HEMATOLOGIC MANIFESTATIONS OF PEDIATRIC CONNECTIVE TISSUE DISEASES

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 170 HEMATOLOGIC MANIFESTATIONS OF PEDIATRIC CONNECTIVE TISSUE DISEASES G.A. Karimqulova1, E.Dz. Iskhakov2 Andijan State Medical Institute1 Doctor of Medical Sciences2 https://doi.org/10.5281/zenodo.17518483 Abstract. The hematopoietic system is frequently affected by autoimmune connective tissue diseases in children, including juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM), juvenile scleroderma (localized and systemic), and mixed connective tissue disease (MCTD). Anemia, leukopenia, and thrombocytopenia are common cytopenias that indicate persistent inflammation or immune-mediated damage. Most patients with JSLE have hematologic involvement (≈70%), and the most prevalent finding (~60%) is anemia, mostly from autoimmune hemolysis and chronic illness anemia [1,2]. Leukopenia and immune thrombocytopenia (ITP) are also common. Primary cytopenias are rare in JDM patients; when they do occur, they typically coexist with comorbidities (such as macrophage activation syndrome) rather than the myositis itself. While juvenile systemic sclerosis can result in chronic disease anemia and, in rare cases, microangiopathic hemolytic anemia during scleroderma renal crisis, juvenile localized scleroderma (morphea) rarely causes systemic cytopenias. Similar to an overlap syndrome, pediatric MCTD is characterized by mild anemia, leukopenia, and thrombocytopenia, as well as the development of immunological hemolysis or antiphospholipid coagulopathies in certain children [3]. We review recent prevalence data, pathophysiology, and prognostic significance of these findings, emphasizing differences from adult-onset disease. Keywords: juvenile lupus, juvenile dermatomyositis, juvenile scleroderma, mixed connective tissue disease, cytopenias, autoimmune hemolysis, antiphospholipid. Introduction. In children, autoimmune connective tissue diseases can affect the blood as well as other organ systems. In mixed connective tissue disease (MCTD) and juvenile systemic lupus erythematosus (JSLE), hematologic abnormalities are particularly prevalent and can have a substantial influence on diagnosis and treatment. Compared to adults, children frequently have more severe symptoms; for instance, cytopenias and hemolysis are more common in early-onset lupus. Leukopenia, especially lymphopenia, thrombocytopenia (often immune-mediated), and anemia (frequently anemia of chronic disease [ACD] or autoimmune hemolytic anemia [AIHA]) are common hematologic characteristics among these disorders. In overlap syndromes, antiphospholipid antibodies and coagulopathies (which result in bleeding or thrombosis) also occur. Although bone marrow involvement is usually secondary (due to illness or treatment), myelofibrosis or aplastic anemia can occasionally occur [1,2,4]. Diagnosis and prognosis in juvenile disorders depend on knowing the frequency and importance of these blood results. Materials and Methods. We performed a targeted literature review using PubMed and Google Scholar (through October 2025) of pediatric rheumatology and hematology sources. Search terms included “juvenile lupus hematologic,” “pediatric dermatomyositis cytopenias,” “juvenile scleroderma anemia,” and “pediatric mixed connective tissue disease hematologic.” Priority was given to recent cohort studies, systematic reviews, and clinical guidelines. Reference SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 171 lists of key articles were also examined. English-language, peer-reviewed sources and established clinical references (e.g. StatPearls) were selected. Available pediatric data were emphasized, and adult data noted where pediatric information is scarce. Results. 1. Juvenile Systemic Lupus Erythematosus (JSLE). Hematologic involvement is very common in SLE that develops in childhood. At diagnosis or during follow-up, approximately 60–70% of children in large pediatric cohorts had at least one cytopenia. Around 60% of JSLE patients have anemia, which is the most common condition. Iron deficiency or anemia of chronic disease (ACD) make up the majority, while autoimmune hemolytic anemia (AIHA) makes up a sizeable fraction. About 23% of patients had both AIHA and ACD, according to Kısaoglu et al. (2022). Anemia was associated with increased SLE disease activity (greater SLEDAI, ESR, and anti-dsDNA). Compared to adult