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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 9
| Issue : 1 | Page : 13-20 |
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Evaluating the efficacy of apremilast combined with low-dose steroids versus combination of apremilast with low-dose steroids and low-dose aspirin for selected cases in the management of erythema nodusum leprosum: A pilot study
Nitin Krishna Patil, Aditya Kumar Bubna
Department of Dermatology, Katihar Medical College, Katihar, Bihar, India
| Date of Submission | 22-Dec-2021 |
| Date of Decision | 12-Dec-2022 |
| Date of Acceptance | 14-Mar-2023 |
| Date of Web Publication | 24-Aug-2023 |
Correspondence Address:
Aditya Kumar Bubna
Department of Dermatology, Katihar Medical College, Karim Bagh, Katihar 854106, Bihar
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijdd.ijdd_47_21
Background: Erythema nodosum leprosum (ENL) is a reactional state observed in the lepromatous spectrum of leprosy. Currently, systemic steroids and thalidomide constitute the backbone of ENL therapy. Aim: The aim of this study was to evaluate the efficacy of apremilast as a standalone steroid-sparing drug for ENL and its combination with aspirin for selected cases. Materials and Methods: This was a pilot study on 10 patients having recrudescence of ENL following reduction of prednisolone dose to 20mg. Apremilast (30 mg twice daily) was administered to these patients as prednisolone was gradually tapered. The severity of ENL was evaluated based on the 16-item ENLIST ENL Severity Scale (EESS). If the EESS score reduced to zero with 20 mg of prednisolone following apremilast addition, patients were considered apremilast responsive. In case the EESS score reduced by> 50% then low-dose aspirin was added to the therapeutic regimen with gradual taper of steroids, and patients were accordingly evaluated. Those patients not responding to apremilast were labeled non-responders and were switched to thalidomide after appropriate investigations. Results: Out of 10 patients, 1 demonstrated complete clinical response with apremilast. In 5 patients the EESS score with apremilast had reduced by 50% or more; and following the addition of low-dose aspirin complete clinical cure was obtained. The remaining 4 patients were apremilast unresponsive. Conclusion: Apremilast may not be an effective standalone steroid-sparing drug for ENL in all patients. EESS scoring is a valuable tool in assessing treatment responses in all patients with ENL. Low-dose aspirin shows efficacy in those ENL patients demonstrating partial response to apremilast. Keywords: Apremilast, aspirin, ENLIST ENL severity scale, erythema nodosum leprosum
How to cite this article:
Patil NK, Bubna AK. Evaluating the efficacy of apremilast combined with low-dose steroids versus combination of apremilast with low-dose steroids and low-dose aspirin for selected cases in the management of erythema nodusum leprosum: A pilot study. Indian J Drugs Dermatol 2023;9:13-20 |
How to cite this URL:
Patil NK, Bubna AK. Evaluating the efficacy of apremilast combined with low-dose steroids versus combination of apremilast with low-dose steroids and low-dose aspirin for selected cases in the management of erythema nodusum leprosum: A pilot study. Indian J Drugs Dermatol [serial online] 2023 [cited 2023 Dec 7];9:13-20. Available from: https://www.ijdd.in/text.asp?2023/9/1/13/384291 |
| Introduction | |  |
Erythema nodosum leprosum (ENL) is a severe reactional state identified in those patients presenting with leprosy, in the lepromatous spectrum. Its management remains a challenge, and if not promptly and appropriately treated the likelihood of debilitating complications become inevitable.
Further, therapy for ENL is generally a prolonged one, precipitating several adverse effects with the present drugs available for its management. Currently, systemic steroids and thalidomide constitute the backbone of ENL therapy. Other drugs like clofazimine, minocycline, methotrexate, azathioprine, cyclosporine, and aspirin have also been used with varying results.
Although relief from ENL following corticosteroid administration is immediate, its prolonged utility heralds profound toxicities owing to persistently high dosing schedules. Thalidomide, like corticosteroids, serves as a wonderful crisis buster for ENL, but using it for a long time may trigger peripheral neuropathy. Also, thalidomide is a highly teratogenic drug and is best avoided in women belonging to the childbearing age group.
