IPSIndian Journal of Pharmacology
Home  IPS  Feedback Subscribe Top cited articles Login 
Users Online : 7109 
Small font sizeDefault font sizeIncrease font size
Navigate Here
  Search
 
  
Resource Links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (2,203 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)

 
In This Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed674    
    Printed50    
    Emailed0    
    PDF Downloaded46    
    Comments [Add]    

Recommend this journal

 


 
 Table of Contents    
CLINICAL RESEARCH ARTICLES
Year : 2022  |  Volume : 54  |  Issue : 3  |  Page : 177-182
 

Thalidomide and steroid in the management of erythema nodosum leprosum


1 Department of Pharmacology, SCB Medical College and Hospital, Cuttack, Odisha, India
2 Department of Skin and VD, SCB Medical College and Hospital, Cuttack, Odisha, India

Date of Submission10-Dec-2021
Date of Decision19-Apr-2022
Date of Acceptance06-Jun-2022
Date of Web Publication12-Jul-2022

Correspondence Address:
Dr. Rajashree Samal
Associate Professor, Department of Pharmacology, Sriram Chandra Bhanja Medical College and Hospital, Cuttack, Odisha
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.ijp_946_21

Rights and Permissions

 » Abstract 


OBJECTIVE: The objective of the study was to assess the efficacy and safety profiles of combined treatment of prednisolone with thalidomide (Gr-A) and prednisolone with clofazimine (Gr. B) in patients with erythema nodosum leprosum (ENL) or type 2 lepra reactions.
MATERIALS AND METHODS: Efficacy of both regimens was assessed on the basis of clinical recovery of recurrent ENL measured by reaction severity score (RSS), Visual Analog Scale (VAS), and recurrence of type 2 lepra reaction. The causality assessment of adverse drug reactions was done using the WHO UMC causality assessment scale.
RESULTS: The average age of patients with recurrent ENL was 42.8 years (male) and 51.8yrs (female) and had mean duration of leprosy and recurrent ENL 2.4 years and 2.09 years, respectively. 80% of nonrecurrence was observed in Gr-A versus 66% in Gr-B. Significant (P < 0.05) lower RSS and VAS was found in both the treatment groups as compared to pretreatment value. The reduction in RSS and VAS was statistically significant (P < 0.05) in Gr-A compared to Gr-B treatment.
CONCLUSION: Thalidomide combination with steroid was found to be more efficacious than clofazimine combination with steroid in the treatment of ENL both the treatment regimens showed few tolerable side effects. Improved strategies for the treatment and management of these reactions need to be developed.


Keywords: Clofazimine, erythema nodosum leprosum, thalidomide


How to cite this article:
P. K. Mishra S R, Samal R, Behera B. Thalidomide and steroid in the management of erythema nodosum leprosum. Indian J Pharmacol 2022;54:177-82

How to cite this URL:
P. K. Mishra S R, Samal R, Behera B. Thalidomide and steroid in the management of erythema nodosum leprosum. Indian J Pharmacol [serial online] 2022 [cited 2022 Aug 12];54:177-82. Available from: https://www.ijp-online.com/text.asp?2022/54/3/177/350780





 » Introduction Top


Leprosy (Hansen's disease) is a public health problem. Erythema nodosum leprosum (ENL) is an immune-mediated complication that occur before, during, and after multiple drug therapy (MDT) for lepromatous leprosy (LL) and Borderline LL.[1] Its pathogenesis is not fully understood; however, it is characterized by immune complex deposition and T-cell activation with high levels of tumor necrosis factor α, interleukin (IL)-6 and IL-1, whose presence has been confirmed by some reports (Sampaio et al. 1991, Pannikar 2003). ENL can manifest as crops of tender erythematous, subcutaneous nodules located on apparently normal looking skin. It may or may not be accompanied with fever, neuritis, orchitis, and bone pain. The incidence of ENL varies in cohorts worldwide from 5% to 49%.[2] The management of this serious, relapsing, and remitting complication is challenging.[1] The extended duration of ENL has both social and medical implications. The WHO has recommended the anti-inflammatory agent, clofazimine, for chronic severe ENL that does not respond well to corticosteroid or for those, the risk of steroid toxicity is high.[12] Clofazimine alone is not sufficient for symptomatic control and it takes for weeks to work.[3] Although steroid (prednisolone) rapidly provides symptomatic relief, it has risk of complications on long-term use.[3] Thalidomide as a potent immunomodulating agent has been reintroduced for the treatment of ENL in 1998 and multiple myeloma in 2006.[4],[5] It appears to be highly effective in treating the acute inflammation as well as maintaining long-term immunosuppression in patients with ENL and also having few side effects due to its steroid-sparing effect.[6] For recurrent or chronic ENL, there is the lack of use of evidence-based standard drug combination regimen, when the individual drug with less side effects fails to control the ENL reaction. Therefore, the present study has been conducted to assess the efficacy and safety of combined treatment regimen of thalidomide plus steroid and clofazimine plus steroid in patients of chronic and recurrent ENL.

Aim and objectives

Aim

To study the effect of steroid and thalidomide in the management of patients with ENL.

Objectives:

  • To compare the efficacy and safety profiles between thalidomide plus steroid and clofazimine plus steroid treatment regimens
  • To evaluate and compare the recurrence rate of ENL between the two groups.



