Get Permission Hussain, Tiwary, and Singh: Role of intralesional platelet-rich plasma (PRP) therapy in the treatment of recalcitrant oral ulcers of pemphigus vulgaris


Introduction

Pemphigus Vulgaris (PV) is a chronic, recurrent, vesiculobullous disorder characterized by intraepithelial vesicles and/or bullae in the skin and mucous membranes. The mucosal dominant type of PV occurs due to auto-immune IgG antibody against Desmoglein-3 whereas both Desmoglein 1 & 3 are targeted in the mucocutaneous type of PV. 80-90% of patients with pemphigus vulgaris develop oral lesions and in 60% of cases, oral lesions are the first sign.1 The oral ulcers are highly debilitating for the patient and difficult to treat for dermatologists as compared to skin lesions. It has been observed that oral lesions tend to persist even after the skin lesions have subsided and a prolonged course of oral/topical/intralesional corticosteroids have to be given adding considerable side effects. Topical corticosteroids cause many complications like secondary fungal and bacterial infections and these erosions also disturb the day-to-day lifestyle of patients.

Autologous platelet-rich plasma (PRP) therapy contains a platelet-rich concentrate with a large number of growth factors like platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), epithelial cell growth factor (ECGF), insulin-like growth factor (IGF), fibronectin and vascular endothelial growth factor (VEGF)2 and has been used in the treatment of various non-healing ulcers like trophic ulcers, diabetic ulcers, neuropathic ulcers. 3 PRP promotes re-epithelialization by regulating the biological function of epidermal stem cells (ESCs). It significantly promotes the angiogenesis of wounded tissue and promotes wound contraction and stabilizes the collagen arrangement.4 PRP also stimulates the production of collagen and extracellular matrix. The wound healing property of PRP can be used to treat recalcitrant oral ulcers of pemphigus as it accelerates the healing process, prevents the patients from side effects of steroids, and reduces the pain and discomfort of the patients.

POLIS- Pemphigus Oral Lesion Intensity Score, is a Novel Scoring System for Assessment of Severity of Oral Lesions in Pemphigus Vulgaris.5 It evaluates 16 parameters of the disease and grades them as None (0), Mild (1), Moderate (2), Severe (3), Very severe (4). This scoring system has been used in the study to evaluate the baseline severity and monitor the response to I/L PRP therapy for recalcitrant oral ulcers in patients of PV.

Table 1

POLIS (Pemphigus oral lesion intensity score) 5

Items

None

Mild

Moderate

Severe

Very Severe

Number of relapse (s) of the disease

0

1

2

3

>4

Duration of oral erosions (present episode)

<1 Week

1 week- 3 months

3-6 months

6-12 months

>12 months

Number of relapse(s) of oral lesions

0

1

2

3

>4

Persistence of oral lesions after subsidence of cutaneous lesions

0

1-12 weeks

12-24 weeks

24-48 weeks

>48 weeks

Change in size of existing oral lesions in last one week

Reduce by >40%

Reduce by 30-39%

Reduce by 20-29%

Reduce by 10-19%

Reduce up to 9%

Number of new oral erosions in last one week

0

1-3

4-6

7-9

>10

Difficulty in eating normal food

None

Mild

Moderate

Severe

Very severe

Difficulty in eating food according to their consistency

None

Mild

Moderate

Severe

Very severe

Difficulty in speaking

None

Mild

Moderate

Severe

Very severe

Difficulty in brushing

None

Mild

Moderate

Severe

Very severe

Difficulty in swallowing

None

Mild

Moderate

Severe

Very severe

Difficulty in mouth opening

None

Mild

Moderate

Severe

Very severe

Number of mucosae involved

0

1

2

3

>4

Number of sites involved in the oral cavity

0

1-2

3-5

6-8

9-11

Overall size of erosions/ulcers

0

Up to 10 cm

10-20 cm

20-30 cm

>30 cm

Depth of the erosions

0

1-10 superficial

11-20 superficial

21-30 superficial

>30 superficial/ any deep erosion

Total

Materials and Methods

The study was conducted at a tertiary health care center in northern India for 2 years. All histopathologically proven cases of Pemphigus Vulgaris with recalcitrant oral erosions were included in the study. All the patients were treated with various modalities such as pulse dosage of corticosteroids, variable tapering doses of oral corticosteroids, injection Rituximab, immuno-suppressants like- Azathioprine, and MMF. In all such cases in which the skin lesions had almost healed (approx. 90%) but the oral lesions were still persistent and the patients were on partial remission at minimal therapy i.e. Tab Prednisolone 10 mg or equivalent and half dose of adjuvant therapy, 5, 6 were labeled as cases of Pemphigus Vulgaris with recalcitrant oral ulcers and included in the study. No topical treatment for oral ulcers was given during the study.

