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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 27  |  Issue : 2  |  Page : 219-222

A review on newer therapeutic modalities for immune-mediated oral mucosal disorders: A start from the dead end


Department of Oral Medicine and Radiology, The Oxford Dental College and Hospital, Bengaluru, Karnataka, India

Date of Submission06-Aug-2014
Date of Acceptance19-Oct-2015
Date of Web Publication21-Nov-2015

Correspondence Address:
Thanuja Raju Jacob
Department of Oral Medicine and Radiology, The Oxford Dental College and Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-1363.170141

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   Abstract 

The immune-mediated oral mucosal lesions pose a challenge to the oral physicians owing to their preplexing diagnosis and management. Steroids are the first line of treatment for these diseases, but they have their limitations. With improved advancements and research being done to understand the pathogenesis behind these diseases, newer modalities of treatment are being introduced as a part of the treatment protocol for long-term remission. Some of the promising ones are plasmapheresis, extracorporeal photopheresis, intravenous immunoglobulin therapy, and rituximab. Their therapeautic efficiency is yet to be established with randomized controlled trials.The purpose of this article is to focus on these novel therapies in the management of immune-mediated oral mucosal lesions and their feasibility in the Indian scenario. A PubMed search was done using the keywords plasmapheresis, extracorporeal photopheresis, immunoadsorption, rituximab, and immune-mediated oral mucosal disorders, which revealed 10,539 articles on plasmapheresis, 925 articles on extracorporeal photopheresis, 76,100 articles on immunoglobulin therapy, and 12,402 articles on rituximab. After a detailed screening, seven articles on plasmapheresis published from the year 2002 to 2012, three articles on extracorporeal photopheresis published from the year 2008 to 2011, three articles on immunoglobulin therapy published from the year 2005 to 2011, and two articles on rituximab published from the year 2006 to 2011 were identified based on their usage in immune-mediated oral mucosal disorders for inclusion in this review.

Keywords: Extracorporeal photopheresis, immune-mediated oral mucosal lesions, immunoglobulin therapy, plasmapheresis, rituximab


How to cite this article:
Patil BA, Pai A, Jacob TR. A review on newer therapeutic modalities for immune-mediated oral mucosal disorders: A start from the dead end. J Indian Acad Oral Med Radiol 2015;27:219-22

How to cite this URL:
Patil BA, Pai A, Jacob TR. A review on newer therapeutic modalities for immune-mediated oral mucosal disorders: A start from the dead end. J Indian Acad Oral Med Radiol [serial online] 2015 [cited 2020 Jul 11];27:219-22. Available from: http://www.jiaomr.in/text.asp?2015/27/2/219/170141


   Introduction Top


Immune-mediated mucocutaneous lesions are invariably associated with intense pain and discomfort. Most often, the compounding factors for the morbidities associated with these conditions are the absence of a definitive diagnosis and unfamiliarity of effective therapeutics. Examples of such immune-mediated oral conditions we come across in our daily practice are pemphigus vulgaris, pemphigoid, systemic lupus erythematosus, oral lichen planus, and Behcet's disease. While corticosteroids remain the main stay of treatment for most of the immune-mediated oral mucosal diseases, the morbidity associated with them is significant. With improved understanding of the pathogenesis of immune-mediated oral mucosal lesions, novel therapies such as plasmapheresis, immunoadsorption, extracorporeal photopheresis, and rituximab have been used for the rapid control of the disease and sustained remission. This article aims to highlight the use, technical aspects, complications, economical considerations, and their availability in India, in order to make the oral physicians aware of the wide option of treatment modalities for immune-mediated oral mucosal lesions and, thus, improve the quality of life of the patients.


   Plasmapheresis Top


Cotterill, in the year 1978, described the first therapeutic implications of plasmapheresis in pemphigus vulgaris. In plasmapheresis, blood is continuously removed from the patient and separated into cellular components and plasma. Replacement fluid, such as albumin, along with cellular components is then returned to the patient. [1],[2],[3]

Technical considerations

Plasma and blood cells are separated by centrifugation or membrane filtration:

  1. Centrifugation technique: The use of centrifugal force causes the whole blood to separate into various components according to their specific gravity. Centrifugation can be intermittent or continuous.
  2. Membrane filtration technique: In this technique, the patient's blood is pumped through a membrane with pores of 0.2-0.6 µm diameter, which is sufficient to allow passage of plasma while retaining the cells. Several membrane plasma separators are commercially available (e.g., Plasmaflo from Asahi Medical Co., Ltd., Tokyo, Japan; Plasmax, CPS-10 from Baxter, Deerfield, IL, USA; Plasmaflux from Fresenius Medical Care AG, Bad Homburg, Germany; Prisma TPE 2000 from Hospal, Lyon, France). [1]
Anticoagulation

Both centrifugation and membrane plasmapheresis require anticoagulation. Citrate is used for centrifugation, while standard unfractionated heparin is used for membrane plasmapheresis. Also, a replacement fluid is added to replace the volume of plasma which is removed in plasmapheresis. The replacement fluids include fresh frozen plasma, 5% albumin or other plasma derivatives and crystalloids.

Selective plasmapheresis techniques and immunoadsorption

Selective plasmapheresis is the selective removal of immunoglobulin and other specific molecules by cooling the plasma (i.e., cryofiltration), passing it through membranes of different pore diameters, or by perfusion through adsorbent columns. Immunoadsorption, also commonly referred to as protein immunoadsorption therapy, mainly consists of a highly purified protein A which is bonded to a silica matrix. The patient's plasma is collected in apheresis procedure by means of utilizing adsorptive forces and then passed over the column. Circulating immune complexes and IgG bind to protein A, and hence, they are selectively removed from plasma.The filtered plasma is then administered back to the patient. [4],[5],[6],[7]

Complications

Though plasmapheresis is relatively safe, there is arisk of infections associated with it. Minor adverse effects that are encountered are hypertension, thrombocytopenia, pulmonary edema, and hypocalcemia.


   Extracorporeal Photopheresis Top


Extracorporeal photopheresis is also called as extracorporeal photochemotherapy and extracorporeal photoimmunotherapy. Extracorporeal photopheresis is now being performed in over 200 centers worldwide. [8]

Technique

The technique mainly comprises three stages which are leukapheresis, photoactivation, and reinfusion of treated blood cells back into the patient. The first step which is leukapheresis involves the collection of white blood cells (WBCs) after establishing a peripheral intravenous or central venous access. The WBCs are mixed with heparin after collection from the patient, which makes the cells more susceptible to apoptosis after irradiation with UV-A. The selected WBCs are then subjected to photoactivation, which is simultaneously exposing the WBCs to ultraviolet radiation and a photosensitizer. The ultraviolet radiation (UV-A) activates the photosensitizer causing the cross-linkage of DNA. 8-methoxypsoralen (8-MOP) is the photosensitizer used in extracorporeal photopheresis. There is an average UV-A exposure of 1.5-2 J/cm 2 per lymphocyte. The treated WBC mixture is then infused back into the patient. [9]

Contraindications and complications

Though a well-tolerated procedure, some of the absolute contraindications include pregnancy, photosensitive comorbidities, anemia, and history of heparin-induced thrombocytopenia. The known adverse effects include low-grade anemia, tachycardia, thrombocytopenia, and transient hypotension. [10]


   Intravenous Immunoglobulin Therapy Top


Intravenous immunoglobulin (IVIG) is a solution of highly purified IgG, derived from large pools of human plasma that contain antibodies against a broad spectrum of bacterial and viral agents. It is used in a wide range of immune-mediated and inflammatory disorders. The dosage is 2 g/kg body weight/month and is used at a replacement dose of 200 mg/kg body weight thrice weekly. The goal is to provide immune-deficient patients with the protection that they need, allowing them to replace and maintain adequate antibody levels protecting them from infection.

Structure

IVIGs are basically proteins which form a Y-shaped structure. They can be divided into four main domains. The first domain is the variable (v) domain which mainly binds to the antigens and its actions are mediated by the variable regions F(ab′) 2 . The second and third domains consist of constant (c) whose main function is activation of compliment. The final domain consists of immunomodulatory substances which include the cytokine receptors, major histocompatibility complex (MHC) class II and stabilizing agents, and CD4. [9],[11]

Mechanism of action of IVIG

Immunomodulatory actions of IVIG include: [11]

  1. Action mediated by the F(ab′) 2 region: IVIG supresses the proliferation of antigen-specific T cells. It also contains important molecules such as tumor necrosis factor (TNF)-α, interleukin (IL)-1α, and interferon (IFN)-g. It neutralizes the antigens and super antigens without inducing cell apoptosis. They also help in modulating the compliment activation system and other idiopathic autoantibodies and inflammatory mediators such as the metalloproteinase and chemokines.
  2. Fc receptor-binding effects: The primary mechanism of action of immunoglobulin is blockade of Fc receptor. It facilitates signaling through blockage of FcR binding sites, which inhibits dendritic cell maturation at immunomodulatory doses.
  3. Compliment Fc binding: Main mechanism of the Fc-binding protein is to scavenge C3a and C5a.
Adverse effects of IVIG therapy

Post-infusion headache, malaise, arthralgia, and myalgia may be an inflammatory response indicating intolerance. Symptomatic pharmacologic (analgesics) and non-pharmacologic measures (rest, heating pad, etc.) can be administered. A short course of steroids may be necessary. Premedication before the next infusion is indicated and if the problems persist, a change in the product or route or administration should be considered. Urticaria may indicate intolerance to the product or a specific lot number of the product. [12]


   Rituximab Top


It is a chimeric monoclonal antibody developed by the IDEC Pharmaceuticals under the name IDEC-C2B8. [9]

Mechanism of action

It mainly acts against the protein CD20 found on the immune system B cells. Rituximab attaches to one of the sides of the B cells, forming a cap and drawing proteins to that particular site. It also mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, bullous skin disorders such as pemphigus and pemphigoid, type 1 diabetes mellitus, Sjogren's syndrome, and Graves' ophthalmopathy. [12]


   Cost and Availability Top


Even though these novel therapies are effective, considering their cost and availability in India, it is not feasible to administer them to all the patients who are suffering from immune-mediated oral mucosal conditions. Plasmapheresis is relatively affordable ranging between INR 10,000 and 15,000, which can be further reduced by replacement of fresh frozen plasma instead of albumin, in comparison with immunoadsorption which is much more expensive owing to the high cost of adsorbers. Four injections of rituximab or one cycle of IVIG costs approximately INR 1.2-1.5 lakhs in India. [1] The cost and availability of the various treatment modalities are enumerated in [Table 1].
Table 1: Cost and availability of the various treatment modalities

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   Conclusion Top


These novel therapies appear to be a useful adjunct compared to conventional therapies used in the treatment of immune-mediated oral mucosal lesion. However, more widespread application of prospective randomized controlled clinical trials is required to establish their efficacy and safety. With adequate awareness, resources, and funding, these novel therapies can be considered as a part of the treatment protocol for immune-mediated oral mucosal conditions in India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Ranugha PS, Kumari R, Kartha LB, Parameswaran S, Thappa DM. Therapeutic plasma exchangeas a crisis optionin severe pemphigus vulgaris. Indian J Dermatol Venereol Leprol 2012;78:508-10.  Back to cited text no. 1
[PUBMED]  Medknow Journal  
2.
Madore F. Plasmapheresis. Technical aspects and indications. Crit Care Clin 2002;18:375-92.  Back to cited text no. 2
    
3.
Sagi L, Baum S, Gendelman V, Trau H, Barzilai A. The role of therapeutic plasma exchange in pemphigus vulgaris. J Eur Acad Dermatol Venereol 2011;25:82-6.  Back to cited text no. 3
    
4.
Schmidt E, Klinker E, Opitz A, Herzog S, Sitaru C, Goebeler M, et al. Protein A immunoadsorption: A novel and effective adjuvant treatment for severe pemphigus. Br J Dermatol 2003;148:1222-9.  Back to cited text no. 4
    
5.
Lüftl M, Stauber A, Mainka A, Klingel R, Schuler G, Hertl M. Successful removal ofpathogenic autoantibodies in pemphigus by immunoadsorption with a tryptophan-linked polyvinylalcohol adsorber. Br J Dermatol 2003;149:598-605.  Back to cited text no. 5
    
6.
Frost N, Messer G, Fierlbeck G, Risler T, Lytton SD. Treatment of pemphigus vulgaris with protein A immunoadsorption: Case report of long-term history showing favorable outcome. Ann NY Acad Sci 2005;1051:591-6.  Back to cited text no. 6
    
7.
Shimanovich I, Herzog S, Schmidt E, Opitz A, Klinker E, Bröcker EB, et al. Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol 2006;31:768-74.  Back to cited text no. 7
    
8.
Chiesa-Fuxench ZC, González-Chávez J. Extracorporeal photopheresis: A review on the immunological aspects and clinical applications. P R Health Sci J 2010;29:337-47.  Back to cited text no. 8
    
9.
Gürcan HM, Ahmed AR. Current concepts in the treatment of epidermolysis bullosa acquisita. Expert Opin Pharmacother 2011;12:1259-68.  Back to cited text no. 9
    
10.
Saraceno R, Ruzzetti M, Lanti A, Marinacci M, Chimenti S. Therapeutic options in an immunocompromised patient with pemphigus vulgaris: Potential interest of plasmapheresis and extracorporeal photochemotherapy. Eur J Dermatol 2008;18:354-6.  Back to cited text no. 10
    
11.
Jolles S, Sewell WA, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol 2005;142:1-11.  Back to cited text no. 11
    
12.
Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 2006;355:1772-9.  Back to cited text no. 12
    



 
 
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