Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217356 on 20 April 2020. Downloaded from

with an initial diagnosis of ITP.14 The Population-­based studies in systemic authors selected 1070 patients hospital- ised during 1997–2013 with ITP, of whom erythematosus: immune 668 were finally included in the study. Next, they matched patients with ITP at thrombocytopenic or ‘blood-­ a ratio of 1:20 to 14.460 controls by sex and age, using propensity score matching dominant’ lupus? at a 1:2 ratio to minimise the potential confounding effects of age, gender and 1 2 3 selected comorbidities on the incidence Antonis Fanouriakis ‍ ‍ , George Bertsias, Dimitrios T Boumpas ‍ ‍ of SLE. After a follow-up­ of 16 years, patients with ITP had 26.8 times higher risk of new-onset­ SLE. The risk was higher for patients aged less than 45 years and Thanks to their large sample size, thus due to an immune response against mega- lower for men. Not surprising, patients reducing the risk of selection and partici- karyocytes may also exacerbate thrombo- with Sjögren’s syndrome or had pation bias, population-based­ studies can cytopenia, while the level of circulating a significantly higher risk for SLE. provide high-­quality data on the preva- thrombopoietin, the main growth factor These findings have important clinical lence and incidence, natural history and of megakaryocytes, is low.6 Genome-­ implications. First and foremost, patients treatment, correlates and associations of a wide expression analyses have shown with ITP—especially those who are antinu- disease, and healthcare utilisation.1 Several dysregulation of genes involved in major clear antibody (ANA) positive—should be nationwide research databases exist in the immune response pathways in ITP, such closely monitored for SLE, especially within world, one of the oldest in Sweden dating as T helper cell activation and differenti- the first 2–5 years of diagnosis, and should back to 1955. The Taiwan National Health ation, autoantibody response and comple- probably be evaluated by a rheumatologist Insurance Research Database (NHIRD) is ment activation both in peripheral and for the identification of non-­haematological one of the largest nationwide population bone marrow-­derived T-­cells.7 8 Autoan- signs and symptoms suggestive of a connec- databases, covering approximately tibodies against antigens repre- tive tissue disease (figure 1). In our expe- 23 million residents in Taiwan and data of sent the diagnostic hallmark of ITP, but rience, non-­rheumatologists may miss more than 99% of the population. Using are detectable in only 50% of patients. subtle signs of SLE, such as synovitis and this unique database, investigators have Using mass spectroscopy-based­ antibody-­ inflammatory , or they may fail to asked important questions regarding the mediated identification of autoantigens evaluate lupus-related­ signs that do not heredity and coaggregation of autoim- for platelet antigens, novel autoantigens occur concurrently with thrombocyto- mune diseases, such as systemic lupus have been identified from patients who penia. Testing for SLE serology and anti- erythematosus (SLE), Sjögren’s syndrome are autoantibody negative. Most antigens phospholipid antibodies, serum creatinine and myasthenia gravis.2–4 are of intracellular origin, with signifi- and urinalysis should be considered in all Immune thrombocytopenic purpura cant association with the actin cytoskel- cases of ITP. Several studies have shown (ITP), formerly known as idiopathic eton and regulation of programmed cell that is associated with thrombocytopenic purpura, is an immune-­ 9 death. Taken together, the aetiopathoge- worse SLE prognosis;15 16 hence, early http://ard.bmj.com/ mediated acquired disease of adults and netic mechanisms operant in ITP, a proto- recognition and management of SLE, espe- children characterised by a transient or typic organ-­specific autoimmune disease, cially renal disease, are essential.17 In chil- persistent decrease of platelet counts and, are reminiscent of those described in the dren with chronic ITP (as opposed to acute depending on the degree of thrombocyto- prototypic systemic autoimmune disease, ITP), routine check for SLE and evaluation penia, increased risk of .5 In ΙΤP, namely SLE. Abberancies in immune cells by a paediatric rheumatologist may also be an abnormal T cell response, supported by in SLE can also be traced back to the advisable.

