eISSN: 2299-0046
ISSN: 1642-395X
Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii
Current issue Archive Manuscripts accepted About the journal Editorial board Journal's reviewers Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
4/2021
vol. 38
 
Share:
Share:
more
 
 
Original paper

A comparative analysis of tuberculosis in vitro screening in pemphigus patients selected for treatment with rituximab

Magdalena Jałowska
1, 2
,
Justyna Gornowicz-Porowska
1, 3
,
Agnieszka Seraszek-Jaros
4
,
Elżbieta Kaczmarek
4
,
Monika Bowszyc-Dmochowska
5
,
Paweł Bartkiewicz
1
,
Marian Dmochowski
1

1.
Autoimmune Blistering Dermatoses Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland
2.
Occupational Medicine Outpatient Clinic, Œwiêcicki Hospital, Poznan University of Medical Sciences, Poznan, Poland
3.
Department and Division of Practical Cosmetology and Skin Diseases Prophylaxis, Poznan University of Medicinal Sciences, Poznan, Poland
4.
Department of Bioinformatics and Computational Biology, Poznan University of Medical Sciences, Poznan, Poland
5.
Cutaneous Histopathology and Immunopathology Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland
Adv Dermatol Allergol 2021; XXXVIII (4): 611–614
Online publish date: 2021/09/14
Article file
- A comparative.pdf  [0.16 MB]
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
 

Introduction

Pemphigus diseases are a group of potentially life-threatening acantholytic illnesses of mucous membranes and/or skin. Pemphigus diseases are diagnosed on the basis of clinical manifestations, direct immunofluorescence of perilesional tissue, that can be visualized with various microscopy systems, for deposition of immunoreactants showing the pemphigus-pattern with, in case of IgG4, dew drops on spider web appearance and serum testing with molecular-biochemical techniques for autoantibodies to desmogleins [13]. Systemic glucocorticosteroids (GCS), alone or in combination with immunosuppressants or immunomodulation, are a long-established option for treating pemphigus diseases.

The programme of rituximab (RTX) treatment of severe immunosuppression-resistant pemphigus financed by a governmental agency functioned in Poland in 2018–2019. People eligible for this program were patients aged 18+ without an active infectious disease suffering from severe pemphigus resistant to immunosuppressive treatment as a principal indication. Main contraindications to the participation in the program included: age under 18, pregnancy, lactation period, hypersensitivity to the medicine’s active substance or excipient, uncontrolled severe infections, including active hepatitis C and HIV infection, NYHA class IV circulatory insufficiency and severe immunodeficiency.

RTX is a chimeric monoclonal human-mouse antibody that has been used worldwide for many years for the treatment of pemphigus [4, 5]. It selectively binds to transmembrane antigen CD20 expressed on the surface of B lymphocytes and absent on other cells. RTX causes the lysis of cells containing CD20 antigen as a result of mechanisms dependent on both the complement system, and associated with antibody-dependent cellular cytotoxicity, and as a result of apoptosis.

Each pemphigus patient eligible for the participation in the programme underwent a whole set of tests, including QuantiFERON-TB Gold Plus (QFT-Plus) test used to exclude latent tuberculosis infection. This test is based on the evaluation of the quantity of interferon-γ (IFN-γ) produced by T lymphocytes as a result of their stimulation with ESAT-6 and CFP 10 antigens by ELISA method [6].

Aim

There has been made a comparative assessment of the clinical usefulness of QFT-Plus test measuring in vitro the secretion of interferon γ (IGRA) in native pemphigus patients examined with this test prior to the intended RTX therapy.

Material and methods

Eighteen pemphigus patients (the study group) were selected in the Autoimmune Blistering Dermatoses Section, Department of Dermatology, the Karol Marcinkowski Poznan University of Medical Sciences for QFT-Plus (Qiagen, Hilden, Germany) test prior to the intended RTX treatment. There were 15 pemphigus vulgaris patients (11 females and 4 males) and 3 pemphigus foliaceus patients (1 female and 2 males). The age range of the patients was 30–84 years. The control group included 90 hospital employees tested with QFT-Plus in the Occupational Medicine Outpatient Clinic due to contact with a cleaner with diagnosed active pulmonary tuberculosis.

