients younger than 2 years). The most common infections were pneumonia (three patients) and gastroenteritis (two patients). Anakinra had similar safety profiles in adults and children.
Cost / cost effectiveness
No comparative cost–effectiveness studies of anakinra in systemic-onset JIA are available.
WHO guidelines
WHO guidelines for the treatment of systemic-onset JIA and macrophage activation syndrome in systemic-onset JIA are not currently available.
Availability
Anakinra does not yet have regulatory approval as a treatment for macrophage activation syndrome. It has regulatory approval for the treatment of systemic-onset JIA in the following countries: Australia, Austria, Belgium, Bulgaria, Canada, Cyprus, Czechia, Denmark, Estonia, Finland, Hungary, Iceland, Ireland, Israel, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Slovakia, Spain, Sweden, United Kingdom and the USA.
Other considerations
Diagnosis and management The diagnosis of macrophage activation syndrome in systemic-onset JIA is based on defined criteria (19) validated in clinical practice (34,35). Macrophage activation syndrome is often triggered by infection, a particular concern in low-resource countries. It is also a life-threatening “cytokine storm” with a high risk of death (36). Access to specialist paediatric rheumatologists, multidisciplinary teams and treatments are challenges in many low-resource countries. Such inequity further contributes to the burden of disease and long-term disability (37). The diagnosis of macrophage activation syndrome and evaluation of its severity, and monitoring of response to treatment are assessed using blood markers of inflammation (C-reactive protein and full blood counts) as well as specific markers of macrophage activation syndrome (ferritin, triglycerides, liver function tests and clotting profiles) (34,35). Monitoring anakinra treatment follows the routine monitoring of systemic-onset JIA in acute disease flare-up, concomitant infection or where macrophage activation syndrome is suspected. Tuberculosis risk Awareness of the risk of tuberculosis in patients treated with anakinra or tocilizumab and other biological DMARD medications is of particular importance in low resource settings with high rates of tuberculosis. This awareness is emphasized in consensus statements on JIA care in low-resource settings as level 3b evidence, strength A statement with 100% consensus (37). It is also recommended that patients with JIA with a positive tuberculosis test should receive appropriate prophylaxis for tuberculosis (as per current national and/or international guidelines) at the start of biological therapy, during biological therapy and when a previously negative purified protein derivative test converts to positive at the mandatory annual tuberculosis screening, and if they have a new exposure to tuberculosis.
1. The selection and use of essential medicines. Report of the WHO Expert Committee, October 2007 (including the Model List of Essential Medicines for Children). Geneva: World Health Organization; 2007 (WHO Technical Report Series, No. 950, https://apps.who.int/iris/handle/10665/43887, accessed 6 June 2021). 2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2019 (WHO Technical Report Series, No. 1021; https://apps.who.int/iris/handle/10665/330668, accessed 6 June 2021). 3. Harris JG, Kessler EA, Verbsky JW. Update on the treatment of juvenile idiopathic arthritis. Curr Allergy Asthma Rep. 2013;13(4):337–46. 4. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767–78. 5. Giancane G, Consolaro A, Lanni S, Davì S, Schiappapietra B, Ravelli A. Juvenile idiopathic arthritis: diagnosis and treatment. Rheumatol Ther. 2016;3(2):187–207. 6. Hinks A, Cobb J, Marion MC, Prahalad S, Sudman M, Bowes J, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet. 2013;45(6):664–9. 7. Sullivan DB, Cassidy JT, Petty RE. Pathogenic implications of age of onset in juvenile rheumatoid arthritis. Arthritis Rheum. 1975;18(3):251–5. 8. Dave M, Rankin J, Pearce M, Foster HE. Global prevalence estimates of three chronic musculoskeletal conditions: club foot, juvenile idiopathic arthritis and juvenile systemic lupus erythematosus. Pediatr Rheumatol. 2020;18(1):1–7. 9. Chausset A, Pereira B, Echaubard S, Merlin E, Freychet C. Access to paediatric rheumatology care in juvenile idiopathic arthritis: what do we know? A systematic review. Rheumatology (Oxford). 2020;59(12):3633–44. 10. Consolaro A, Giancane G, Alongi A, van Dijkhuizen EHP, Aggarwal A, Al-Mayouf SM, et al. Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study. Lancet Child Adolesc Health. 2019;3(4):255–63. 11. Glerup M, Rypdal V, Arnstad ED, Ekelund M, Peltoniemi S, Aalto K, et al. Long-term outcomes in juvenile idiopathic arthritis: eighteen years of follow-up in the population-based Nordic juvenile idiopathic arthritis cohort. Arthritis Care Res (Hoboken). 2020;72(4):507–16. 12. Coulson EJ, Hanson HJ, Foster HE. What does an adult rheumatologist need to know about juvenile idiopathic arthritis? Rheumatology (Oxford). 2014;53(12):2155–66. 13. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–2. 14. Katsicas MM, Russo RAG. Systemic-onset juvenile idiopathic arthritis. In: Cimaz R, editor. Periodic and non-periodic fevers. Cham: SpringerNature; 2020:65–91. 15. De Benedetti F, Schneider R. Systemic juvenile idiopathic arthritis. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors. Textbook of pediatric rheumatology. Seventh edition. Philadelphia: Elsevier; 2016:205–16. 16. Kunjir V, Venugopalan A, Chopra A. Profile of Indian patients with juvenile onset chronic inflammatory joint disease using the ILAR classification criteria for JIA: a community-based cohort study. J Rheumatol. 2010;37(8):1756–62. 17. Behrens EM, Beukelman T, Gallo L, Spangler J, Rosenkranz M, Arkachaisri T, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008;35(2):343–8. 18. Dewoolkar M, Cimaz R, Chickermane PR, Khubchandani RP. Course, outcome and complications in children with systemic onset juvenile idiopathic arthritis. Indian J Pediatr. 2017;84(4):294–8. 19. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13(4):289–98. 20. Davies R, Southwood T, Kearsley-Fleet L, Lunt M, Baildam E, Beresford MW, et al. Mortality rates are increased in patients with systemic juvenile idiopathic arthritis. Arch Dis Child. 2017;102(2):206–7. 21. Shenoi S, Horneff G, Cidon M, Ramanan AV, Kimura Y, Quartier P, et al. The burden of systemic juvenile idiopathic arthritis for patients and caregivers: an international survey and retrospective chart review. Clin Exp Rheumatol. 2018;36(5):920–8. 22. Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10):2499–512. 23. Ringold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA, Becker ML, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res (Hoboken). 2019;71(6):717–34. 24. Batu ED. Glucocorticoid treatment in juvenile idiopathic arthritis. Rheumatol Int. 2019;39(1):13–27. 25. Ter Haar NM, van Dijkhuizen EHP, Swart JF, van Royen-Kerkhof A, El Idrissi A, Leek AP, et al. Treatment to target using recombinant interleukin-1 receptor antagonist as first-line monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a five-year follow-up study. Arthritis Rheumatol. 2019;71(7):1163–73. 26. Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77(6):819–28. 27. Pardeo M, Pires Marafon D, Insalaco A, Bracaglia C, Nicolai R, Messia V, et al. Anakinra in systemic juvenile idiopathic arthritis: a single-center experience. J Rheumatol. 2015;42(8):1523–7. 28. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheumatol. 2011;63(2):545–55. 29. Zeft A, Hollister R, LaFleur B, Sampath P, Soep J, McNally B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol. 2009;15(4):161–4. 30. Hedrich CM, Bruck N, Fiebig B, Gahr M. Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA). Rheumatol Int. 2012;32(11):3525–30. 31. Sönmez HE, Demir S, Bilginer Y, Özen S. Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of literature. Clin Rheumatol. 2018;37(12):3329–35. 32. Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 2011;50(2):417–9. 33. Kullenberg T, Löfqvist M, Leinonen M, Goldbach-Mansky R, Olivecrona H. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford). 2016;55(8):1499–506. 34. Minoia F, Bovis F, Davì S, Horne A, Fischbach M, Frosch M, et al. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2019;78(10):1357–62. 35. Shimizu M, Mizuta M, Yasumi T, Iwata N, Okura Y, Kinjo N, et al. Validation of classification criteria of macrophage activation syndrome in Japanese patients with systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2018;70(9):1412–5. 36. Boom V, Anton J, Lahdenne P, Quartier P, Ravelli A, Wulffraat NM, et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13:55. 37. Scott C, Chan M, Slamang W, Okong’o L, Petty R, Laxer RM, et al. Juvenile arthritis management in less resourced countries (JAMLess): consensus recommendations from the cradle of humankind. Clin Rheumatol. 2019;38(2):563–75.