Comparative efficacy and safety of intralesional mitomycin C to intralesional interferon alpha-2b in the management of primary pterygium: A randomised controlled trial

INTRODUCTION

Pterygium is a proliferative, inflammatory and invasive ocular surface disease associated with exposure to ultraviolet (UV) light.^[1] It is characterised by a wing-shaped growth of limbal and conjunctiva tissue over the adjacent cornea.^[2] It is worldwide in distribution, with a global prevalence ranging between 0.7% and 33%.^[3-7] Increased incidence is noted in the tropics and equatorial zones between 30° north and south latitudes.^[8] Although poorly understood, its pathophysiology has been linked to signalling pathways activated by UV light exposure, which induce inflammatory mediators responsible for pterygium growth.^[1,9] Based on size measured from the limbus, pterygium may be graded as follows:^[10]

• Grade 1: 0–<2 mm from the limbus

• Grade 2: 2–4 mm from the limbus

• Grade 3: >4 mm from the limbus.

The current definitive management for pterygium is surgical excision, with adjuvant application of antimetabolites, or with conjunctival autograft or amniotic membrane grafting to prevent recurrence.^[11-14] Non-surgical treatment options for primary pterygium are currently limited. Beta-irradiation has also been successfully used in managing primary pterygium and as an adjuvant following the surgical excision of primary and recurrent pterygia.^[15,16] Adjuvant therapies, such as intralesional injections of mitomycin C (MMC), 5-FU alone or in combination with bevacizumab (Avastin), and others, have shown potential in inducing regression, improving surgical outcomes, and reducing recurrence post-surgery.^[17]

MMC, an antimetabolite, has demonstrated efficacy in reducing fibrovascular proliferation^[18] and Interferon (IFN) alpha-2b possesses both anti-inflammatory and anti-proliferative properties.^[19,20] Both agents have shown comparative efficacy and safety in the post-operative prevention of pterygium recurrence and in the management of ocular conjunctival intraepithelial neoplasia, amongst others.^[21,22] This study compares the short-term outcomes of these two agents, given as intralesional agents, in the non-surgical treatment of primary pterygium.

MATERIALS AND METHODS

The study was carried out at the eye clinic of the Lagos State University Teaching Hospital (LASUTH), Ikeja. It was a double-masked, randomised controlled study, conducted at LASUTH. The study adhered to ethical principles, with ethics approval granted by the LASUTH Research Ethics Committee. The trial was registered with the Pan African Clinical Trials Registry and assigned the trial number PACTR202302902720138. The study was conducted over 1 year, from February 2023 to May 2024. Written informed consent was obtained from all participants to participate in the study and for findings to be published.

One hundred consenting participants with grades 1 or 2 pterygium, who had no prior corneal trauma, ulcer or surgery, were enrolled in this study. Participants with inflamed or uninflamed pterygia were enrolled. Pregnant and lactating patients were excluded from the study.

Participants were randomised into two study groups as follows:

• Group A received 0.1 mL of 0.2 mg/mL of MMC

• Group B received 0.1 mL of 3 mIU of IFN alpha-2b.

RESULTS

There was a total of 100 participants (100 eyes) in this study at the beginning, 50 (50%) in each interventional group [Table 1].

Results in Table 1 showed a comparable gender and age distribution between the groups. Most participants (45.0%) had a tertiary education, level was comparable between the two groups (P = 0.294).

More than half of the participants, 56 (56.0%), were exposed to dust at work, 37 (66.07%) being exposed for >6 h per day. Over half of the participants, 57 (57.0%), spent more than 6 hours per day outdoors. Work dust exposure, duration of exposure and duration spent outdoors were not statistically significant risk factors for pterygium between the two groups (P = 0.227, 0.784 and 0.840, respectively) in this study.

Inflammation

In the IFN alpha-2b group, 9 participants (18.0%) had an inflamed pterygium at the start of the study, 3 months after, 2 participants (4.5%) had an inflamed pterygium. A statistically significant reduction in inflammation (P = 0.043) was observed at the end of the follow-up period in this study group [Tables 3 and 4].