Statistical analysis

The statistical analysis of positive QFT-Plus test results was done with Fisher’s exact test using Statistica, version 13 (StatSoft, Inc, Tulsa, OK, USA). A p < 0.05 was arbitrarily considered statistically significant.

Results

In 6 of 18 (33.33%) pemphigus patients the test result was positive, in 1 the result was indefinite, and in 1 initially indefinite, and then negative. In 26 of 90 (28.88%) hospital employees the test result was positive, in none of them the result was indefinite. The statistical analysis of positive QFT-Plus test results with Fisher’s exact test revealed no statistically significant difference between both groups (p = 0.5577) (Table 1).

Table 1

QuantiFERON-TB Gold Plus test results and their statistical analysis in examined groups

QuantiFERON-TB Gold Plus test resultsExamined groupsStatistical analysis of positive results
Pemphigus patients selected for rituximab (n = 18)Hospital employees (n = 90)
Positive626Fisher’s exact test p = 0.5577
Indefinite10
Initially indefinite then negative10
Negative1064

[i] n – number of individuals.

In 1 patient, with recurring mucocutaneous pemphigus vulgaris (mcPV) (Figure 1) previously treated with traditional immunosuppression, the QFT-Plus test result was positive and lung lesions were shown in chest X-ray, in the form of a 7 mm oval shade in the left central lung area, and an oval shade of 8 mm diameter in the left lung apex. Fibrotic and tumour lesions in the left lung were shown in lung computed tomography (CT). The patient was not treated with RTX. She was referred for further treatment at the Outpatient Pulmonary Clinic.

Figure 1

A middle-aged female with relapsing mucocutaneous pemphigus vulgaris having lesions around natural body orifices including erosions on the vulva (A). Direct immunofluorescence of perilesional skin visualized with the blue light-emitting diode technology-operated microscopy showed pemphigus IgG4(++) intercellular deposits having dew drops on spider web appearance (original objective magnification 40×) (B) and multi-analyte ELISA revealed elevated levels of serum anti-DSG1 (of 1.68), anti-DSG3 (of 5.2) and anti-envoplakin (of 1.86) IgG antibodies (cut-off ratio = 1)

/f/fulltexts/PDIA/45075/PDIA-38-45075-g001_min.jpg

Among the patients with originally non-negative test result, 1 patient with a positive result and with persistent mcPV coexisting with idiopathic thrombocytopenic purpura, after preventive administration of isoniazid + rifampicin for 6 months by the pulmonologist, was treated with RTX which resulted in normalisation of the thrombocytes count and temporary healing of mucosal lesions. The patient’s chest X-ray performed before and after chemo-prophylactic treatment has shown no abnormalities. The patient did not report any problems with the pulmonary system, in the form of dyspnoea or cough. In the remaining 7 patients having initially non-negative results, an initial decision was to refrain from RTX treatment.

All persons in the control group of the medical staff, both with the positive and the negative result of QFT-Plus, had a comprehensive medical history check with regard to the manifestations of active tuberculosis done and chest X-ray performed. Persons with a positive QFT-Plus result underwent additional pulmonary consultations. None of the persons reported subfebrile conditions, night sweat, cough, or fatigue. In none of the patients, deviations in chest X-ray view were shown. Those persons were not administered preventive pharmacotherapy after the pulmonary consultation.

Discussion

Among many contagious diseases, tuberculosis still remains one of the most frequent causes of sicknesses and deaths in the world [6]. It is estimated that one third of global population is infected with Mycobacterium tuberculosis, and most of the cases have the form of the latent tuberculosis infection. Most of the reported tuberculosis cases in Europe come from Romania, Poland, and the United Kingdom. Nowadays, humanity faces the challenge of drug resistant tuberculosis [7].

The described risk factors for the Mycobacterium tuberculosis infection being transformed into an active disease include, among other things, immunosuppressive treatment and systemic glucocorticosteroids (GCS) therapy [8]. Chronic GCS therapy increases the risk of primary infection with tuberculosis mycobacterium and reactivation of latent tuberculosis [9]. Usually, the course of tuberculosis infection in those patients is more severe than in the general population, taking even the form of miliary tuberculosis [9]. GCS medications inhibit immune response of both T- and B-cells. They decrease the level of cytokines: Interleukin (IL) 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-8 and IFN-γ. They reduce proliferation of T lymphocytes, and induce their apoptosis, reduce the production of antibodies by B lymphocytes. Other immunosuppressive therapies increasing the risk of tuberculosis infection include: azathioprine, dose ≥ 2 mg/kg/day, methotrexate, dose ≥ 25 mg/week, anti-TNF-α [9].

