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Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217356 on 20 April 2020. Downloaded from are reminiscent of those described in the Population-­based studies in systemic prototypic systemic autoimmune , namely SLE. Abberancies in immune cells erythematosus: immune in SLE can also be traced back to the haematopoietic progenitor stem cells in or ‘blood-­ the .10 is a common clin- dominant’ lupus? ical manifestation of SLE and one of the haematological classification criteria, 1 2 3 with an overall of approxi- Antonis Fanouriakis ‍ ‍ , George Bertsias, Dimitrios T Boumpas ‍ ‍ mately 20%. In a recent community-based­ SLE cohort of average disease duration less than 3 years, thrombocytopenia was present in 15.2% of patients, being Thanks to their large sample size, thus due to an immune response against mega- 11 reducing the of selection and partici- karyocytes may also exacerbate thrombo- severe (≤20 000 platelets/μL) in 4.6%. pation bias, population-based­ studies can cytopenia, while the level of circulating In our tertiary referral centre cohort (the provide high-­quality data on the preva- thrombopoietin, the main growth factor ‘Attikon’ cohort), thrombocytopenia was lence and incidence, natural history and of megakaryocytes, is low.6 Genome-­ present at diagnosis in 12% and cumu- 12 treatment, correlates and associations of a wide expression analyses have shown latively in 16%. Notably, in an older disease, and healthcare utilisation.1 Several dysregulation of genes involved in major study, ~12% of cases had been initially 13 nationwide research databases exist in the immune response pathways in ITP, such diagnosed as ITP. world, one of the oldest in Sweden dating as T helper cell activation and differenti- In Annals of the Rheumatic , back to 1955. The Taiwan National Health ation, response and comple- Zhu et al used data from the Taiwan Insurance Research Database (NHIRD) is ment activation both in peripheral and NHIRD to estimate the risk for subse- one of the largest nationwide population bone marrow-­derived T-­cells.7 8 Autoan- quent (incident) SLE among patients 14 databases, covering approximately tibodies against platelet antigens repre- with an initial diagnosis of ITP. The 23 million residents in Taiwan and data of sent the diagnostic hallmark of ITP, but authors selected 1070 patients hospital- more than 99% of the population. Using are detectable in only 50% of patients. ised during 1997–2013 with ITP, of whom this unique database, investigators have Using mass spectroscopy-based­ -­ 668 were finally included in the study. asked important questions regarding the mediated identification of autoantigens Next, they matched patients with ITP at and coaggregation of autoim- for platelet antigens, novel autoantigens a ratio of 1:20 to 14.460 controls by sex mune diseases, such as systemic lupus have been identified from patients who and age, using propensity score matching erythematosus (SLE), Sjögren’s syndrome are autoantibody negative. Most antigens at a 1:2 ratio to minimise the potential and .2–4 are of intracellular origin, with signifi- confounding effects of age, gender and Immune thrombocytopenic purpura cant association with the actin cytoskel- selected comorbidities on the incidence (ITP), formerly known as idiopathic eton and regulation of programmed cell of SLE. After a follow-up­ of 16 years, thrombocytopenic purpura, is an immune-­ death.9 Taken together, the aetiopathoge- patients with ITP had 26.8 times higher

mediated acquired disease of adults and netic mechanisms operant in ITP, a proto- risk of new-onset­ SLE. The risk was higher http://ard.bmj.com/ children characterised by a transient or typic organ-­specific , for patients aged less than 45 years and persistent decrease of platelet counts and, depending on the degree of thrombocyto- 5 penia, increased risk of bleeding. In ΙΤP, Patient with immune thrombocyto penia an abnormal response, supported by

splenic T follicular helper cells, stimulates ● Check for ANA

the proliferation and differentiation of ● Consider rheumatologic evaluation and on October 1, 2021 by guest. Protected copyright. testing for anti-ENA, C3/C4, aPL autoreactive B cells producing antiplatelet that facilitate platelet phagocytosis by macrophages, predom- No features of SLE Features of SLE inantly in the spleen. Macrophages also

contribute to the perpetuation of the ITP Possible blood-dominant SLE Definite (Classified SLE) autoimmune response in ITP, functioning as the principal antigen-presenting­ cells. 26.8x ↑ risk for SLE Inappropriate bone marrow production Treat as ITP Haematologic-Rheumatologic Treat with SLE-direcrted Collaboration therapies ● Monitoring sor SLE, especially 1 Department of , "Asklepieion" General (kidney function tests, ●●Consider HCQ as add-on Early institution of HCQ ± Hospital, Athens, Greece urinalysis) therapy steroid-sparing durgs 2 Rheumatology, Clinical and , ● Delay splenectomy University Hospital of Heraklion, Heraklion, Greece ● Consider CYC or RTX 3 Rheumatology and Clinical Immunology Unit, 4th Figure 1 Approach to the patient who presents with immune thrombocytopenia. Department of Internal Medicine, University Hospital 3 "Attikon", Athens, Greece n.b. Thrombocytopenia (<100 000/mm ) is present in ~10% of patients with systemic (SLE) at diagnosis and in ~15-20% cumulatively over the course of the disease. Correspondence to Dr Dimitrios T Boumpas, Rheumatology and Clinical Immunology Unit, 4th ANA, antinuclear ; anti-­ENA, antibodies to extractable nuclear antigens; aPL, Department of Internal Medicine, University Hospital antiphospholipid antibodies; CYC, ; HCQ, ; ITP, immune "Attikon", Chaidari 124 62, Greece; ​boumpasd@uoc.​ gr​ thrombocytopenic purpura; RTX, .

