The Rheumatic Manifestations in Patients with Combined Immunodeficiency
-
Leila Ghasemi Hashtrodi
,
Zahra Chavoshzadeh
,
Mehrnaz Mesdaghi
,
Narges Eslami
,
Golnaz Eslamian
,
Mehdi Alizadeh
,
Leily Sokoty
,
Shahrzad Fallah
,
Maryam Asarehzadegan Dezfouli
,
Maryam Heydarazad Zadeh
,
Shabnam Hajiani Ghotbabadi
,
Hedieh Haji Khodavardi Khani
,
Nima Parvaneh
,
Reza Sinaee
,
Azadeh Zeinab Mirzaee
,
Nima Rezaei
,
Samin Sharafian
,
Reza Shiari
Abstract
Combined immunodeficiencies (CIDs) represent a rare group of inherited immune disorders in which defects in T- and B-lymphocyte function lead to recurrent infections, immune dysregulation, and an increased tendency toward autoimmune and rheumatologic complications.
A retrospective cross-sectional analysis was performed on 150 patients with CID, diagnosed according to the European Society for Immunodeficiencies (ESID) criteria and followed at the Children’s Medical Center and Mofid Children’s Hospital (Tehran, Iran) between 2009 and 2020. Clinical records, immunologic evaluations, and rheumatologic findings were reviewed, with particular attention to autoantibody detection and disease frequency. Among 150 patients, 42 (28%) exhibited rheumatologic manifestations, with a higher frequency in females. Undifferentiated rheumatoid arthritis, undifferentiated juvenile idiopathic arthritis, and Kawasaki disease were the predominant conditions. Although lower lymphocyte counts and immunoglobulin levels were observed among non-rheumatologic patients, the differences were not statistically significant.
Impairments in T-cell–mediated immunity and antibody synthesis among individuals with CID hinder the recognition of autoantibody-associated rheumatologic disorders and delay diagnosis. Moreover, these conditions often present atypically in immunocompromised hosts; therefore, a vigilant clinical approach is essential for early identification and management.
1. Poli MC, Aksentijevich I, Bousfiha AA, Cunningham-Rundles C, Hambleton S, Klein C, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. J Human Immunity. 2025;1(1):e20250003.
2. Costagliola G, Cappelli S, Consolini R. Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications. J Clin Med. 2021;10(20).
3. Meyts I, Bousfiha A, Duff C, Singh S, Lau YL, Condino-Neto A, et al. Primary Immunodeficiencies: A Decade of Progress and a Promising Future. Fron Immunol. 2021;11.
4. Aranda CS, Guimarães RR, de Gouveia-Pereira Pimentel M. Combined immunodeficiencies. Jornal de pediatria. 2021;97 Suppl 1(Suppl 1):S39-s48.
5. Al-Saud B, Al-Mousa H, Al Gazlan S, Al-Ghonaium A, Arnaout R, Al-Seraihy A, et al. Primary Immunodeficiency Diseases in Saudi Arabia: a Tertiary Care Hospital Experience over a Period of Three Years (2010–2013). J Clin Immunol. 2015;35(7):651-60.
6. Yazdani R, Tavakol M, Vosughi Motlagh A, Shafiei A, Darougar S, Chavoshzadeh Z, et al. Chapter 3 - Combined immunodeficiencies with associated or syndromic features. In: Aghamohammadi A, Abolhassani H, Rezaei N, Yazdani R, editors. Inborn Errors Immunity: Academic Press; 2021. p. 41-91.
7. Al-Herz W, Al-Mousa H. Combined immunodeficiency: The Middle East experience. J Allergy Clin Immunol. 2013;131(3):658-60.
8. Azizi G, Ziaee V, Tavakol M, Alinia T, Yazdai R, Mohammadi H, et al. Approach to the Management of Autoimmunity in Primary Immunodeficiency. Scandinavian J Immunol. 2017;85(1):13-29.
9. Azizi G, Ghanavatinejad A, Abolhassani H, Yazdani R, Rezaei N, Mirshafiey A, et al. Autoimmunity in primary T-cell immunodeficiencies. Exp Rev Clin Immunol. 2016;12(9):989-1006.