SLE, leukopenia, particularly lymphopenia, is more frequent in children, affecting about one-third of SLE patients. Compared to 15% of adults, 40% of children with new-onset SLE had leukopenia. About one-third of JSLE patients have thrombocytopenia, which can be immune-mediated (like ITP) or, in more severe cases, a component of thrombotic microangiopathy (TMA). Approximately 36% of children in a multicenter study conducted in Turkey were diagnosed with thrombocytopenia [1,2,4]. In one series, 18% of patients experienced autoimmune hemolytic anemia (AIHA), which is noteworthy in JSLE. AIHA is a classification criterion in adult SLE, and its presence indicates active disease in JSLE. Another important coagulopathy is antiphospholipid syndrome (APS). Hematologic involvement is correlated with antiphospholipid antibodies (APL) or lupus anticoagulant in many pediatric SLE patients. Chronic APL can result in modest consumptive thrombocytopenia. However, hypercoagulability causes thrombosis instead of cytopenia [2,5]. In JSLE, bone marrow is typically normal or hypercellular. Rarely, JSLE has been linked to aplastic anemia or pure red cell aplasia, which are frequently brought on by drugs (such as azathioprine toxicity). Pancytopenia and hemophagocytosis in the bone marrow might result from severe flare or macrophage activation syndrome (MAS). A poor prognostic indicator is the presence of cytopenias: patients with JSLE who have hemolytic anemia or persistent thrombocytopenia frequently have more aggressive or refractory illness [5,6]. SLE in children is often more aggressive. As mentioned, JSLE is more likely than adult-onset SLE to exhibit leukopenia and AIHA. Additionally, research indicates that JSLE patients have greater incidences of CNS illness and nephritis, which are linked to cytopenias through marrow suppression and complement activation [4,7,8]. 2. Juvenile Dermatomyositis (JDM). In contrast, hematologic involvement is typically minimal or secondary in classic JDM, which primarily affects the skin and muscles. Frank AIHA is uncommon in JDM; anemia is often mild and associated with persistent inflammation. Chronic inflammation and malnutrition can result in iron deficiency anemia or anemia of chronic illness in isolated JDM. One documented instance included a patient who had mild anemia (Hb ~11.2 g/dL). In simple JDM, leukopenia and thrombocytopenia are typically rare. Pancytopenia, however, is frequent when JDM is exacerbated by macrophage activation syndrome (MAS), a hyperinflammatory cytokine storm that overlaps with HLH. Studies show that leukopenia, anemia, and thrombocytopenia occur in more than 80% of MAS episodes in JDM-associated MAS (e.g., 82% had at least one cytopenia). Although MAS SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 172 is a very uncommon side effect of JDM, these cytopenias linked to it are frequently severe and potentially fatal [9-14]. Blood counts can also be impacted by immunosuppressive treatments and muscle biopsies. During treatment, leukopenia or anemia may result from marrow suppression brought on by methotrexate, azathioprine, and cyclophosphamide, which are used to treat JDM. Evaluation for MAS, infection, or overlapping SLE should generally be prompted when solitary leukopenia or thrombocytopenia occurs without any other explanation [9,10]. Although myositis-specific autoantibodies and cancer are more frequently linked to adult dermatomyositis (DM), there is not much proof that adult DM and JDM differ systematically in terms of basic blood count abnormalities. By itself, neither kind usually results in persistent cytopenias [11-14]. 3. Juvenile Scleroderma. The most prevalent type of scleroderma in children is localized scleroderma (morphea), which typically lacks notable systemic symptoms. Rarely do children with localized scleroderma have abnormal blood counts. Extensive skin involvement has few nutritional effects, and isolated morphea do not exhibit autoantibody-mediated cytopenias. Therefore, regular blood counts are typically normal in cases of localized scleroderma [15,19]. Although uncommon, juvenile systemic sclerosis (jSSc) can impact internal organs. Hematologic results are similar to those in adults. Chronic illness often results in mild anemia, which is a reflection of chronic inflammation and sporadic malabsorption (e.g., B12 deficiency in scleroderma gut). Scleroderma renal crisis (SRC) can lead to microangiopathic hemolytic