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Infliximab for Treatment of Granulomatous Disease in Patients with Common Variable Immunodeficiency

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Abstract

Purpose

Eight to 22 % of common variable immunodeficiency (CVID) patients exhibit granulomas of the lungs, spleen, liver, and/or skin. Granulomas can be the most medically significant day-to-day problem for CVID patients. Currently, there are limited options for treatment of granulomas associated with CVID.

Methods

We treated five patients with CVID who exhibited significant clinical symptoms secondary to granulomas with infliximab. The patients were selected and treated based solely on clinical need and were not otherwise controlled or blinded to the therapy. After obtaining baseline studies (labs, spirometry, radiology) and excluding infection, they were treated with infliximab 5 mg/kg at week 0, 2, 6 and every 4 weeks thereafter.

Results

Post treatment improvements were seen in all 5 patients with significant clinical responses observed for both visceral and cutaneous granulomata. Four of the five patients were maintained on infliximab for 5 to 18 months (mean 9.4 months) without adverse reaction or increased susceptibility to infection. One patient completed 6 months of therapy with improvement of respiratory parameters but discontinued infliximab due to joint stiffness and rash that she attributed to the medication.

Conclusion

In our series, infliximab (5 mg/kg monthly) was an effective treatment for cutaneous and visceral granulomas in patients with CVID.

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References

  1. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190–7.

    Article  PubMed  CAS  Google Scholar 

  2. Morimoto Y, Routes JM. Granulomatous disease in common variable immunodeficiency. Curr Allergy Asthma Rep. 2005;5(5):370–5.

    Article  PubMed  CAS  Google Scholar 

  3. Cunningham-Rundles C. How I, treat common variable immune deficiency. Blood. 2010;116(1):7–15.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin Immunol. 2009;133(2):198–207.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol. 1997;159(12):6236–41.

    PubMed  CAS  Google Scholar 

  6. Boursiquot JN, Gerard L, Malphettes M, Fieschi C, Galicier L, Boutboul D, et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol. 2013;33(1):84–95.

    Article  PubMed  CAS  Google Scholar 

  7. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. 1997;127(8 Pt 1):613–7.

    Article  PubMed  CAS  Google Scholar 

  8. Kanathur N, Byrd Jr RP, Fields CL, Roy TM. Noncaseating granulomatous disease in common variable immunodeficiency. South Med J. 2000;93(6):631–3.

    Article  PubMed  CAS  Google Scholar 

  9. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol. 2005;95(3):293–300.

    Article  PubMed  Google Scholar 

  10. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol. 2002;168(9):4620–7.

    Article  PubMed  CAS  Google Scholar 

  11. Aukrust P, Lien E, Kristoffersen AK, Muller F, Haug CJ, Espevik T, et al. Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency–possible immunologic and clinical consequences. Blood. 1996;87(2):674–81.

    PubMed  CAS  Google Scholar 

  12. Lin JH, Liebhaber M, Roberts RL, Dyer Z, Stiehm ER. Etanercept treatment of cutaneous granulomas in common variable immunodeficiency. J Allergy Clin Immunol. 2006;117(4):878–82.

    Article  PubMed  CAS  Google Scholar 

  13. Malbran A, Juri MC, Fernandez Romero DS. Common variable immunodeficiency and granulomatosis treated with infliximab. Clin Immunol. 2010;134(3):359–60.

    Article  PubMed  CAS  Google Scholar 

  14. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114(2):415–21.

    Article  PubMed  Google Scholar 

  15. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, Tomita-Mitchell A, Casper JT, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). J Clin Immunol. 2013;33(1):30–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Hatab AZ, Ballas ZK. Caseating granulomatous disease in common variable immunodeficiency treated with infliximab. J Allergy Clin Immunol. 2005;116(5):1161–2.