In the MMC group, 8 participants (16.0%) had an inflamed pterygium at the start of the study, and 3 months after, only 1 participant (2.6%) had an inflamed pterygium. There was a statistically significant reduction in inflammation (P = 0.040) at the end of the follow-up period in this study group.

In the IFN alpha-2b group, mean IOP was 14.84 ± 2.4 mmHg at the start of the study and 13.80 ± 2.6 mmHg at 3 months post-injection. A statistically significant decrease in IOP (P = 0.020) was observed at the end of the follow-up period in this study group. In the MMC group, the mean IOP was 13.44 ± 2.4 at the start of the study and 13.26 ± 3.1 at 3 months. There was no statistically significant difference in IOP (P = 0.915) at the end of the follow-up period in this study group.

In the IFN alpha-2b group, the median ocular surface disease index (OSDI) score at the start of the study was 3, and at 3 months median OSDI score was 1. Although there was a statistically significant improvement in the OSDI score (P < 0.001), the median scores at the start and end of the study remained within normal ranges.

In the MMC group, the median OSDI score at the start was 4, and at 3 months, the median score was 1. This also showed a statistically significant improvement in the OSDI score (P < 0.001) but a normal median OSDI score at both times.

In the IFN alpha-2b group, median autorefraction was 1.00D before and 1.00D 3 months after the injection; this was not statistically significant (P = 0.659).

In the MMC group, median autorefraction was 0.75D before and 0.75D 3 months after the injection; this was not statistically significant (P = 0.666).

In the IFN alpha-2b group, keratometry values showed a median astigmatism of 0.50D before injection and 0.04D 3 months after the injection; this was a statistically significant decrease in corneal astigmatism (P < 0.001) after 3 months.

In the MMC group, keratometry values showed a median astigmatism of 0.65D before and 0.5D 3 months after the injection; this was not statistically significant (P = 0.299).

The median size of pterygium remained 1 mm at 3 months in the IFN alpha-2b group, not statistically significant (P = 0.344), while the median size in the MMC group was found to significantly reduce (P = 0.026) from a median of 1 mm to 0.5 mm at 3 months.

Tear breakup time significantly improved in both groups, from a median of 10.5 s to a median of 14.0 s (P < 0.001) in the IFN alpha-2b group and from a median of 9.0 s to a median of 14.0 s (P = 0.001) in the MMC group.

A comparison of outcomes (grade, vascularity, inflammation, IOP, OSDI score, autorefraction, keratometry values and tear breakup time) between the two study groups at the conclusion of data collection shows that there is no statistically significant difference in these outcomes between the two groups.

Figure 1 is a box plot comparing the median size of pterygium at 3 months post-injection in both groups. There is a statistically significant difference between the two groups (P = 0.041), with the median size in the MMC group being smaller post-injection than in the IFN alpha-2b group.

Close

Figure 1:

Median comparison of size of pterygium at 3 months post-injection. Mann-Whitney U-test = 2.039, P = 0.041*.

Export to PPT

There were more side effects in the MMC study group (46.0%) than in the IFN alpha-2b group (8.0%) (P < 0.001), as seen in Figure 2. Figures 3-5 are all images of eyes, in which sub [Figures 3a, 4a and 5a] show eyes before respective injection while sub [Figures 3b, 4b and 5b] show eyes after 3 months post respective injections.

Close

Figure 2:

Overall occurrence of side effects among participants. χ2 = 18.315; P < 0.001*

Export to PPT

Close

Figure 3:

(a) Before mitomycin C (MMC) injection (b) 3 months after MMC injection reduced vascularity and inflammation.

Export to PPT

Close

Figure 4:

(a) Before mitomycin C (MMC) injection (b) 3 months after MMC injection regression in size of pterygium.

Export to PPT

Close

Figure 5:

(a) Before interferon (IFN) alpha-2b injection (b) 3 months after IFN alpha-2b injection reduced vascularity and inflammation.

Export to PPT

Table 5 shows the side effects of the intralesional injections. Pain was the only side effect seen more significantly in both groups; the MMC group, however, had participants with photophobia and itching.

Table 5: Types of side effects among participants.