splenic T follicular helper cells, stimulates on September 25, 2021 by guest. Protected copyright. haematopoietic progenitor stem cells in Second, although in general terms, SLE-­ the proliferation and differentiation of 10 the bone marrow. related thrombocytopenia and ITP are autoreactive B cells producing antiplatelet Thrombocytopenia is a common clinical managed initially with identical drugs, autoantibodies that facilitate platelet manifestation of SLE and one of the haema- recognising and diagnosing an under- phagocytosis by macrophages, predom- tological classification criteria, with an lying lupus may lead to reconsideration inantly in the spleen. Macrophages also overall prevalence of approximately 20%. of thoughts for splenectomy (ie, post- contribute to the perpetuation of the In a recent community-­based SLE cohort of poning it for later) in patients with refrac- autoimmune response in ITP, functioning average disease duration less than 3 years, tory disease and may lead to the use, in as the principal antigen-presenting­ cells. thrombocytopenia was present in 15.2% of addition to rituximab, of SLE-directed­ Inappropriate bone marrow production patients, being severe (≤20 000 / therapies, like pulse cyclophosphamide 11 17 18 1 μL) in 4.6%. In our tertiary referral centre (figure 1). Moreover, patients who Department of Rheumatology, "Asklepieion" General Hospital, Athens, Greece cohort (the ‘Attikon’ cohort), thrombocyto- are ANA positive or have additional but 2Rheumatology, Clinical and Allergy, penia was present at diagnosis in 12% and not enough features to allow a confident University Hospital of Heraklion, Heraklion, Greece cumulatively in 16%.12 Notably, in an older diagnosis or classification of SLE (incom- 3 Rheumatology and Clinical Immunology Unit, 4th study, ~12% of cases had been initially plete SLE) may be considered for treat- Department of Internal Medicine, University Hospital 13 "Attikon", Athens, Greece diagnosed as ITP. ment with hydroxychloroquine. In this In Annals of the Rheumatic Diseases, regard, a small study from France with 40 Correspondence to Dr Dimitrios T Boumpas, Zhu et al used data from the Taiwan patients with ITP and ANA positivity and/ Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine, University Hospital NHIRD to estimate the risk for subse- or lupus-­like features who were refractory "Attikon", Chaidari 124 62, Greece; ​boumpasd@uoc.​ gr​ quent (incident) SLE among patients to initial therapy has shown efficacy in

Fanouriakis A, et al. Ann Rheum Dis June 2020 Vol 79 No 6 683 Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217356 on 20 April 2020. Downloaded from

Patient with immune thrombocyto penia 5 Cines DB, Bussel JB, Liebman HA, et al. The ITP syndrome: pathogenic and clinical diversity. Blood 2009;113:6511–21. ● Check for ANA 6 Audia S, Mahévas M, Samson M, et al. Pathogenesis ● Consider rheumatologic evaluation and testing for anti-ENA, C3/C4, aPL of immune thrombocytopenia. Autoimmun Rev 2017;16:620–32. 7 Jernås M, Nookaew I, Wadenvik H, et al. Differential

No features of SLE Features of SLE expression of T-cell­ genes in blood and bone marrow between ITP patients and controls. Thromb Haemost 2013;109:112–7. ITP Possible blood-dominant SLE Definite (Classified SLE) 8 Jernås M, Nookaew I, Wadenvik H, et al. Microrna regulate immunological pathways in T-­cells in immune 26.8x ↑ risk for SLE thrombocytopenia (ITP). Blood 2013;121:2095–8. 9 Bal G, Futschik ME, Hartl D, et al. Identification of Treat as ITP Haematologic-Rheumatologic Treat with SLE-direcrted novel biomarkers in chronic immune thrombocytopenia Collaboration therapies ● Monitoring sor SLE, especially (ITP) by microarray-­based serum protein profiling. Br J nephritis (kidney function tests, ●●Consider HCQ as add-on Early institution of HCQ ± Haematol 2016;172:602–15. urinalysis) therapy steroid-sparing durgs 10 Grigoriou M, Banos A, Filia A, et al. Transcriptome ● Delay splenectomy reprogramming and myeloid skewing in ● Consider CYC or RTX haematopoietic stem and progenitor cells in Figure 1 Approach to the patient who presents with immune thrombocytopenia. systemic lupus erythematosus. Ann Rheum Dis n.b. Thrombocytopenia (<100 000/mm3) is present in ~10% of patients with systemic lupus 2020;79:242–53. 11 Adamichou C, Nikolopoulos D, Genitsaridi I, et al. In erythematosus (SLE) at diagnosis and in ~15-20% cumulatively over the course of the disease. an early SLE cohort the ACR-1997, SLICC-2012 and ANA, antinuclear antibodies; anti-­ENA, antibodies to extractable nuclear antigens; aPL, EULAR/ACR-2019 criteria classify non-­overlapping antiphospholipid antibodies; CYC, cyclophosphamide; HCQ, hydroxychloroquine; ITP, immune groups of patients: use of all three criteria ensures thrombocytopenic purpura; RTX, rituximab. optimal capture for clinical studies while their modification earlier classification and treatment. Ann Rheum Dis 2020;79:232–41. glucocorticoid sparing and prevention of © Author(s) (or their employer(s)) 2020. No commercial 12 Nikolopoulos D, Kostopoulou M, Pieta A, et al. flares.19 re-­use. See rights and permissions. Published by BMJ. Evolving phenotype of systemic lupus erythematosus in Caucasians: low incidence of lupus nephritis, high Finally, this study also poses the burden of neuropsychiatric disease and increased important question: is the concurrence of rates of late-­onset lupus in the ’Attikon’ cohort. Lupus ITP and SLE related to a common genetic To cite Fanouriakis A, Bertsias G, Boumpas DT. 2020;39:096120332090893. background shared by several autoim- Ann Rheum Dis 2020;79:683–684. 13 Mestanza-­Peralta M, Ariza-Ariza­ R, Cardiel MH, et al. Thrombocytopenic purpura as initial manifestation mune diseases,20 or is it due to the fact that Received 28 March 2020 of systemic lupus erythematosus. J Rheumatol several cases of SLE represent incomplete Revised 2 April 2020 1997;24:867–70. forms of the disease or a ‘blood-­dominant’ Accepted 2 April 2020 14 Zhu F-­X, Huang J-Y­ , Ye Z, et al. Risk of systemic lupus.21 To this end, studies comparing Published Online First 20 April 2020 lupus erythematosus in patients with idiopathic thrombocytopenic purpura: a population-­based cohort molecular signatures of these two diseases study. Ann Rheum Dis 2020;79:772–9. may help to decipher this, as signatures 15 Scofield RH, Bruner GR, Kelly JA, et al. specific for SLE such as type I interferon Thrombocytopenia identifies a severe familial or plasmablasts,22 23 may not be present in phenotype of systemic lupus erythematosus and http://ard.bmj.com/ ►► http://dx.​ doi.​ org/​ 10.​ 1136/​ annrheumdis-​ 2020-​ ​ reveals genetic linkages at 1q22 and 11p13. Blood pure ITP. 217013 2003;101:992–7. In conclusion, population-­based studies Ann Rheum Dis 2020;79:683–684. 16 Ziakas PD, Giannouli S, Zintzaras E, et al. Lupus offer the unique opportunity to provide doi:10.1136/annrheumdis-2020-217356 thrombocytopenia: clinical implications and prognostic high-quality­ evidence regarding, among significance. Ann Rheum Dis 2005;64:1366–9. ORCID iDs 17 Fanouriakis A, Kostopoulou M, Alunno A, et al. Update others, the heredity and coaggregation of Antonis Fanouriakis http://orcid.​ ​org/0000-​ ​0003-2696-​ ​ of the EULAR recommendations for the management autoimmune diseases with apparent clin- of systemic lupus erythematosus. Ann Rheum Dis

031X on September 25, 2021 by guest. Protected copyright. ical implications. Dimitrios T Boumpas http://orcid.​ ​org/0000-​ ​0002-9812-​ ​ 2019;2019:736–45. 4671 18 Boumpas DT, Barez S, Klippel JH, et al. Intermittent cyclophosphamide for the treatment of autoimmune Handling editor Josef S Smolen thrombocytopenia in systemic lupus erythematosus. Twitter Dimitrios T Boumpas @none References Ann Intern Med 1990;112:674. 1 Hsing AW, Ioannidis JPA. Nationwide population 19 Khellaf M, Chabrol A, Mahevas M, et al. Contributors DTB drafted the manuscript. AF and GB science: lessons from the Taiwan National health edited the manuscript. All authors read and approved Hydroxychloroquine is a good second-line­ treatment insurance research database. JAMA Intern Med for adults with immune thrombocytopenia and positive its final form. 2015;175:1527. antinuclear antibodies. Am J Hematol 2014;89:194–8. Funding The authors have not declared a specific 2 Kuo C-­F, Grainge MJ, Valdes AM, et al. Familial 20 Yamamoto K, Okada Y. Shared genetic factors and grant for this research from any funding agency in the aggregation of systemic lupus erythematosus and their causality in autoimmune diseases. Ann Rheum public, commercial or not-­for-­profit sectors. coaggregation of autoimmune diseases in affected Dis 2019;78:1449–51. families. JAMA Intern Med 2015;175:1518. 21 Bertsias GK, Pamfil C, Fanouriakis A, et al. Diagnostic Competing interests None declared. 3 Kuo C-­F, Grainge MJ, Valdes AM, et al. Familial criteria for systemic lupus erythematosus: has the time Patient and public involvement Patients and/ risk of Sjögren’s syndrome and co-aggregation­ come? Nat Rev Rheumatol 2013;9:687–94. or the public were not involved in the design, or of autoimmune diseases in affected families: a 22 Banchereau R, Hong S, Cantarel B, et al. Personalized conduct, or reporting, or dissemination plans of this nationwide population study. Arthritis Rheumatol Immunomonitoring uncovers molecular networks that research. 2015;67:1904–12. stratify lupus patients. Cell 2016;165:1548–50. 4 Liu F-­C, Kuo C-­F, See L-­C, et al. Familial 23 Panousis NI, Bertsias GK, Ongen H, et al. Combined Patient consent for publication Not required. aggregation of myasthenia gravis in affected genetic and transcriptome analysis of patients with Provenance and peer review Commissioned; families: a population-­based study. Clin Epidemiol SLE: distinct, targetable signatures for susceptibility internally peer reviewed. 2017;9:527–35. and severity. Ann Rheum Dis 2019;78:1079–89.

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