    Article  PubMed  CAS  Google Scholar 

  18. Smith KJ, Skelton H. Common variable immunodeficiency treated with a recombinant human IgG, tumour necrosis factor-alpha receptor fusion protein. Br J Dermatol. 2001;144(3):597–600.

    Article  PubMed  CAS  Google Scholar 

  19. Douni E, Akassoglou K, Alexopoulou L, Georgopoulos S, Haralambous S, Hill S, et al. Transgenic and knockout analyses of the role of TNF in immune regulation and disease pathogenesis. J Inflamm. 1995–1996;47(1–2):27–38.

    CAS  Google Scholar 

  20. Myatt N, Coghill G, Morrison K, Jones D, Cree IA. Detection of tumour necrosis factor alpha in sarcoidosis and tuberculosis granulomas using in situ hybridisation. J Clin Pathol. 1994;47(5):423–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Joseph AL, Boros DL. Tumor necrosis factor plays a role in Schistosoma mansoni egg-induced granulomatous inflammation. J Immunol. 1993;151(10):5461–71.

    PubMed  CAS  Google Scholar 

  22. Aukrust P, Muller F, Froland SS. Elevated serum levels of interleukin-4 and interleukin-6 in patients with common variable immunodeficiency (CVI) are associated with chronic immune activation and low numbers of CD4+ lymphocytes. Clin Immunol Immunopathol. 1994;70(3):217–24.

    Article  PubMed  CAS  Google Scholar 

  23. North ME, Spickett GP, Webster AD, Farrant J. Raised serum levels of CD8, CD25 and beta 2-microglobulin in common variable immunodeficiency. Clin Exp Immunol. 1991;86(2):252–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H, Dayer JM. Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. The J5 study group. Immunology. 1992;76(1):20–3.

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Flammiger A, Fiedler W, Bacher U, Bokemeyer C, Schneider M, Binder M. Critical imbalance of TNF-alpha and soluble TNF receptor 1 in a patient with macrophage activation syndrome: potential implications for diagnostics and treatment. Acta Haematol. 2012;128(2):69–72.

    Article  PubMed  Google Scholar 

  26. Heaney ML, Golde DW. Soluble receptors in human disease. J Leukoc Biol. 1998;64(2):135–46.

    PubMed  CAS  Google Scholar 

  27. Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002;301(2):418–26.

    Article  PubMed  CAS  Google Scholar 

  28. Ehlers S. Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept? Clin Infect Dis. 2005;41 Suppl 3:S199–203.

    Article  PubMed  CAS  Google Scholar 

  29. Fallahi-Sichani M, Flynn JL, Linderman JJ, Kirschner DE. Differential risk of ctuberculosis reactivation among anti-TNF therapies is due to drug bindingckinetics and permeability. J Immunol. 2012;188(7):3169–78.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum. 2008;58(5):1248–57.

    Article  PubMed  CAS  Google Scholar 

  31. Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37(8):820–8.

    Article  PubMed  CAS  Google Scholar 

  32. Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005;37(8):829–34.

    Article  PubMed  CAS  Google Scholar 

  33. Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom Q, Jennings S, Lougaris V, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113(9):1967–76.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA

    Timothy J. Franxman, Laura E. Howe & James R. Baker Jr.

  2. 24 Frank Lloyd Wright Drive, Suite H-2100, PO Box 442, Ann Arbor, MI, 48106, USA

    Timothy J. Franxman & James R. Baker Jr.

Authors
  1. Timothy J. Franxman
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  2. Laura E. Howe
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  3. James R. Baker Jr.
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Correspondence to Timothy J. Franxman or James R. Baker Jr..

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Franxman, T.J., Howe, L.E. & Baker, J.R. Infliximab for Treatment of Granulomatous Disease in Patients with Common Variable Immunodeficiency. J Clin Immunol 34, 820–827 (2014). https://doi.org/10.1007/s10875-014-0079-3

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  • DOI: https://doi.org/10.1007/s10875-014-0079-3

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