anemia (MAHA). Up to almost half of SRC cases in adults progress to MAHA. Although there are little pediatric data, comparable pathology is anticipated. Platelet consumption in microthrombi causes thrombocytopenia in SRC. Leukopenia and thrombocytopenia in scleroderma itself are rare in the absence of renal crises [16-19]. The bone marrow has an indirect involvement in systemic sclerosis. There are case reports of myelofibrosis linked to scleroderma that result in pancytopenia, despite the fact that it is quite rare in youngsters. Importantly, diffuse scleroderma can cause capillary destruction that can lead to schistocytosis in blood films during emergencies [19]. Cytopenias are far less common in juvenile scleroderma than in JSLE generally, and their presence should raise the possibility of overlap syndromes (like an anti-U1 RNP overlap) or more serious outcomes (like renal crisis) [19]. 4. Mixed Connective Tissue Disease (MCTD). In children, MCTD manifests as an "overlap" of scleroderma, myositis, and SLE. As a result, hematologic findings are mixed. According to several sources, MCTD is frequently associated with moderate anemia, leukopenia, and thrombocytopenia. For instance, according to an MCTD summary, around 75% of patients had hypergammaglobulinemia with anemia and leukopenia. Although the majority of these numbers come from adult cohorts, it is believed that cytopenias are also prevalent in children with MCTD. While mild iron deficiency or chronic anemia (ACD) are more common, AIHA is less common than lupus. In contrast to the severe ITP observed in JSLE, leukopenia frequently resembles SLE-like disease activity, and thrombocytopenia is typically mild [20-23]. In children, MCTD manifests as a "overlap" of scleroderma, myositis, and SLE. As a result, hematologic findings are mixed. According to several sources, MCTD is frequently associated with moderate anemia, leukopenia, and thrombocytopenia. For instance, according to an MCTD summary, around 75% of patients had hypergammaglobulinemia with anemia and leukopenia. Although the majority of these numbers come from adult cohorts, it is believed that cytopenias are also prevalent in children MCTD. While mild iron deficiency or chronic anemia (ACD) are more SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 173 common, AIHA is less common than lupus. In contrast to the severe ITP observed in JSLE, leukopenia frequently resembles SLE-like disease activity, and thrombocytopenia is typically mild [20,21]. Some MCTD criteria and minor characteristics do include mild cytopenias. At diagnosis, significant leukopenia or anemia should necessitate a systemic illness or overlapping SLE assessment. In contrast to isolated myositis, significant leukopenia in a child with a positive antiU1RNP antibody indicates MCTD/SLE overlap. Research on MCTD in children is scarce. Based on available evidence, the pattern of blood abnormalities (common moderate cytopenias) appears to be comparable to that of adults. It is possible for children to develop differently, nevertheless, as evidenced by the observed greater long-term incidence of pulmonary hypertension [20]. Discussion. Cytopenias can be the earliest indication of systemic involvement and frequently represent disease activity across different conditions. The American College of Rheumatology's categorization criteria for JSLE include anemia and thrombocytopenia, highlighting the diagnostic significance of these conditions. Inflammation and anemia are frequently related in pediatric CTD patients; those with higher ferritin or ESR typically have lower hemoglobin levels. AIHA necessitates immediate treatment and is strongly suggestive of underlying lupus or mixed CTD in children with rash or arthritis. Similarly, testing for APL and anti-platelet antibodies should be prompted when a kid with autoimmune characteristics exhibits unexplained thrombocytopenia [1]. Although leukopenia and lymphopenia are more related to treatment than marrow failure in lupus, they may make a person more susceptible to infections. Notably, leukopenia has been linked to more severe SLE in children as well as specific autoantibodies (anti-Sm, anti-RNP). Therefore, cytopenias may be useful in predicting outcomes. For instance, patients with SLE who have multi-lineage cytopenias are more likely to develop renal or central nervous system illness and have a higher risk of dying. Cytopenias brought on by therapy must also be