Allergy Asthma Immunol Res.  2019 Sep;11(5):736-755. 10.4168/aair.2019.11.5.736.

Factors Predicting the Response to Cyclosporin Treatment in Patients With Chronic Spontaneous Urticaria: A Systematic Review

• Kulthanan
• Subchookul C
• Hunnangkul S
• Chularojanamontri L
• Tuchinda P

• KMID: 2452762
• DOI: http://doi.org/10.4168/aair.2019.11.5.736

Abstract

PURPOSE
This study aimed to systemically review literature relating to factors that could potentially predict a favorable response to cyclosporine A (CsA) treatment for chronic spontaneous urticaria (CSU).
METHODS
A systematic literature review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations.
RESULTS
A total of 13 studies (404 patients with CSU and 200 healthy patients) were included. There were only 1 randomized controlled trial (RCT) and 12 non-RCTs. Our systematic review showed that positive autologous serum skin test results, positive baseline basophil histamine release assays, positive baseline basophil activation test responses, elevated baseline plasma D-dimer levels, elevated baseline serum interleukin (IL)-2, IL-5, and tumor necrosis factor-alpha (TNF-α) levels, and low baseline serum IgE levels might assist in predicting favorable CsA responses in CSU patients. Decreased plasma D-dimer levels; and decreased serum IL-2, IL-5, and TNF-α levels were reported to be correlated with clinical improvement after CsA treatment.
CONCLUSIONS
Since most positive results were from non-RCT articles and some data were still inconsistent, this systematic review identified no reliable practical biomarker for predicting CsA treatment response in patients with CSU. There were no positive predictors with good consistency and mechanical plausibility.

Keyword

Urticaria; cyclosporine; treatment outcome

MeSH Terms

Basophils
Cyclosporine*
Histamine Release
Humans
Immunoglobulin E
Interleukin-2
Interleukin-5
Interleukins
Plasma
Skin Tests
Treatment Outcome
Tumor Necrosis Factor-alpha
Urticaria*
Cyclosporine
Immunoglobulin E
Interleukin-2
Interleukin-5
Interleukins
Tumor Necrosis Factor-alpha

Figure

• 

  Figure Flow diagram of literature review in this study. Thirteen studies met the inclusion criteria and were included in our systematic review. CsA, cyclosporine A; CSU, chronic spontaneous urticaria; RCT, randomized controlled trial; ASST, autologous serum skin test; BHRA, basophil histamine release assay; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ANA, antinuclear antibody; TA, thyroid autoantibody; Ig, immunoglobulin; CIC, circulating immune complex; IL, interleukin; TNF-α, tumor necrosis factor alpha. *For analysis of relationship between clinical factors—including prior histories of urticaria, disease severity and disease duration—4 studies were included13162223; †For the correlation between histamine-releasing activity and CsA response in CSU, 8 studies were included614151618192123, involving the ASST,6151618192123 and BHRA61416; ‡Three studies showed a correlation between coagulation and inflammatory factors and the CsA response, involving D-dimer,13 CRP,131722 and ESR13; §Autoantibodies, including ANA,1622 TAs,131622 and other autoantibodies2223 were shown in 4 studies; llFour studies showed a correlation between cytokines and the CsA response, involving immunophenotypical lymphocytes (CD3, CD4, CD56, CD57, CD19, CD19+CD5+, and CD19+CD23+)20; Igs, C3, C4, and CICs20; serum IgE22, 23; IL-2; IL-5; and TNF-α.7

Reference

1. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA(2)LEN/EDF/WAO Guideline for the definition, classification, diagnosis and management of urticaria. The 2017 revision and update. Allergy. 2008; 73:1393–1414.

2. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000; 47:119–125.

3. Marsland AM, Soundararajan S, Joseph K, Kaplan AP. Effects of calcineurin inhibitors on an in vitro assay for chronic urticaria. Clin Exp Allergy. 2005; 35:554–559.

4. de Montjoye L, Herman A, Nicolas JF, Baeck M. Treatment of chronic spontaneous urticaria: immunomodulatory approaches. Clin Immunol. 2017; 190:53–63.

5. Harrison CA, Bastan R, Peirce MJ, Munday MR, Peachell PT. Role of calcineurin in the regulation of human lung mast cell and basophil function by cyclosporine and FK506. Br J Pharmacol. 2007; 150:509–518.

6. Grattan CE, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, et al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol. 2000; 143:365–372.