The baseline POLIS score was calculated and labeled as POLIS-0. All the cases included in the study were off all topical treatments for oral erosions. The cases were subjected to autologous intra-lesional PRP weekly for 3 sessions. For PRP preparation, the first centrifugation spin was done at 2400 rpm for 10 minutes and the second spin was done at 3600 rpm for 5 minutes. 5ml of freshly prepared PRP was injected intralesionally along the margins and base of the oral erosions using a tuberculin syringe. Then, the POLIS score was calculated at each session i.e. POLIS-1 at 7 days, POLIS-2 at 14 days, and POLIS-3 at 21 days. The result was evaluated by a change in POLIS score after each session. Results were analyzed using statistical software SPSS version 26.0. We performed a test of normality on our data set to guarantee the accuracy of our ensuing statistical analysis. The Shapiro-Wilk test was chosen due to the small sample (<50) of participants.

Results & Observation

Out of the total 15 cases, 12 were female and 3 were male i.e. the gender ratio was 4:1 (Figure 1) (Table 2). The minimum and maximum age of the cases were 24 and 62 respectively (Table 2) with the mean age of participants being 40 ± 9.5 years.

Their disease duration ranged from 3 months to 2 years (Table 2).

11 patients had bilateral erosions in their buccal mucosa whereas 4 had unilateral erosions. Lips and gingiva were involved in 8 cases.

POLIS score ranges from 0 to 64.5 The mean of POLIS-0, POLIS-1, POLIS-2, and POLIS-3 for the oral lesions were 19, 16.06, 12.26, and 6.60, respectively. It was observed that there was a gradual reduction in POLIS score after subsequent PRP sessions (Figure 2) and pain during brushing, eating, swallowing, and talking reduced on the Likert scale after each PRP session. There was a significant difference between the mean POLIS-0 score and POLIS-3 score in the cases, from baseline and after 3 sessions of I/L PRP therapy, (p<0.001) (Figure 3).

No major side effects were seen in any patients. Pain, burning sensation, and swelling during injection were complained by a few patients that subsided after some time without any treatment.

The Shapiro-Wilk test yielded a p-value larger than 0.05, meaning that the normalcy null hypothesis could not be disproved.

These findings give our analysis and interpretations a strong basis. Our data's normal distribution improves the generalizability of our conclusions.

“The t-test was conducted to compare test scores between the POLIS-0 and the POLIS-3. There was a significant difference in test scores between the baseline POLIS-0 (M = 19.0, SD = 3.25) and the POLIS-3 (M = 6.60, SD = 2.97); t(13.33) = 14, p = <0.0001.” also showing the test is significant.

Table 2

Summary of the clinical characteristics of the PV patients

S.No.

Age

Gender

Disease Duration

Duration of oral lesions

Treatment received

POLIS-0

POLIS-1

POLIS-2

POLIS-3

1.

24

F

8 months

8 months

Pulse MP RTX AZT

18

16

10

04

2.

50

F

3 months

4 months

Pulse Dexa Pred. AZT

22

18

09

03

3.

37

M

14 months

5 months

Pulse MP Pred. RTX AZT

17

15

09

04

4.

62

F

8 months

7 months

Pred. RTX AZT

24

20

11

07

5.

43

M

5 months

4 months

Pred. RTX MMF

23

19

18

13

6.

32

F

18 months

7 months

Pulse MP RTX AZT

16

16

10

06

7.

46

F

6 months

8 months

Pulse Dexa Pred. AZT

22

17

09

04

8.

26

F

7 months

7 months

Pulse MP RTX Pred.

15

14

10

03

9.

41

F

24 months

4 months

Pulse MP RTX Pred. AZT

18

15

12

07

10.

35

M

8 months

5 months

Pulse Dexa Pred. AZT

20

16

14

08

11.

42

F

9 months

6 months

Pulse MP Pred. MMF

18

15

13

06

12.

38

F

15 months

7 months

Pred. RTX AZT

19

14

15

09

13.

47

F

10 months

3 months

Pulse MP RTX Pred. AZT

17

12

18

11

14.

45

F

5 months

4 months

Pred. AZT

13

16

11

05

15.

40

F

8 months

8 months

Oral MP Pred. RTX AZT

23

18

15

09

[i] Pulse MP/ Dexa- Injection Methylprednisolone Pulse 15 mg/kg or Inj. Dexamethasone100 mg monthly until disease control

[ii] RTX- Injection Rituximab 500mg weekly- 4 doses

[iii] Pred.- Tapering dose of Oral Prednisolone until disease remission on minimal therapy.

[iv] AZT- Oral Azathioprine; MMF- Mycophenolate Mofetil

Graph 1

Gender distribution of participants

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image1.png

Graph 2

Reduction of POLIS from baseline to POLIS-3 i.e. after 4 sessions of I/L PRP sessions.