Parameters	Interferon alpha-2B (n=4)	Mitomycin C (n=23)	Chi-square	P-value
Type of side effect
Pain	4 (100.0)	15 (65.2)	3.230	0.038*
Photophobia	0 (0.0)	7 (30.4)
Itching	0 (0.0)	1 (4.3)

*Values in bold indicate values of statistical significance, with P value set at <0.05, Values in parenthesis indicate percentages unless otherwise stated.

DISCUSSION

Most participants in this study had a tertiary level of education, which may have positively influenced their willingness to try intralesional injections as a less invasive option to surgery, due to cosmetic concerns and awareness of the risk of recurrence post-surgery. Over half of the participants spent more than 6-h outdoors daily, increasing their risk of developing pterygium. This finding correlates with those of Anbesse et al.,^[6] Liu et al.,^[8] and Viso et al.,^[24] who have also identified cumulative UV light exposure from outdoor work as a known risk factor for pterygium development. In this study, the mean age of participants was comparable between both groups (P = 0.902). The mean age was approximately 48.48 ± 9.1 years for the IFN alpha-2b group and 48.22 ± 11.9 years for the MMC group, respectively. This similarity in age distribution might be related to the average workforce age group in the local area around the study centre. Being in an urban and densely populated area, the study participants may have been exposed to urban particulate matter due to pollution, which is a known risk factor for ocular surface diseases. Presbyopia in this age range may have also prompted more visits to the emergency triage clinic from which participants were recruited. Interestingly, this contrasts slightly with previous studies on the use of intralesional IFN alpha-2b by Daryabari et al.^[25] and by Mohammadi et al.^[26] where the mean ages were 42.11 years and 40.7 ± 13.8 years in the primary pterygium group, and with a study on the use of intralesional MMC for management of primary pterygium by Davari et al.^[17] where the mean age was 41.50 years. Both groups had a nearly equal gender distribution (P = 0.689), comparable to that of Mohammadi et al.^[26] and Davari et al.^[17] Daryabari et al.^[25] However, their trial of intralesional IFN alpha-2b had more male than female participants, which may be due to variations in healthcare access and awareness influencing recruitment at the study centre.

The most frequently recorded symptoms before treatment in this study were grittiness and redness in both arms. Other pre-treatment symptoms included tearing and burning/peppery sensations. Following injection, these symptoms significantly reduced (P < 0.001) in both arms of the study as follow-up progressed. There was an initial worsening of symptoms on the 1^st-day post-injection in both study arms, probably due to localised irritation and inflammation from the trauma of the injections. This had largely subsided in the IFN-alpha-2 b group by the 2^nd week of follow-up. The MMC study arm, however, recorded a sustained relative worsening of symptoms, especially redness, likely due to localised toxicity of MMC on the ocular surface. The gradual dissolution of MMC from the ocular surface and clearance in tears over the course of follow-up, however, resulted in a comparable outcome at 3 months. Davari et al found irritation accompanied by mild conjunctival swelling, hyperemia and tearing in 15% of their study patients within 1-3 days of the injection, these resolved with use of topical steroids and was absent at 6 months follow-up.^[17] In another study by Donnenfeld et al.^[27] Using 0.1 mL of 0.15 mg of MMC subconjunctival injection before pterygium excision, there was less hyperaemia at 1-month post-injection. In contrast, Mohammadi et al.^[26] using IFN alpha-2b found no significant difference in symptoms, congestion and photophobia, at the end of their study, this may be due to a difference in the tools of measurement of the efficacy in their study.