Clofazimine, although a safer alternative, may be associated with troublesome gastrointestinal toxicity and cutaneous pigmentation that may not be acceptable to many for social reasons.
Minocycline, a second-line drug for leprosy possesses anti-inflammatory, anti-apoptotic, and anti-nociceptive properties which may be of value in ENL. However, owing to its bactericidal effects on Mycobacterium leprae, minocycline may also instigate the development of ENL, thereby functioning as a double-edged sword, warranting caution.[1]
Other immunosuppressive drugs like methotrexate and cyclosporine elaborate their own toxicity profile, some of which are serious enough to discontinue treatment.
Owing to the pros and cons of the aforementioned drugs, it becomes evident that monotherapy certainly has no place in the management of ENL.
Effective management would therefore mandate the combination of drugs like steroids to counter the acute attack, with gradual taper, as safer and effective drugs are introduced and continued to maintain the therapeutic benefit obtained.
Currently, two publications have emphasized the profitability of apremilast in the management of ENL.[2],[3]
Although apremilast is not indicated in ENL, it may serve as a potential therapeutic agent for the same, as gauged by its anti-inflammatory properties against similar cytokines detected in patients with psoriasis and psoriatic arthropathy.[4]
Aspirin has been shown to be effective in milder ENL. Besides its easy availability and low cost, a favorable toxicity profile could make it an advantageous drug that could serve as a valuable adjunct in the therapeutic armamentarium of ENL.
We conducted a pilot study on 10 patients with recurring lesions of ENL in order to estimate the therapeutic efficacy of apremilast as a maintenance drug individually; and in combination with aspirin for selected cases.
| Materials and Methods | | |
This was a pilot study conducted on 10 patients presenting with recurring lesions of ENL after obtaining permission from the institutional ethical clearance committee (Registration number: KMC/ IEC/ Dept. Res./012/ 2021-2024 DVL). Once patients were enrolled, a written and informed consent was obtained from each of them, following which relevant history concerning the disease was recorded, and a complete clinical examination (including blood pressure measurement) was performed. This was furthered by laboratory tests that included a complete blood count, fasting and postprandial blood sugar, bleeding time, clotting time, C reactive protein, erythrocyte sedimentation rate, renal function test, liver function test, HBsAg, anti-HCV, HIV 1 and 2, urinalysis and chest X-ray. Also, a cutaneous biopsy was done from the lesional skin and sent for histopathological examination. A clinical diagnosis of ENL was concluded based on Naafs criteria [Table 1].[5]
This was followed by grading the intensity of reaction in each patient using the 16-item ENLIST ENL severity scale (EESS) [Table 2].[6]
All patients presenting to us were receiving world health organization multibacillary multidrug therapy (WHO MB-MDT) along with steroid monotherapy for ENL. When the dose of prednisolone was reduced to 20mg/day, it was characterized by recrudescence of ENL skin lesions associated with moderate/severe constitutional symptoms.
After assessing the laboratory parameters, WHO MB-MDT was continued, along with prednisolone (40mg/day) and apremilast (30mg twice daily). Apremilast was started at this dose in all patients, without the usual dose escalation that is generally employed while initiating treatment with it.
Patients were asked to follow up every 2 weeks and prednisolone was tapered according to the protocol stated in [Figure 1].
If the ENLIST score had reduced to zero with 20mg of prednisolone and apremilast, then prednisolone was tapered as per the program in [Figure 1]. After stopping prednisolone, in those patients who were receiving apremilast alone, the drug was continued in the same dose for another 1 month, followed by half the dose in the next month. This was succeeded by 30mg of apremilast on alternate days for 2 months, followed by a complete halt.
In case there occurred a recurrence of ENL with 20mg of prednisolone, post addition of apremilast, the EESS score was assessed to detect whether the value had plummeted from the baseline score, and if so, what was the level of reduction.
If there existed a diminution to half the baseline score or more, then the same dose of prednisolone (20mg) was maintained, along with the addition of aspirin (300mg in two divided doses) to apremilast. Follow-up remained at 2 weeks, and patients were similarly evaluated.
If scores remained unchanged with respect to the baseline value or portrayed minimal reduction or an increase, then those patients were labeled as apremilast unresponsive and switched over to thalidomide (after appropriate counseling and nerve conduction studies). The dose of thalidomide employed at the initiation of therapy ranged from 300 mg to 400 mg per day in three divided doses. This was gradually tapered till a dose of 100 mg was arrived at. This dosing was then continued for a period of 2 months, following which it was stopped. The total duration of treatment with thalidomide in those patients who did not respond to apremilast ranged from 7 to 9 months.
In those patients also receiving aspirin, after cessation of prednisolone, apremilast (30mg twice daily) and aspirin (300mg in two daily divided doses) were continued for another 1 month. Following this aspirin was reduced by 75 mg every 2 weeks, until it was totally stopped. Apremilast was then tapered in the same manner as described above.
| Results | | |
Salient information regarding our patients is elaborated in [Table 3].
Out of the 10 patients, only one (patient 3) demonstrated complete alleviation in the symptomatology of ENL with apremilast as an individual steroid-sparing drug [Figure 2]. Besides, we witnessed that this patient did not encounter any further ENL episode following treatment completion with apremilast. | Figure 2: (a1) ENL lesions at baseline over the right cheek. (a2) ENL lesions at baseline over the left cheek. (b1) Complete clinical remission of ENL lesions following apremilast therapy as a standalone steroid-sparing drug (right cheek). (b2) Complete clinical remission of ENL lesions following apremilast therapy as a standalone steroid-sparing drug (left cheek)
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In five patients, the EESS score at baseline and after 2 months with gradual prednisolone taper (from 40mg to 20mg) along with apremilast, revealed the following values as represented in [Table 4]. | Table 4: EESS score at baseline and after 2 months of prednisolone taper in those five patients who showed significant reduction in the score after treatment with apremilast
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Addition of aspirin to the therapeutic regimen in these five patients heralded excellent clinical improvement, with EESS scores receding to zero in their next visit, and no subsequent recurrence of lesions [Figure 3][Figure 4][Figure 5].  | Figure 4: Partial response of ENL lesions following apremilast intake and when prednisolone was reduced to 20 mg (EESS score reduction >50%). Black arrows highlight two ENL lesions. Although, the intensity of ENL has reduced it has not resolved completely after apremilast intake
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 | Figure 5: Complete clinical remission following addition of low-dose aspirin to apremilast in the treatment regimen
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The remaining 4 patients were labeled unresponsive to apremilast owing to no evident improvement following institution of the drug. Their baseline score and post-treatment score following apremilast were almost similar and are delineated in [Table 5]. | Table 5: EESS score at baseline and after 2 months of prednisolone taper in those four patients who did not show significant reduction in the score after treatment with apremilast
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Further, it was observed that all patients were able to tolerate the given dose of apremilast without any untoward effects despite the non-implementation of routine apremilast dose titration.
| Discussion | | |
The propitious effect of apremilast as a standalone steroid-sparing agent for ENL was first illustrated in two patients by Narang et al.[2]. This was succeeded by a Spanish report on one patient that reiterated the above observation.[3]
The role of apremilast in ENL has been attributed to its potential anti-inflammatory properties.
Apremilast, is an orally administered small molecule that inhibits the enzyme phosphodiesterase E4 (PDE4) and increases levels of the anti-inflammatory cytokine interleukin (IL)-10. It also binds to toll like receptor 4 in peripheral blood mononuclear cells and reduces levels of pro-inflammatory cytokines like TNFα, interferon (IFN)γ, IL-12, and leukotriene B4, which play a role in the pathogenesis of ENL.[4]
Further, owing to the absence of intensive immunosuppressive effects and a safer toxicity profile, the promising role of apremilast as a newer therapeutic option for ENL has been propounded.
The authors of this study attempted to gauge the effectiveness of apremilast as a standalone steroid-sparing drug for ENL as well as its efficacy in combination with aspirin in those patients showing partial response to treatment with apremilast as an individual drug.
For this, we took into consideration the 16-item ENLIST ENL severity scale (EESS) to enable us obtain specific values with regard to treatment responses.[6]
EESS can be considered a reasonable and veritable tool to measure the intensity of ENL, equipping the clinician to differentiate mild ENL from a more severe disease presentation.
Moreover, the uncomplicated nature of the scale and its accompanying guidelines makes its usage simple and straightforward.
According to this system, an EESS score ≥ 9 constitutes severe ENL and a score ≤ 8 depicts mild ENL.
Among our 10 cohorts, only one delineated a complete clinical cure with apremilast as a standalone steroid sparing drug.
Five of them showed a substantial reduction of their EESS score following therapy with apremilast (but not complete remission).
Besides, their EESS score had shifted to mild ENL from the severe spectrum; suggesting the ongoing anti-inflammatory role of apremilast for the same. As these patients had not achieved clinical remission, aspirin (150mg twice daily) was added to the therapeutic regimen.
Aspirin is an anti-inflammatory drug that has been useful in the management of mild cases of ENL. It has been used in varying dosing schedules for ENL that include 400 mg 6 hourly, 1 g 8 hourly, and 1.8 g/day in four divided doses.[7],[8],[9]
Within 48 h of treatment 48% improvement in lesions has been witnessed following administration of aspirin.[7]
In a report comparing aspirin (1gm Q8H), indomethacin (50 mg Q8H), and chloroquine (250mg Q8H) in ENL, it was observed that patients treated with aspirin had fewest side effects and all three drugs were found to be equally effective in controlling symptoms.[8]
Further, in an Indian study that compared aspirin and colchicine for mild to moderate ENL, it was concluded that both aspirin and colchicine were equally effective in mild ENL, but in moderate ENL colchicine demonstrated superiority.[9]
The main reason for including aspirin as an adjunct with apremilast was its favorable toxicity profile and its proven effectiveness in mild ENL. The commonest side effect encountered with aspirin is peptic ulcer disease which can be prevented by appropriate addition of proton pump inhibitors to the therapeutic regimen. Further, this adverse effect has been documented in only 2% of patients.[10]
The dosing employed by us was a low dosing schedule utilized for most chronic dermatologic disorders thereby giving us the liberty to continue its usage for long duration if mandated.
Moreover, as apremilast was already included in the treatment regimen, we inferred that even a lower dose of aspirin could suffice, until proved otherwise.
Following addition of aspirin to the therapeutic regimen, complete resolution of cutaneous ENL lesions was documented, even as prednisolone was gradually tapered and finally stopped with no recurrence during subsequent visits (in those five patients).
The mechanism of action of aspirin in ENL can be linked to its ability to inhibit both cyclooxygenase enzymes. Once these enzymes are blocked, there is reduced production of prostaglandins (PGs), particularly PGE2 thereby facilitating its anti-inflammatory and analgesic effects.[10]
Further, aspirin also impairs lymphocytic activation at therapeutic concentrations, thereby substantially reducing the production of lymphokines, that play major roles in perpetuating inflammation. Besides, aspirin has also demonstrated reduced reactivity to antigen/mitogen stimulation which again accounts for its beneficial effects in ENL.[11]
Our observation in relation to the varied therapeutic responses to apremilast becomes an important point to mull over. A major question arises as to why this disparity in clinical outcomes among our 10 cohorts.
We hereby postulate suggestions that could help in delineating an acceptable conclusion.
The pathogenic process of ENL is a highly complex one, involving an elaborate interplay of cytokines. Further, in some patients genetic polymorphisms have also been associated with increased susceptibility to type 2 reactions.[12]
Among the numerous cytokines expressed; TNFα and IFNγ have been considered the major culprits involved in ENL.
Apremilast has certainly demonstrated its efficacy against both these inflammatory mediators, and in those ENL patients in whom TNFα and IFNγ constitute the major cytokine profile, a highly favorable outcome with apremilast would be expected.
However, heterogeneity involving the entire spectrum of ENL may result in the heightened elaboration of other cytokines as well, whose levels (mild, moderate, and severe) may differ considerably in each patient.
Though apremilast may be effective in antagonizing the effects of TNFα and IFNγ, its efficacy against other lymphokines (IL1β, IL2, IL2R, IL6, IL12, and IL17) may be negligible and in those patients where the expression of these inflammatory mediators is massive, there would be a high likelihood of treatment failure with apremilast. This could be a plausible explanation in those patients expressing the above cytokines as principal mediators in ENL.
The observation with regard to partial responses with apremilast could again be linked with varying levels of expression of different cytokines involved in ENL.
If expression of the above interleukins is not excessive, then perhaps the role of aspirin as a synergistic drug with apremilast in the therapeutic regimen can be contemplated upon. As the EESS score had reduced > 50% with apremilast, our aim in introducing aspirin was to counteract the milder pathogenic effects produced by other lymphokines, against which apremilast was ineffective.
Further, as aspirin was introduced as a synergistic drug with apremilast, we considered that a low-dose schedule with aspirin would be sufficient. Interestingly, in all patients who demonstrated a reduction in their EESS score > 50%, it was observed that low-dose aspirin was adequate enough in bringing about remission.
Currently, all our patients are on regular follow-up (for 1-year post cessation of steroids) without any recrudescence of lesions till date.
The only method to analyze these cytokines would be their quantitative estimation. These diagnostic tests, however, are not commonly available in India and are also associated with high costs, which make this an extremely unpractical proposition for routine patient management. However, this could prove to be of immense advantage for research purposes.
One major limitation of our study was the small sample size. Despite that, we were able to obtain important findings with regard to apremilast and its combination with aspirin in the management of ENL. Large-scale studies emulating our protocol would definitely help in confirming our observation further.
| Conclusion | | |
Apremilast may not be very effective as a standalone steroid-sparing agent in all patients with ENL. Nevertheless, it would be worthwhile dispensing this drug initially along with systemic steroids and studying the EESS scores at each juncture of patient management.
In those cases with > 50% reduction of the EESS score, low-dose aspirin could be a valuable add-on to the therapeutic armamentarium.
The main idea for utilizing the above drugs for ENL was predominantly linked to their safety profile. Besides, low-dose aspirin along with apremilast was found to be adequate enough to show clinical remission in cases of mild ENL.
However, a subset of patients may not be responsive to apremilast. In such cases, it would be prudent to immediately initiate treatment with thalidomide, if not contraindicated.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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| 2. | Narang T, Kaushik A, Dogra S Apremilast in chronic recalcitrant erythema nodosum leprosum: A report of two cases. Br J Dermatol 2020;182:1034-7. |
| 3. | Sanchez-Martinez EM, Melgosa-Ramos FJ, Moneva–Leniz LM, Gejunder Hernandez H, Prats-Manez A, Mateu Puchades A Erythema nodosum leprosum successfully treated with apremilast: More effective and safer than classic treatments. Int J Dermatol 2021;60:e74-6. |
| 4. | Bubna AK Apremilast: A dermatologic Perspective. Indian J Drugs Dermatol 2016;2:75-82. |
| 5. | Naafs B Treatment duration of reversal reaction: A reappraisal back to the past. Lepr Rev 2003;74:328-36. |
| 6. | Walker SL, Sales AM, Butlin CR, Shah M, Maghanoy A, Lambert SM, et al; Erythema Nodosum Leprosum International Study Group. A Leprosy Clinical Severity Scale for erythema nodosum leprosum: An international, multicenter validation study of the ENLIST ENL Severity Scale. PLoS NeglTrop Dis 2017;11:e0005716. |
| 7. | Lockwood DNJ The management of erythema nodosum leprosum: Current and future options. Lepr Rev 1996;67:253-9. |
| 8. | Karat AB, Thomas G, Rao PS Indomethacin in the management of erythema nodosum leprosum- A double blind controlled trial. Lepr Rev 1969;40:153-8. |
| 9. | Kar HK, Roy RG Comparison of colchicine and aspirin in the treatment of type 2 lepra reaction. Lepr Rev 1988;59:201-3. |
| 10. | Bubna AK Aspirin in dermatology-Revisited. Indian Dermatol Online J 2015;6:428-35. |
| 11. | Morley J Mechanism of action of aspirin in inflammation. Proc Roy Soc Med 1977;70:32-6. |
| 12. | Sousa ALM, Fava VM, Sampaio LH, Martelli CMT, Costa MB, Mira MT, et al. Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction. J Infect Dis 2012;205:1417-24. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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