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image2.png

Graph 3

Mean reduction in POLIS

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image3.png

Figure 1

A: Baseline; B: After 3 sessions of I/L PRP

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image4.png
Figure 2

A: Baseline; B: After 3 sessions of I/L PRP

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image5.png
Figure 3

A: Baseline; B: After 3 sessions of I/L PRP

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image6.png
Figure 4

A: Baseline; B: After 3 sessions of I/L PRP

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/a2ea110e-e285-41c8-864e-7445e940b520image7.png

Discussion

The mucosal erosions of Pemphigus Vulgaris are often the most difficult sites to treat for dermatologists as compared to the cutaneous lesions.7, 8 The oral lesions severely hamper the day-to-day activity of the patients like brushing, eating, swallowing, and talking which affects the dietary intake of the patients. Improper nutrition of the patients delays the recovery and adds on to the disease burden. 9 Oral, I/L and topical corticosteroids have to be continued for a longer duration even after the skin lesions have subsided. The use of ILS has been found to be effective in treating recalcitrant oral erosions, 7 nonetheless, few patients do not respond to it satisfactorily. In this pilot study, we aimed to evaluate the efficacy of I/L autologous PRP in recalcitrant oral lesions of PV. It was observed that POLIS (Pemphigus oral lesion intensity score) significantly reduced after 3 sessions of I/L PRP therapy. Poor quality of life has a significant impact on treatment outcome of pemphigus. 10 Also, the overall quality of life of cases improved significantly.

PRP contains a milieu of growth factors & cytokines that promotes the healing process and has been used in treatment of chronic, non-healing ulcers being an easy, day care and cost effective procedure.11 PRP has also been used in various oral surgeries & regenerative endodontic procedures due to its effect of wound healing and maintaining pulp vitality.12

I/L Rituximab and I/L methotrexate have been tried for recalcitrant oral lesions with variable results. Vinay et al13 reported 3 OPV patients who had inadequate response to ILS but responded to I/L Rituximab injection. Another study conducted by Hrin, Mathhew et al on cases of mucous membrane pemphigoid showed promising results with I/L methotrexate.14

Taking into account that POLIS measures all the aspects of oral lesions of PV like sites, extent, duration, pain and difficulty in day to day activities; gradual reduction of POLIS in the study participants can be attributed to wound healing properties of PRP where it has shown to accelerate soft tissue healing. Also, it prevents the patients from side effects of I/L and topical corticosteroids like soft tissue atrophy, 15 secondary bacterial and fungal infections like-candidiasis, granuloma formation & gingival neovascularization.16

In conclusion, in this preliminary study, there appears to be significant improvement in recalcitrant ulcers of oral PV with I/L PRP therapy and no major side effects apart from pain and discomfort during injection was seen in the study participants. However, because of small sample size, further large-scale studies are needed to confirm our findings and explore the potential of PRP therapy as an adjunct to management of mucosal lesions of PV. We suggest that I/L autologous PRP must be used for treatment of mucosal erosions of PV cases who develop side effects to I/L and topical corticosteroids and when I/L and oral corticosteroids are contraindicated.

Source of Funding

None.

Conflict of Interest

None.

References

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P Xu Y Wu L Zhou Z Yang X Zhang X Hu Platelet-rich plasma accelerates skin wound healing by promoting re-epithelializationBurns Trauma20208tkaa02810.1093/burnst/tkaa028PMCID

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AJ Kanwar D De Pemphigus in IndiaIndian J Dermatol Venereol Leprol201177443949

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A Baican R Chiorean DC Leucuta C Baican S Danescu D Ciuce Prediction of survival for patients with pemphigus vulgaris and pemphigus foliaceus: a retrospective cohort studyOrphanet J Rare Dis2015104810.1186/s13023-015-0263-4PMCID

11 

EJ Dougherty An evidence-based model comparing the cost-effectiveness of platelet-rich plasma gel to alternative therapies for patients with nonhealing diabetic foot ulcersAdv Skin Wound Care2008211256875

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N Meschi A B Castro K Vandamme M Quirynen P Lambrechts The impact of autologous platelet concentrates on endodontic healing: a systematic reviewPlatelets201627761333

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K Vinay A J Kanwar A Mittal S Dogra RW Minz T Hashimoto Intralesional rituximab in the treatment of refractory oral pemphigus vulgarisJAMA Dermatol2015151887882

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L Matthew JA Williams NL Bowers CS Ahn LC Strowd Methotrexate for oral mucous membrane (cicatricial) pemphigoid: experience at an academic dermatology outpatient clinic-HrinJ Am Acad Dermatol202287614313

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PD Reddy SB Zelicof C Ruotolo J Holder Interdigital neuroma. Local cutaneous changes after corticosteroid injectionClin Orthop Relat Res19953171857

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G Fortuna M D Mignogna Clinical guidelines for the use of adjuvant triamcinolone acetonide injections in oro-pharyngeal pemphigus vulgaris: the oral medicine point of viewJ Oral Pathol Med201140435960



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Received : 04-09-2024

Accepted : 11-10-2024


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https://doi.org/10.18231/j.ijced.2024.077


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