Chan and Yosipovitch [10] established that taking systemic GCS even in relatively low oral doses, by patients with dermatoses (pemphigus diseases, dermatomyositis) increases the probability of reactivation of latent tuberculosis or primary infection with tuberculosis. Therefore, all dermatological patients undergoing chronic treatment with GCS medications should undergo periodic screening tests for tuberculosis infection.

In this study the statistical analysis has not demonstrated any significant difference in positive results between pemphigus patients and medical staff members, which may indicate that the immunosuppressants used in patients and their autoimmune disease did not increase the probability of tuberculosis incidence. Both in the group of patients with pemphigus and in the group of hospital staff, the percentage of persons with positive QFT-Plus results was around 30%. Similar results were obtained in the doctoral thesis by Gruszczyński, in persons with other pulmonary disease than tuberculosis; QUANTIFERON-TB GOLD IN TUBE result was positive in 29% of persons [11]. In our study, QFT-Plus test reveals significant exposure of the native population to the Mycobacterium tuberculosis infection, regardless of the pemphigus autoimmunity, and its result may be the starting point for detection of patients requiring pharmaceutical prophylaxis against tuberculosis prior to the application of RTX combined with GCS.

As biological treatment with tumor necrosis factor α (TNF-α) inhibitors usually causes activation of the latent form of tuberculosis (transition from latent to active form), candidates for biological treatment are diagnosed for mycobacterium infection, and treated, even for latent forms of the disease, in order to prevent the development of active tuberculosis. However, despite the negative test results of the presence of tuberculosis mycobacterium infection before the treatment, the patients may develop tuberculosis. Therefore, it seems relevant to repeat the tests in patients during the treatment. In the prospective study the data of 70 patients with rheumatic diseases (33 with rheumatoid arthritis, 33 with spondyloarthritis and 4 with other diagnosis) were analysed, in which, before the inclusion of medication from the group of TNF-α inhibitors, the tests for tuberculosis infection were negative (chest X-ray, IGRA tests and tuberculin sensitivity test). For a year the patients used different TNF-α inhibitors: adalimumab, etanercept, infliximab, golimumab, and certolizumab. After that period screening tests for tuberculosis infection were performed again. Positive results were obtained in 20 (29%) patients. The tuberculin sensitivity test was positive in 9 (10%) patients, T-SPOT.TB test was positive in 7 (10%) patients, and QFT-GIT test was positive in 5 (7%) patients. Only in 1 patient two tests gave positive results. In 40% of patients with the conversion of the tuberculosis test it was decided that a prophylactic treatment with anti-mycobacterium medication (isoniazid) should be used. During the follow-up period, lasting on average 27 ±12 months, none of the patients has developed an active form of tuberculosis [12].

In case of rheumatoid arthritis treatment with RTX (2 × 1000 mg), the studies confirmed the occurrence of severe infections in comparison to persons receiving placebo, however, the increased frequency of tuberculosis incidence was not proven [13, 14]. Alkadi et al. studied the influence of RTX on new tuberculosis infection and reactivation of latent tuberculosis in patients treated with RTX due to rheumatoid arthritis. The authors considered the screening test for tuberculosis prior to the inclusion of rituximab treatment pointless as the immune system uses cellular immunity to fight tuberculosis, whereas rituximab disables humoral immunity [15]. However, due to our patients’ prior therapy with high doses of GCS before administering RTX, and the necessity to use GCS at the maintenance doses after RTX treatment as the response to of RTX may be delayed for months [16], the screening tests for tuberculosis seem to be fully justified.

Acknowledgments

A part of this study was presented at the Congress of the Youth Forum Section of the Polish Dermatological Society (24-25.10.2019, Lodz, Poland) and published as an abstract in Polish: Bartkiewicz P, Jałowska M, Gornowicz-Porowska J, Bowszyc-Dmochowska M, Seraszek-Jaros A, Kaczmarek E, Dmochowski M. Ocena porównawcza przydatności badania przesiewowego w kierunku gruźlicy testem in vitro mierzącym wydzielanie interferonu gamma u rodzimych chorych z pęcherzycą kwalifikowanych do leczenia rytuksymabem. Forum Dermatologicum 2019; 5: 138. This work was also undertaken in conjunction with activities of the European Reference Network-Skin.