7. Serhat Inaloz H, Ozturk S, Akcali C, Kirtak N, Tarakcioglu M. Low-dose and short-term cyclosporine treatment in patients with chronic idiopathic urticaria: a clinical and immunological evaluation. J Dermatol. 2008; 35:276–282.

8. Kulthanan K, Chaweekulrat P, Komoltri C, Hunnangkul S, Tuchinda P, Chularojanamontri L, et al. Cyclosporine for chronic spontaneous urticaria: a meta-analysis and systematic review. J Allergy Clin Immunol Pract. 2018; 6:586–599.

9. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4:1.

10. Higgins J. Cochrane handbook for systematic reviews of interventions version 5.1.0 [Internet]. Chichester: John Wiley & Son;2011. cited 2019 Jan 10. Available from: http://handbook.cochrane.org.

11. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003; 73:712–716.

12. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336:924–926.

13. Asero R. Plasma D-dimer levels and clinical response to ciclosporin in severe chronic spontaneous urticaria. J Allergy Clin Immunol. 2015; 135:1401–1403.

14. Iqbal K, Bhargava K, Skov PS, Falkencrone S, Grattan CE. A positive serum basophil histamine release assay is a marker for ciclosporin-responsiveness in patients with chronic spontaneous urticaria. Clin Transl Allergy. 2012; 2:19.

15. Boubouka CD, Charissi C, Kouimintzis D, Kalogeromitros D, Stavropoulos PG, Katsarou A. Treatment of autoimmune urticaria with low-dose cyclosporin A: a one-year follow-up. Acta Derm Venereol. 2011; 91:50–54.

16. Hollander SM, Joo SS, Wedner HJ. Factors that predict the success of cyclosporine treatment for chronic urticaria. Ann Allergy Asthma Immunol. 2011; 107:523–528.

17. Ohtsuka T. Response to oral cyclosporine therapy and high sensitivity-CRP level in chronic idiopathic urticaria. Int J Dermatol. 2010; 49:579–584.

18. Baskan EB, Tunali S, Turker T, Saricaoglu H. Comparison of short- and long-term cyclosporine A therapy in chronic idiopathic urticaria. J Dermatolog Treat. 2004; 15:164–168.

19. Di Gioacchino M, Di Stefano F, Cavallucci E, Verna N, Ramondo S, Paolini F, et al. Treatment of chronic idiopathic urticaria and positive autologous serum skin test with cyclosporine: clinical and immunological evaluation. Allergy Asthma Proc. 2003; 24:285–290.

20. Loria MP, Dambra PP, D’Oronzio L, Nettis E, Pannofino A, Cavallo E, et al. Cyclosporin A in patients affected by chronic idiopathic urticaria: a therapeutic alternative. Immunopharmacol Immunotoxicol. 2001; 23:205–213.

21. Toubi E, Blant A, Kessel A, Golan TD. Low-dose cyclosporin A in the treatment of severe chronic idiopathic urticaria. Allergy. 1997; 52:312–316.

22. Santiago L, Ferreira B, Ramos L, Goncalo M. IgE levels are negatively correlated with clinical response to ciclosporin in chronic spontaneous urticaria. Br J Dermatol. 2019; 180:199–200.

23. Endo T, Toyoshima S, Kanegae K, Izaki S, Nishimori N, Ito M, et al. Identification of biomarkers for predicting the response to cyclosporine A therapy in patients with chronic spontaneous urticaria. Allergol Int. 2019; 68:270–273.

24. Schroeder JT, MacGlashan DW Jr, Lichtenstein LM. Human basophils: mediator release and cytokine production. Adv Immunol. 2001; 77:93–122.

25. Falcone FH, Haas H, Gibbs BF. The human basophil: a new appreciation of its role in immune responses. Blood. 2000; 96:4028–4038.

26. Ye YM, Yang EM, Yoo HS, Shin YS, Kim SH, Park HS. Increased level of basophil CD203c expression predicts severe chronic urticaria. J Korean Med Sci. 2014; 29:43–47.

27. Knol EF, Mul FP, Jansen H, Calafat J, Roos D. Monitoring human basophil activation via CD63 monoclonal antibody 435. J Allergy Clin Immunol. 1991; 88:328–338.

28. Asero R, Tedeschi A, Coppola R, Griffini S, Paparella P, Riboldi P, et al. Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria. J Allergy Clin Immunol. 2007; 119:705–710.

29. Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993; 328:1599–1604.

30. Tokura Y, Röcken M, Clark RA, Haliasos E, Takigawa M, Sinha AA. What are the most promising strategies for the therapeutic immunomodulation of allergic diseases? Exp Dermatol. 2001; 10:128–140.