10. Ren A, Yin W, Miller H, Westerberg LS, Candotti F, Park CS, et al. Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity. Front Immunol. 2021;12:725587.
11. Todoric K, Koontz JB, Mattox D, Tarrant TK. Autoimmunity in immunodeficiency. Current Allergy Asthma Rep. 2013;13(4):361-70.
12. Notarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020;5(49).
13. Dimitriades VR, Sorensen R. Rheumatologic manifestations of primary immunodeficiency diseases. Clinical rheumatology. 2016;35(4):843-50.
14. Goyal R, Bulua AC, Nikolov NP, Schwartzberg PL, Siegel RM. Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders. Curr Opin Rheumatol. 2009;21(1):78-84.
15. Kitcharoensakkul M, Cooper MA. Rheumatologic and autoimmune manifestations in primary immune deficiency. Curr Opinion Allergy Clin Immunol. 2019;19(6):545-52.
16. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Practice. 2019;7(6):1763-70.
17. Bedran Z, Quiroz C, Rosa J, Catoggio LJ, Soriano ER. Validation of a prediction rule for the diagnosis of rheumatoid arthritis in patients with recent onset undifferentiated arthritis. Int J Rheumatol. 2013;2013:548502.
18. Zaripova LN, Midgley A, Christmas SE, Beresford MW, Baildam EM, Oldershaw RA. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Ped Rheumatol Online J. 2021;19(1):135.
19. Schmidt RE, Grimbacher B, Witte T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol. 2017;14(1):7-18.
20. Fischer A, Provot J, Jais JP, Alcais A, Mahlaoui N. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-93.e8.
21. Azizi G, Kiaee F, Hedayat E, Yazdani R, Dolatshahi E, Alinia T, et al. Rheumatologic complications in a cohort of 227 patients with common variable immunodeficiency. Scandinavian J Immunol. 2018;87(5):e12663.
22. Rezaei N, Aghamohammadi A, Moin M, Pourpak Z, Movahedi M, Gharagozlou M, et al. Frequency and Clinical Manifestations of Patients with Primary Immunodeficiency Disorders in Iran: Update from the Iranian Primary Immunodeficiency Registry. J Clin Immunol. 2006;26(6):519-32.
23. Fairweather D, Beetler DJ, McCabe EJ, Lieberman SM. Mechanisms underlying sex differences in autoimmunity. The Journal of clinical investigation. 2024;134(18).
24. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38.
25. Shashaani N, Chavoshzadeh Z, Ghasemi L, Ghotbabadi SH, Shiari S, Sharafian S, et al. Immunodeficiency due to a novel variant in PIK3CD: a case report. Pediatric Rheumatol. 2023;21(1):71.
2. Costagliola G, Cappelli S, Consolini R. Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications. J Clin Med. 2021;10(20).
3. Meyts I, Bousfiha A, Duff C, Singh S, Lau YL, Condino-Neto A, et al. Primary Immunodeficiencies: A Decade of Progress and a Promising Future. Fron Immunol. 2021;11.
4. Aranda CS, Guimarães RR, de Gouveia-Pereira Pimentel M. Combined immunodeficiencies. Jornal de pediatria. 2021;97 Suppl 1(Suppl 1):S39-s48.
5. Al-Saud B, Al-Mousa H, Al Gazlan S, Al-Ghonaium A, Arnaout R, Al-Seraihy A, et al. Primary Immunodeficiency Diseases in Saudi Arabia: a Tertiary Care Hospital Experience over a Period of Three Years (2010–2013). J Clin Immunol. 2015;35(7):651-60.
6. Yazdani R, Tavakol M, Vosughi Motlagh A, Shafiei A, Darougar S, Chavoshzadeh Z, et al. Chapter 3 - Combined immunodeficiencies with associated or syndromic features. In: Aghamohammadi A, Abolhassani H, Rezaei N, Yazdani R, editors. Inborn Errors Immunity: Academic Press; 2021. p. 41-91.