Conflict of interest

The authors declare no conflict of interest.

References

1 

Dmochowski M , author. Naturalne otwory ciała i błony śluzowe w pęcherzycy zwykłej. Dermatol Klin. 2007. 9:p. 124–31

2 

Dmochowski M, Gornowicz-Porowska J, Bowszyc-Dmochowska M , authors. Dew drops on spider web appearance: a newly named pattern of IgG4 deposition in pemphigus with direct immunofluorescence. Adv Dermatol Allergol. 2017. 24:p. 1–4

3 

Gornowicz-Porowska J, Bowszyc-Dmochowska M, Raptis-Bolwach M, et al. , authors. Blue light-emitting diode technology-operated microscopy is preferable to both short arc mercury lamp-operated microscopy and laser scanning confocal microscopy for direct immunofluorescence images evaluation in routinely diagnosing subepidermal autoimmune blistering diseases. Microsc Res Tech. 2019. 82:p. 1735–40

4 

Frampton JE , author. Rituximab: a review in pemphigus vulgaris. Am J Clin Dermatol. 2020. 21:p. 149–56

5 

Mohamad AF, Iversen L, Bech R , authors. Pemphigus vulgaris: short time to relapse in patients treated in a Danish tertiary referral center. Front Med. 2019. 6:p. 259

6 

Borkowska D, Radzikowska E, Załęska J, et al. , authors. Interferon-gamma release assays in the diagnosis of latent tuberculosis infection in clinical situations. Pneumonol Alergol Pol. 2014. 81:p. 39–45

7 

Gupta-Wright A, Tomlinson GS, Rangaka MX, Fletcher HA , authors. World TB Day 2018: the challenge of drug resistant tuberculosis. F1000Research. 2018. 7:p. 217

8 

Jick SS, Lieberman ES, Rahman MU, et al. , authors. Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum. 2006. 55:p. 19–26

9 

Butt G, Faria A, Ijaz H , authors. Pulmonary tuberculosis in dermatological patients on high-dose, long-term steroid therapy. J Pakistan Assoc Dermatol. 2015. 15:p. 119–31

10 

Chan YC, Yosipovitch G , authors. Suggested guidelines for screening and management of tuberculosis in patients taking oral glucocorticoids – an important but often neglected issue. J Am Acad Dermatol. 2003. 49:p. 91–5

11 

Gruszczyński P , author. Evaluation of significance of QUANTIFERON-TB GOLD IN TUBE diagnostic test for identifying Mycobacterium tuberculosis pulmonary infections/Ocena znaczenia testu diagnostycznego QUANTIFERON-TB GOLD IN TUBE w rozpoznawaniu zakażeń płucnych Mycobacterium tuberculosis. 2011. Poznan: Poznan University of Medical Sciences; p. 1–93. Ph.D. thesis.

12 

Hatzara C, Hadziyannis E, Kandili A, et al. , authors. Frequent conversion of tuberculosis screening tests during anti-tumour necrosis factor therapy in patients with rheumatic diseases. Ann Rheum Dis. 2015. 74:p. 1848–53

13 

Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. , authors. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006. 54:p. 1390–400

14 

Cohen SB, Emery P, Greenwald MW, et al. , authors. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006. 54:p. 2793–806

15 

Alkadi A, Alduaiji N, Alrehaily A , authors. Risk of tuberculosis reactivation with rituximab therapy. Int J Health Sci. 2017. 11:p. 41–4

16 

Bartkiewicz P, Gornowicz-Porowska J, Bowszyc-Dmochow-ska M, et al. , authors. No response to rituximab in a case of mucosal-dominant to and fro mucocutaneous shifting pemphigus vulgaris previously treated with a range of more traditional anti-pemphigus therapies: clinical hint relevant to pemphigus pathogenesis. PPP 2016 - Pathogenesis of Pemphigus and Pemphigoid, The Open Blister/Mind Meeting. Satellite Symposium to the 46th Annual ESDR Meeting; 5-7 September 2016; Munich, Germany. p. 39Program and abstracts book.

Copyright: © 2021 Termedia Sp. z o. o. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
 
Quick links
© 2021 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe