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Current status of clinical diagnosis and treatment of pemphigus (part two)

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3 Benign Mucous Membrane Pemphigoid

3.1 Clinical manifestations

  Conjunctival and oral mucosal damage accounted for 60% to 90%, patients with nasal, pharyngeal, genital and anal mucosa accounted for about 25%, skin involvement is rare, skin damage is very similar to the lesions of bullous pemphigoid, but the time is short, and the stenosis or adhesion caused by scar healing and scar formation is characteristic.

3.1.1 Eye damage

The eye is the only affected part, and the damage usually occurs asymmetrically. After 1 to 2 years, the contralateral eye mucosa is involved. There are symptoms of catarrhal conjunctivitis. Transparent blisters can be found and quickly ruptured. Subsequently, scar atrophy, conjunctival and bulbar conjunctiva adhesions, eye movement involvement, tendon varus leading to secondary corneal changes, corneal opacity, scar formation of the tarsal plate with mucosa, atrophy of the gland and blockage of the lacrimal duct, thus corneal dryness, discoloration and blinding ulcers are formed.

3.1.2 Mucosal damage

Multiple blisters quickly form painful erosions and the scars heal. If the damage occurs in the tongue ligament, the contracted scar can limit the movement of the tongue. Damage that occurs in soft palate, tonsil, and buccal mucosa may limit food intake. The genital area of the vulva can form a head adhesion, a vaginal stenosis, and the like.

3.1.3 Skin damage

The incidence of skin damage is only about 25%, the damage is a tension blisters, the blister wall is not easy to rupture, occurs on erythematous skin, one or more parts. Healed with atrophic scars. If bullae occur in the head, scarring hair loss may occur. Generalized lesions are extremely rare, and even if there are secondary scar formation.

Benign mucosal pemphigoid can occur repeatedly for several years without significant effect on general health. The faster the disease progresses, the worse the prognosis. Due to eating difficulties, malnutrition and cachexia may occur, and the incidence of blindness is approximately 20% to 60%. Although extremely rare, there have been reports of cancerous changes in the scars of the oral mucosa.

3.2 Laboratory examination

3.2.1Histopathology: typical epidermis blister, no spine release. Infiltration of inflammatory cells composed of lymphocytes, plasma cells, and eosinophils can be seen in the upper dermis. Subsequently, there were a large number of fibroblasts with superficial dermal fibrosis and vascular hyperplasia and scar contracture.

3.2.2 Immunofluorescence: direct immunofluorescence of skin mucosa to detect IgG and C3 deposition in the basement membrane zone, and IgA and C3 deposition were also observed. The homogenous linear deposition was almost the same as that in bullous pemphigoid. The positive rate of indirect immunofluorescence detection of anti-basal membrane circulating antibodies was <10%, and the titer was low. If the DIF is negative, the fresh tissue should be removed from the erythema around the lesion for repeated testing.

4 Pathogenesis of Pemphigus

In the plasma of patients with pemphigus, there is anti-Dsg3 and/or anti-Dsg1 IgG, and no anti-Dsg2 antibody exists. This autoreactive antibody binds to its corresponding antigen, leading to a series of clinical pemphigus. The emergence of performance. In the active phase of pemphigus vulgaris, the serum is mainly pathogenic IgG4 subclass and IgG1, while in the serum of patients with long-term remission, there are low-valency IgG1 subclasses, IgG4 and Dsg1 and Dsg13 on keratinocytes. The combination causes the loss of adhesion between cells, leading to the release of intercellular cells and the formation of blisters in the epidermis.

The antigen Dsg produced in the MMP autoimmune disease belongs to the transmembrane component of desmos, belonging to the cadherin superfamily in the adhesion molecule, whose gene is located at 18q12.1. Dsg is divided into three categories: Dsg1, Dsg2, and Dsg3. Among them, Dsg2 is expressed in all tissues with desmosome, including monolayer epithelial cells and myocardial tissue. Dsg1 and Dsg3 are mainly restricted to stratified squamous cells. Current studies have shown that Dsg1 and Dsg3 are target antigens of pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively. The relative molecular mass of Dsg3 is about 130 kD. which is mainly distributed on the surface of keratinocytes in the basal layer of the epidermis and the upper layer of the basal layer. The relative molecular mass of Dsg1 is about 160 kD, which is mainly distributed on the keratinocyte membrane in the upper layer of the epidermis, with the advantage of granular layer and subgranular layer expression. The Dsg3 and Dsg1 molecules, like other cadherin molecules, have five tandem repeats of approximately equal size extracellular domain (EC), each of which is approximately 100 amino acid residues in length, of which EC1 the region corresponds to the extracellular amino terminal residue and EC5 is at the carboxy terminus. The difference between Dsg1 and Dsg3 is mainly due to the homology of the 1 to 4 extracellular domains of Dsg1 and the homology of the 5 extracellular domains of Dsg3. Unlike classical cadherins, Dsg1 has a longer intracellular fragment, and the extracellular fragment of Dsg3 is slightly longer than Dsg1, but its intracellular domain is slightly shorter and has no glycine/serine-rich region.

In the five extracellular domains of the pemphigus antigen, EC1, EC2, and EC4 have relatively large homology and can be specifically recognized by the plasma of pemphigus patients. Therefore, these epitopes are called "an immune-dominant epitope, or a "pathogenic epitope," an antibody that specifically recognizes an epitope is called a "pathogenic antibody." The pemphigus antigen contains at least one "pathogenic epitope" in the EC1 -2 region, and antibodies against EC1 -2 are closely related to the pathogenesis of pemphigus. The recombinant protein expressed by the EC1 -2 and EC3 -4 gene sequences of Dsg3 only reacted with the plasma of pemphigus patients, and the response rates of the two were 57.9 % and 52.6%, respectively, and the bullous pemphigoid, system Lupus erythematosus and normal people do not respond. This indicates that EC1 -2 and EC3 -4 are antigen-specific and have a high affinity with pemphigus antibodies, thus providing a new approach for serological diagnosis and identification of pemphigus.

In Dsg1 and Dsg3, when either function is lost, the other can partially compensate for its function. This theory explains the tissue specificity of the loss of intercellular adhesion caused by autoantibodies in pemphigus patients. Because Dsg1 and Dsg3 have a certain distribution pattern, the difference in anti-Dsg antibodies also leads to differences in the clinical manifestations of pemphigus. By inserting the Dsg1 gene into Dsg3 knockout mice to form a transgenic mouse capable of expressing Dsg1, it was found that Dsg1 can compensate for partial Dsg3-mediated loss of intercellular adhesion function, which is confirmed genetically.

5 Treatment

Glucocorticoid is preferred for the treatment of pemphigus. Most scholars at home and abroad are empirical drugs. There are ethnic and regional differences in the choice of hormone dose. At present, the severity of the disease is not unified by using the scoring system. If the two are linked to the hormone dose and applied to the clinic, the treatment plan will be more reasonable. Determine the initial dose of hormone according to the ABSIS system: ABSIS skin severity score 10, give 30 ~ 40 mg / d, skin score of 10 ~ 50, 60 mg / d is appropriate, skin score > 50 points, give 80 mg /d. If the skin lesions are not controlled for 5 to 7 days, increase the dose by 50%. Reduced indications: Daily new blistering number <5, no new erythema; no obvious exudation of erosion surface; pemphigus antibody titer decreased earlier; ABSIS skin score decreased by more than 35%.

The long-term use of large doses of hormones can easily lead to many drug reactions. Therefore, the combination of immunosuppressive agents, including azathioprine, cyclophosphamide, mycophenolate mofetil, etc., is generally used to reduce the number of hormones and shorten the treatment time. At the same time, it can be combined with an immune-modulator (Amlalazine, etc.), plasma exchange method and in vitro. Photochemotherapy, etc. Randomized controlled observation of prednisone combined with mycophenolate mofetil, azathioprine and prednisone alone in the treatment of 42 cases of pemphigus, combined with the ABSIS system to assess the severity of the disease before and after treatment, the results show that the three treatment days The short-term efficacy and safety of acne are similar, but prednisone combined with mycophenolate mofetil reduces the dose of hormones most significantly. In recent years, some biological agents and treatments have become new choices for the treatment of pemphigus, such as rituximab, high-dose intravenous immunoglobulin (IVIG), immunosorbent assay, TNF-α antagonist and hematopoietic stem cell transplantation therapy.

 For the severe bullous disease such as pemphigus, detecting the Dsg ELISA index has certain guiding significance for judging its severity. However, if medical workers are to accurately grasp the changes in their condition, they also rely on an effective and widely recognized scoring system to provide a reliable clinical basis for the treatment and adjustment of pemphigus. At present, there are few clinical applications of ABSIS and PDAI. Both have their own advantages and disadvantages. If they can be combined, it is expected to improve the evaluation method. The correlation between the disease scoring system and antibody levels, and the number of hormones controlled by scoring will be important research topics. Many new drugs and treatments have emerged in recent years, and multi-center large-scale clinical trials are still needed to explore the best treatment options.

 

Reference

[1] Barnadas MA, Rubiales MV, Gich I, et al. Usefulness of specific anti-desmoglein 1 and 3 enzyme-linked immunoassay and indirect immunofluorescence in the evaluation of pemphigus activity [J]. Int J Dermatol, 2015, 54(11): 1261-1268.

[2] Daneshpazhooh M, Kamyab K, Kalantari MS, et al. Comparison of desmoglein 1 and 3 enzyme - linked immunosorbent assay and direct immunofluorescence for evaluation of immunological remission in pemphigus vulgaris [J]. Clinical & Experimental Dermatology, 2014, 39(1): 41-47.

[3] Nakahara T, Takagi A, Yamagami J, et al. High anti-desmoglein 3 antibody ELISA index and negative indirect immunofluorescence result in a patient with pemphigus vulgaris in remission: evaluation of the antibody profile by newly developed methods [J]. Jama Dermatology, 2014, 150(12): 1327-1330.

[4] Pfutze M, Niedermeier A, Eming R. Introducing a novel autoimmune bullous skin disorder intensity score ( ABSIS) in pemphigus [J]. Eur J Dermatol, 2007, 17(1): 4-11.

[5] Murrell DF, Dick S, Amagai M, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus [J]. J Am Acad Dermatol, 2008, 58(6): 1043-1046.

[7] Chams-Davatchi C, Rahbar Z, Daneshpazhooh M, et al. Pemphigus vulgaris activity score and assessment of convergent validity [J]. Acta Med Iran, 2013, 51(51): 224-230.

[8] Sebaratnam DF, Frew JW, Davatchi F, et al. Quality -of-Life Measurement in Blistering Diseases [J]. Dermatol Clin, 2012, 30(2): 301-307.

[9] Mahajan VK, Sharma NL, Sharma RC, et al. Twelve-year clinicotherapeutic experience in pemphigus: a retrospective study of 54 cases [J]. Int J Dermatol, 2005, 44(10): 821-827.

[10] Agarwal M, Walia R, Kochhar AM, et al. Pemphigus Area and Activity Score (PAAS) --a novel clinical scoring method for monitoring of pemphigus vulgaris patients [J]. Int J Dermatol, 1998, 37(2): 158-160.


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