7. Al-Herz W, Al-Mousa H. Combined immunodeficiency: The Middle East experience. J Allergy Clin Immunol. 2013;131(3):658-60.
8. Azizi G, Ziaee V, Tavakol M, Alinia T, Yazdai R, Mohammadi H, et al. Approach to the Management of Autoimmunity in Primary Immunodeficiency. Scandinavian J Immunol. 2017;85(1):13-29.
9. Azizi G, Ghanavatinejad A, Abolhassani H, Yazdani R, Rezaei N, Mirshafiey A, et al. Autoimmunity in primary T-cell immunodeficiencies. Exp Rev Clin Immunol. 2016;12(9):989-1006.
10. Ren A, Yin W, Miller H, Westerberg LS, Candotti F, Park CS, et al. Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity. Front Immunol. 2021;12:725587.
11. Todoric K, Koontz JB, Mattox D, Tarrant TK. Autoimmunity in immunodeficiency. Current Allergy Asthma Rep. 2013;13(4):361-70.
12. Notarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020;5(49).
13. Dimitriades VR, Sorensen R. Rheumatologic manifestations of primary immunodeficiency diseases. Clinical rheumatology. 2016;35(4):843-50.
14. Goyal R, Bulua AC, Nikolov NP, Schwartzberg PL, Siegel RM. Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders. Curr Opin Rheumatol. 2009;21(1):78-84.
15. Kitcharoensakkul M, Cooper MA. Rheumatologic and autoimmune manifestations in primary immune deficiency. Curr Opinion Allergy Clin Immunol. 2019;19(6):545-52.
16. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Practice. 2019;7(6):1763-70.
17. Bedran Z, Quiroz C, Rosa J, Catoggio LJ, Soriano ER. Validation of a prediction rule for the diagnosis of rheumatoid arthritis in patients with recent onset undifferentiated arthritis. Int J Rheumatol. 2013;2013:548502.
18. Zaripova LN, Midgley A, Christmas SE, Beresford MW, Baildam EM, Oldershaw RA. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Ped Rheumatol Online J. 2021;19(1):135.
19. Schmidt RE, Grimbacher B, Witte T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol. 2017;14(1):7-18.
20. Fischer A, Provot J, Jais JP, Alcais A, Mahlaoui N. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-93.e8.
21. Azizi G, Kiaee F, Hedayat E, Yazdani R, Dolatshahi E, Alinia T, et al. Rheumatologic complications in a cohort of 227 patients with common variable immunodeficiency. Scandinavian J Immunol. 2018;87(5):e12663.
22. Rezaei N, Aghamohammadi A, Moin M, Pourpak Z, Movahedi M, Gharagozlou M, et al. Frequency and Clinical Manifestations of Patients with Primary Immunodeficiency Disorders in Iran: Update from the Iranian Primary Immunodeficiency Registry. J Clin Immunol. 2006;26(6):519-32.
23. Fairweather D, Beetler DJ, McCabe EJ, Lieberman SM. Mechanisms underlying sex differences in autoimmunity. The Journal of clinical investigation. 2024;134(18).
24. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38.
25. Shashaani N, Chavoshzadeh Z, Ghasemi L, Ghotbabadi SH, Shiari S, Sharafian S, et al. Immunodeficiency due to a novel variant in PIK3CD: a case report. Pediatric Rheumatol. 2023;21(1):71.
| Files | ||
| Issue | Articles in Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Autoimmune Combined immunodeficiency Inborn errors of immunity (IEI) Rheumatologic manifestations Undifferentiated juvenile idiopathic arthritis | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Ghasemi Hashtrodi L, Chavoshzadeh Z, Mesdaghi M, Eslami N, Eslamian G, Alizadeh M, Sokoty L, Fallah S, Asarehzadegan Dezfouli M, Heydarazad Zadeh M, Hajiani Ghotbabadi S, Haji Khodavardi Khani H, Parvaneh N, Sinaee R, Mirzaee AZ, Rezaei N, Sharafian S, Shiari R. The Rheumatic Manifestations in Patients with Combined Immunodeficiency. Iran J Allergy Asthma Immunol. 2026;:1-9.