In this study, although the pterygium grade did not significantly improve in either of the study groups (P = 0.797 and 0.973, respectively), the vascularity and size of pterygium improved significantly in the MMC group (P = 0.026). The intralesional application of MMC brings it in direct contact with the pterygium tissue bed, where it promotes apoptosis and retards angiogenesis and fibroblast proliferation. Davari et al.^[17] Also recorded a similar clinically significant decrease in size and vascularity 6 months after a 0.1 mL subconjunctival injection of MMC. There was also reduced vascularity in the study by Donnenfeld et al.^[27] using 0.1 mL of 0.15 mg of MMC subconjunctival injection. The IFN alpha-2b group, despite receiving an equal volume of injection and the same route of administration, did not, however, show any significant decrease in the size or vascularity of the pterygium. Intralesional IFN alpha-2b eliminated OSSN in 13 of the 15 eyes treated by Karp et al.,^[28,29] with patients having an average of 6 injections before resolution over 55 months, our study did not find IFN alpha-2b effective as an intralesional agent for the management of primary pterygium, which is comparable to studies on intralesional IFN alpha-2b for primary and recurrent pterygium done by Mohammadi et al.^[26] and Daryabari et al.^[25] OSSN and pterygium share the same pathological features, including UV exposure as a risk factor, but their underlying pathology differs significantly. OSSN involves neoplastic change, while pterygium is primarily degenerative and inflammatory. This difference in the pathology of both conditions, along with a cumulative dose-dependent effect in the case of OSSN may account for the lack of efficacy in the management of pterygium.

Spherical equivalent using autorefraction values did not improve in either the IFN alpha-2b arm (P = 0.659) or the MMC arm (P = 0.666) of the study at 3 months. This is comparable to the findings of Daryabari et al.^[25] where no statistically significant improvement was found in refraction at either 3 months or 6 months following intralesional IFN-alpha-2 b. In contrast, Davari et al.^[17] In their study on the use of subconjunctival MMC, they found a statistically significant difference in refraction values at the end of their study. This contrast in the MMC treatment group may be due to the longer follow-up period of 12 months in Davari et al.^[17]

Mean keratometry values reduced significantly in the IFN alpha-2b arm 3 months post-injection (P < 0.001), but there was no statistically significant difference in the MMC arm 3 months post-injection (P = 0.299). On comparison of outcomes at 3 months in both groups, there was no statistically significant difference in keratometry values between both arms (P = 0.104). The lack of a significant difference in the MMC arm contrasts with the finding of significant improvement in keratometry value by Davari et al.^[17] This may be due to the longer follow-up period in the latter study. Our findings in the IFN arm of this study are, however, like the findings of Daryabari et al.^[25]

Side effects in this study were generally mild, with 8.0% of participants in the IFN alpha-2b arm reporting pain on the 1^st post-injection day, which resolved without any systemic or topical analgesic or anti-inflammatory. No participants in our study had constitutional symptoms following the injection of IFN alpha-2b; this is unlike with 5 out of 15 patients who had constitutional symptoms following perilesional injections of IFN alpha-2b in the management of OSSN by Karp et al.^[29] This difference may be due to the single dosing and localised application reducing systemic absorption in our study. More than half of the participants in the MMC arm had pain, which also resolved over time with no intervention. Other side effects in the MMC arm included photophobia and itching, both of which improved over the follow-up period. This was comparable to previous studies on the use of intralesional injections, including low-dose mitomycin C, in the management of primary and recurrent pterygium.^[17,25]

Low-dose MMC (0.02 mg, i.e., 0.1 mL of 0.2 mg/mL) was safe and had a more favourable outcome in terms of reducing the size of primary pterygium, compared to the same volume of IFN alpha-2b (0.1 mL of 3mIU), which had fewer side effects but no significant reduction in pterygium size at the end of this study. A comparison of other outcomes (grade, vascularity, inflammation, IOP, OSDI score, autorefraction, keratometry values and tear breakup time) showed similarities in both groups.

CONCLUSION

This study compared the efficacy of intralesional injections of IFN alpha-2b to that of MMC in the management of primary pterygium. Both groups showed significant improvement in symptoms by the 3-month follow-up visit, highlighting the effectiveness of these intralesional agents in reducing the discomfort from pterygium. Intralesional MMC was found to be more effective in reducing the size and vascularity of pterygium by 3 months, with only a slight improvement in astigmatism that was not statistically significant. IFN alpha-2b showed comparable safety and efficacy in reducing inflammation and significantly improved corneal astigmatism. Both interventions were well tolerated, demonstrating their safety as non-surgical alternatives. These suggest that intralesional MMC may be an option for patients with primary pterygium who wish to delay or avoid surgical intervention, particularly for grades 1 and 2 primary pterygium.