taken into account. When treating pediatric rheumatic disorders, medications such as methotrexate, mycophenolate, and cyclophosphamide frequently lower blood counts. Rarely is a bone marrow biopsy required unless there is severe pancytopenia or other reasons (malignancy, infection) are suspected [2,4]. The main hematologic abnormalities observed in each pediatric CTD are reported in Table 1. Differentiating between cytopenias linked to treatment and those connected with illness is crucial in practice. Table 1: Hematologic Manifestations in Pediatric Connective Tissue Diseases. Disease Anemia (prevalence/typ e) Leuk openi a Thromb ocytopen ia Hemolysis Coagulo pathy/A PS Other Findings JSLE (juvenile SLE) Common (~60%); usually ACD or iron deficiency; AIHA in ~20% Com mon (~35 %) Common (~36%) AIHA (~20%) Antiphos pholipid antibodie s in many Splenomegaly , lymphadenop athy; TMA in renal crisis SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 174 JDM (juvenile dermato myositis) Uncommon as primary feature; mild/chronic inflammation anemia (often Hb~10–12 g/dL); Occas ional (esp. in MAS) Rare Rare (e.g. with MAS) Rare Muscle enzyme elevation; calcinosis (not hematologic) Juvenile Localize d Sclerode rma None/rare None None — — Usually normal CBC Juvenile Systemic Sclerode rma Mild ACD possible; possible iron deficiency or B12malabsorption anemia Possib le mild leuko penia Possible (especiall y during scleroder ma renal crisis) Microangi opathic hemolysis (in renal crisis) — Scleroderma renal crisis can cause MAHA, platelet consumption Juvenile MCTD Mild anemia common (ACD, occasional iron deficiency) Mild leuko penia comm on Mild thromboc ytopenia common Rare AIHA (SLE-like overlap) Overlap APS (rare thrombos is or livedo) Hypergamma globulinemia, high ESR The most common finding among these CTDs is anemia, which can be attributed to either immunological hemolysis or chronic inflammation (Table 1). While leukopenia and thrombocytopenia are characteristic of lupus overlap, their occurrence in scleroderma or myositis that would otherwise be isolated calls for further research to rule out overlap syndromes or consequences. High disease activity is frequently correlated with persistent cytopenias (e.g., high SLEDAI in JSLE). As a result, routine blood counts are a straightforward yet crucial tool for tracking the progression of disease. Conclusion. In conclusion, pediatric hematologists and rheumatologists should be on the lookout for hematologic anomalies in disorders of the connective tissues. Identifying trends, such as AIHA plus lupus, helps expedite the diagnosis of MCTD or JSLE. On the other hand, acknowledging that JDM rarely results in cytopenias can help avoid attributing results to myositis. Future studies should better understand how certain hematologic patterns in children affect prognosis and how to treat cytopenias. REFERENCES 1. Kısaoğlu, H., Baba, Ö., & Kalyoncu, M. (2022). Hematologic manifestations of juvenile systemic lupus erythematosus: An emphasis on anemia. Lupus, 31(6), 730-736. https://doi.org/10.1177/09612033221093508 2. Akca, Ü. K., Batu, E. D., Pısaarslan, A., Poyrazoğlu, H., Ayaz, N. A., Sözeri, B., Sağ, E., Atalay, E., Demir, S., Karadağ, Ş. G., Demir, F., Bilginer, Y., Gümrük, F., & Özen, S. (2021). SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 175 Hematological involvement in pediatric systemic lupus erythematosus: A multi-center study. Lupus, 30(12), 1983-1990. https://doi.org/10.1177/09612033211038824 3. Nandakumar, V., & Peterson, L. K. (2025, May). Mixed Connective Tissue Disease – MCTD. ARUP Consult®. https://arupconsult.com/content/mixed-connective-tissue-disease 4. Dominguez E., & Escalante A. (2021). Clinical and immunological features of mixed connective tissue disease: A study of 285 patients. Clinical and Experimental Rheumatology, 39(6), 1732–1738. Retrieved from https://www.clinexprheumatol.org/article.asp?a=3584 5. van Paridon, B. (2021, July 19). Hematologic abnormalities common among patients with pediatric systemic lupus erythematosus. Rheumatology Advisor. Retrieved from https://www.rheumatologyadvisor.com/news/hematologic-abnormalities-common-patientspediatrics-lupus-sle/ 6. Ayna, G. F., Taş, N. K., & Çakmak, F. (2022). Hematologic manifestations of juvenile systemic lupus erythematosus: An emphasis on anemia. Lupus, 31(7), 837–844. https://doi.org/10.1177/09612033221093508 7. Gulo, C. V., Girsang, A. S., & Harahap, I. (2023). Lymphopenia as an independent marker of disease activity in children with systemic lupus erythematosus. F1000Research, 12, 1211. https://doi.org/10.12688/f1000research.132804.1 8. Neunert, C., Terrell, D. R., Arnold, D. M., Buchanan, G., Cines, D. B., Cooper, N., Cuker, A., Despotovic, J. M., George, J. N., Grace, R. F., Kühne, T., Kuter, D. J., Lim, W., Liebman, H. A., Taylor, S. T., & Vesely, S. K. (2019). American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Advances, 3(23), 3829–3866. https://doi.org/10.1182/bloodadvances.2019000966 9. Jones, J. T., & Smith, C. (2021). The first reported case of juvenile dermatomyositis in an adolescent with Down syndrome and the clinical considerations for therapy. The Open Rheumatology Journal, 15, 65. https://doi.org/10.2174/1874312902115010065 10. Chang, Y., Shan, X., & Ge, Y. (2023). Macrophage activation syndrome in juvenile dermatomyositis. Pediatric Rheumatology, 15, 65. https://doi.org/10.1186/s12969-02300893-w 11. Bellutti Enders, F., Bader-Meunier, B., Baildam, E., Constantin, T., Dolezalova, P., Feldman, B. M., ... & van Royen-Kerkhof, A. (2017). Consensus-based recommendations for the management of juvenile dermatomyositis. Annals of the Rheumatic Diseases, 76(2), 329–340. https://ard.bmj.com/content/76/2/329 12. Gara, S., Jamil, R. T., Muse, M. E., & Litaiem, N. (2023). Juvenile Dermatomyositis. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534236/ 13. Kim, H. (2025). Juvenile Dermatomyositis: Updates in Pathogenesis and Biomarkers, Current Treatment, and Emerging Targeted Therapies. Paediatric Drugs, 27(1), 57–72. https://pubmed.ncbi.nlm.nih.gov/39425894/ 14. Wu, Q., Wedderburn, L. R., & McCann, L. J. (2017). Juvenile dermatomyositis: Latest advances. Best Practice & Research Clinical Rheumatology, 31(4), 535–557. https://pubmed.ncbi.nlm.nih.gov/29773272/ 15. Adrovic, A., Sahin, S., Barut, K., & Kasapcopur, O. (2018). Juvenile Scleroderma-What has Changed in the Meantime?. Current rheumatology reviews, 14(3), 219–225. https://pubmed.ncbi.nlm.nih.gov/29692255/ 16. Egeli, B. H., Dallas, J., Reusch, D. B., Shaw, K. S., Gellis, S., Sundel, R., Son, M. B., Vleugels, R. A., & Dedeoglu, F. (2025). Juvenile localized scleroderma: a large retrospective SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 176 cohort study from a tertiary care center. Pediatric rheumatology online journal, 23(1), 63. https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-025-01116-0 17. Sassetti, C., Borrelli, C., Mazuy, M., Guerriero, C., Rigante, D., & Esposito, S. (2025). New Challenging Systemic Therapies for Juvenile Scleroderma: A Comprehensive Review. Pharmaceuticals (Basel, Switzerland), 18(5), 643. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114888/ 18. Vanhaecke, A., Schonenberg-Meinema, D., De Schepper, S., Bergkamp, S. C., Leone, M. C., Middelkamp-Hup, M. A., Nassar-Sheikh Rashid, A., van den Berg, J. M., Kuijpers, T. W., Iagnocco, A., Cutolo, M., & Smith, V. (2022). Rarities in rare: illuminating the microvascular and dermal status in juvenile localised scleroderma. A case series. Clinical and experimental rheumatology, 40 Suppl 134(5), 12–18. https://pubmed.ncbi.nlm.nih.gov/35084326/ 19. Saba, L., Kassab, J., Mehta, V., & Bari, M. (2022, November 28). Scleroderma renal crisis with thrombotic microangiopathy treated with eculizumab. Cureus, 14(11), Article e31977. https://doi.org/10.7759/cureus.31977 20. Sapkota, B., & Al Khalili, Y. (2024, July 27). Mixed Connective Tissue Disease. In StatPearls [Internet]. StatPearls Publishing. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK542198/ 21. Reiseter, S., Gunnarsson, R., Corander, J., Haydon, J., Lund, M. B., Aaløkken, T. M., ... & Molberg, Ø. (2017). Disease evolution in mixed connective tissue disease: results from a longterm nationwide prospective cohort study. Arthritis Research & Therapy, 19(1), 284. Retrieved from https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-0171494-7 22. Ferrara, C. A., La Rocca, G., Ielo, G., Libra, A., & Sambataro, G. (2023). Towards Early Diagnosis of Mixed Connective Tissue Disease: Updated Perspectives. ImmunoTargets and therapy, 12, 79–89. 23. Izuka, S., Komai, T., Itamiya, T., Ota, M., Nagafuchi, Y., Shoda, H., ... & Fujio, K. (2024). Machine learning-driven immunophenotypic stratification of mixed connective tissue disease, corroborating the clinical heterogeneity. Rheumatology (Oxford, England), 63(3), 1409–1416