Fanouriakis A, et al. Ann Rheum Dis Month 2020 Vol 0 No 0 1 Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217356 on 20 April 2020. Downloaded from lower for men. Not surprising, patients or plasmablasts,22 23 may not be present in 5 Cines DB, Bussel JB, Liebman HA, et al. The ITP with Sjögren’s syndrome or had pure ITP. syndrome: pathogenic and clinical diversity. Blood 2009;113:6511–21. a significantly higher risk for SLE. In conclusion, population-­based studies 6 Audia S, Mahévas M, Samson M, et al. Pathogenesis These findings have important clinical offer the unique opportunity to provide of immune thrombocytopenia. Autoimmun Rev implications. First and foremost, patients high-quality­ evidence regarding, among 2017;16:620–32. with ITP—especially those who are anti- others, the heredity and coaggregation of 7 Jernås M, Nookaew I, Wadenvik H, et al. Differential autoimmune diseases with apparent clin- expression of T-cell­ genes in blood and bone marrow nuclear antibody (ANA) positive—should between ITP patients and controls. Thromb Haemost be closely monitored for SLE, especially ical implications. 2013;109:112–7. within the first 2–5 years of diagnosis, 8 Jernås M, Nookaew I, Wadenvik H, et al. Microrna and should probably be evaluated by Handling editor Josef S Smolen regulate immunological pathways in T-­cells in immune thrombocytopenia (ITP). Blood 2013;121:2095–8. a rheumatologist for the identification Twitter Dimitrios T Boumpas @none 9 Bal G, Futschik ME, Hartl D, et al. Identification of of non-­haematological signs and symp- Contributors DTB drafted the manuscript. AF and GB novel biomarkers in chronic immune thrombocytopenia toms suggestive of a edited the manuscript. All authors read and approved (ITP) by microarray-­based serum profiling. Br J disease (figure 1). In our experience, non-­ its final form. Haematol 2016;172:602–15. rheumatologists may miss subtle signs of Funding The authors have not declared a specific 10 Grigoriou M, Banos A, Filia A, et al. Transcriptome reprogramming and myeloid skewing in SLE, such as synovitis and inflammatory grant for this research from any funding agency in the public, commercial or not-for­ -profit­ sectors. haematopoietic stem and progenitor cells in , or they may fail to evaluate lupus-­ systemic lupus erythematosus. Ann Rheum Dis related signs that do not occur concur- Competing interests None declared. 2020;79:242–53. rently with thrombocytopenia. Testing for Patient and public involvement Patients and/ 11 Adamichou C, Nikolopoulos D, Genitsaridi I, et al. In an early SLE cohort the ACR-1997, SLICC-2012 and SLE and antiphospholipid anti- or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this EULAR/ACR-2019 criteria classify non-­overlapping bodies, serum creatinine and urinalysis research. groups of patients: use of all three criteria ensures should be considered in all cases of ITP. optimal capture for clinical studies while their Patient consent for publication Not required. Several studies have shown that throm- modification earlier classification and treatment. Ann Provenance and peer review Commissioned; Rheum Dis 2020;79:232–41. bocytopenia is associated with worse SLE 12 Nikolopoulos D, Kostopoulou M, Pieta A, et al. 15 16 internally peer reviewed. ; hence, early recognition Evolving phenotype of systemic lupus erythematosus and management of SLE, especially renal © Author(s) (or their employer(s)) 2020. No commercial in Caucasians: low incidence of , high re-­use. See rights and permissions. Published by BMJ. disease, are essential.17 In children with burden of neuropsychiatric disease and increased rates of late-­onset lupus in the ’Attikon’ cohort. Lupus chronic ITP (as opposed to acute ITP), 2020;39:096120332090893. routine check for SLE and evaluation by 13 Mestanza-­Peralta M, Ariza-Ariza­ R, Cardiel MH, et al. a paediatric rheumatologist may also be To cite Fanouriakis A, Bertsias G, Boumpas DT. Thrombocytopenic purpura as initial manifestation advisable. Ann Rheum Dis Epub ahead of print: [please of systemic lupus erythematosus. J Rheumatol Second, although in general terms, SLE-­ include Day Month Year]. doi:10.1136/ 1997;24:867–70. annrheumdis-2020-217356 14 Zhu F-­X, Huang J-Y­ , Ye Z, et al. Risk of systemic related thrombocytopenia and ITP are lupus erythematosus in patients with idiopathic managed initially with identical drugs, Received 28 March 2020 thrombocytopenic purpura: a population-­based recognising and diagnosing an under- Revised 2 April 2020 cohort study. Ann Rheum Dis 2020. doi:10.1136/ Accepted 2 April 2020 lying lupus may lead to reconsideration annrheumdis-2020-217013. [Epub ahead of print: 02 Apr 2020]. of thoughts for splenectomy (ie, post- 15 Scofield RH, Bruner GR, Kelly JA, et al. poning it for later) in patients with refrac- Thrombocytopenia identifies a severe familial http://ard.bmj.com/ tory disease and may lead to the use, in phenotype of systemic lupus erythematosus and addition to rituximab, of SLE-directed­ ►► http://dx.​ doi.​ org/​ 10.​ 1136/​ annrheumdis-​ 2020-​ ​ reveals genetic linkages at 1q22 and 11p13. Blood 217013 2003;101:992–7. therapies, like pulse cyclophosphamide 16 Ziakas PD, Giannouli S, Zintzaras E, et al. Lupus 17 18 Ann Rheum Dis 2020;0:1–2. (figure 1). Moreover, patients who are thrombocytopenia: clinical implications and prognostic doi:10.1136/annrheumdis-2020-217356 ANA positive or have additional but not significance. Ann Rheum Dis 2005;64:1366–9. enough features to allow a confident diag- ORCID iDs 17 Fanouriakis A, Kostopoulou M, Alunno A, et al. Update of the EULAR recommendations for the management Antonis Fanouriakis http://orcid.​ ​org/0000-​ ​0003-2696-​ ​ on October 1, 2021 by guest. Protected copyright. nosis or classification of SLE (incomplete of systemic lupus erythematosus. Ann Rheum Dis SLE) may be considered for treatment 031X Dimitrios T Boumpas http://orcid.​ ​org/0000-​ ​0002-9812-​ ​ 2019;2019:736–45. with hydroxychloroquine. In this regard, 4671 18 Boumpas DT, Barez S, Klippel JH, et al. Intermittent a small study from France with 40 patients cyclophosphamide for the treatment of autoimmune thrombocytopenia in systemic lupus erythematosus. with ITP and ANA positivity and/or lupus-­ References Ann Intern Med 1990;112:674. like features who were refractory to initial 1 Hsing AW, Ioannidis JPA. Nationwide population 19 Khellaf M, Chabrol A, Mahevas M, et al. therapy has shown efficacy in glucocorti- science: lessons from the Taiwan National health Hydroxychloroquine is a good second-­line treatment coid sparing and prevention of flares.19 insurance research database. JAMA Intern Med for adults with immune thrombocytopenia and positive 2015;175:1527. antinuclear antibodies. Am J Hematol 2014;89:194–8. Finally, this study also poses the 2 Kuo C-­F, Grainge MJ, Valdes AM, et al. Familial 20 Yamamoto K, Okada Y. Shared genetic factors and important question: is the concurrence of aggregation of systemic lupus erythematosus and their causality in autoimmune diseases. Ann Rheum ITP and SLE related to a common genetic coaggregation of autoimmune diseases in affected Dis 2019;78:1449–51. background shared by several autoim- families. JAMA Intern Med 2015;175:1518. 21 Bertsias GK, Pamfil C, Fanouriakis A, et al. Diagnostic 3 Kuo C-­F, Grainge MJ, Valdes AM, et al. Familial mune diseases,20 or is it due to the fact that criteria for systemic lupus erythematosus: has the time risk of Sjögren’s syndrome and co-­aggregation come? Nat Rev Rheumatol 2013;9:687–94. several cases of SLE represent incomplete of autoimmune diseases in affected families: a 22 Banchereau R, Hong S, Cantarel B, et al. Personalized forms of the disease or a ‘blood-­dominant’ nationwide population study. Rheumatol Immunomonitoring uncovers molecular networks that lupus.21 To this end, studies comparing 2015;67:1904–12. stratify lupus patients. Cell 2016;165:1548–50. molecular signatures of these two diseases 4 Liu F-­C, Kuo C-­F, See L-­C, et al. Familial 23 Panousis NI, Bertsias GK, Ongen H, et al. Combined aggregation of myasthenia gravis in affected genetic and transcriptome analysis of patients with may help to decipher this, as signatures families: a population-­based study. Clin Epidemiol SLE: distinct, targetable signatures for susceptibility specific for SLE such as type I interferon 2017;9:527–35. and severity. Ann Rheum Dis 2019;78:1079–89.

2 Fanouriakis A, et al. Ann Rheum Dis Month 2020 Vol 0 No 0