 » Materials and Methods Top


This open label, prospective, observational study was conducted in eligible consented patients of both gender aged 18 yrs and above attending the dermatology outpatient department/inpatient department for the treatment of recurrent ENL, from June 2018 to November 2018. Our study protocol was approved by the Institutional Ethics Committee of SCB MCH Cuttack.

Recurrent ENL is defined as having four to seven episodes per year, with or without treatment. All clinically diagnosed (by the dermatologist) recurrent ENL cases had completed the treatment for leprosy with MDT and also treated with steroid to which they were found to be not responding.

Pregnant and lactating women or women planning for conception and not using effective contraceptive measures and men who were planning to start a family were excluded. Patients with history of allergy, contraindication for steroid use (diabetes, tuberculosis, gastritis, etc., existing peripheral neuropathy (by SNAP study), hypothyroidism (thyroid profile study), and critically ill patients were excluded. A total of 30 patients were included in the study out of which 15 were in Gr-A (thalidomide plus steroid) and 15 were in Gr-B (clofazimine plus steroid). All the patients had already been treated with steroid and were found to be nonresponders to it. All patients were examined for ENL lesions based on the reaction severity score (RSS).[2] The episodes of recurrence of ENL were also determined by using the RSS. The pain severity was assessed using the Visual Analog Scale (VAS).[7] Adverse drug reactions (ADR) were assessed by using the WHO UMC causality assessment scale.

Data were expressed as mean ± standard deviation and analyzed by using unpaired t-test and by percentage (%) calculation.

Group A: Capsule thalidomide 300 mg and tablet prednisolone 40 mg were administered for a duration of 3 months. Then gradual tapering of thalidomide dose to 200 mg for 1st month, 100 mg for next month and 100 mg on alternate day in the last month along with prednisolone 30 mg for 2 weeks, 20 mg for next 2 weeks, 15 mg for next 2 weeks and 10 mg for next 2 weeks then were weaned off completely. Treatment was continued with thalidomide 100 mg every alternate day for 1 month.



Group B: Capsule clofazimine 300 mg and tablet prednisolone 40 mg were administered for a duration of 3 months, tapered dose of clofazimine 200 mg for 2 months and 100 mg for 1 month along with prednisolone 30 mg for 2 weeks, 20 mg for 2 weeks, 15 mg for 2 weeks, 10 mg for 2 weeks then weaned off completely and continued the treatment with only clofazimine 100 mg every day for 1 month.

The baseline and follow-up parameters were recorded in a predesigned case record form [[Figure 1]: Case Record Form)], which included the demographic profile, duration of leprosy, and ENL. The clinical assessment in all patients was made before and after treatment by using RSS [[Figure 2]: RSS], and VAS ) [[Figure 3]: VAS]. The ADRs were assessed by using the WHO UMC causality assessment scale [[Figure 4]: WHO UMC causality assessment scale].
Figure 1: Case study from

Click here to view
Figure 2: Observations

Click here to view
Figure 3: Visual analogue scale

Click here to view
Figure 4: WHO-UMC ADR Assessment sacle

Click here to view


The patients were followed up on day 0, day 7, and day 30 of 1st month and at monthly interval for the rest 5 months. The follow-up parameters such as RSS (determined by crops of nodules and erythema) were studied. The incidence of recurrence (RSS), pain by VAS, and ADRs were assessed by using WHO-UMC scale and were analyzed.


 » Results Top


In our study, a total of 30 patients (25 male/5 female) were included, out of which 15 patients (13 male/2 female) received thalidomide and steroid (Gr-A), rest 15 patients (12 male/3 female) received clofazimine and steroid (Gr-B). The mean age of the males was 42.81 ± 11.04 years and that of the females was 51.8 ± 3.63 years, [as shown in [Table 1], [Graph 1]]. The mean duration of leprosy was 2.4 ± 0.621yrs and mean duration of ENL was 2.09 ± 0.79 years [as shown in [Table 2], [Graph 2]].
Table 1: Age & Gender Distribution of Study Subjects

Click here to view
Table 2: Mean Duration of Leprosy and Mean Duration of ENL

Click here to view



The mean RSS of Gr-A and Gr-B before treatment was 5.46 ± 0.516 and 5.2 ± 0.414, respectively, as shown in [Table 3].
Table 3: Comparison of Mean RSS Score between 2 Groups

Click here to view



This study showed significant lower RSS in both the treatment groups from the 3rd month to 6th month of the study in comparison to pretreatment value. When compared between two treatment groups, significant reduction was observed in RSS in Gr-A treatment in comparision to Gr-B treatment (P < 0.05) from the 3rd month to 6th month of study as depicted in [as shown in [Table 3]].

The percentage episodes of recurrence of ENL determined by using the RSS were found to be lower in Gr-A in comparison to Gr-B (20% vs. 34%) as depicted in [as shown in [Table 4], [Graph 3]].
Table 4: Comparison of Recurrence in Two Groups at end of 6 months using Reaction Severity Score

Click here to view



[Table 5] depicted the mean VAS (pain) in Gr-A and Gr-B before treatment as 6.8 ± 1.01 and 7.2 ± 1.01, respectively, and gradual reduction in VAS started from the 2nd month onward of treatment in both the groups compared to pretreatment value (percentage wise). Significant reduction in mean VAS was observed in Gr A treatment as compared to Gr B treatment (P < 0.05) from the 2nd month onward, as shown in [Table 5].
Table 5: Comparison of Pain (VAS) between Two Groups

Click here to view


The mean VAS (pain) in Gr-A & Gr-B before treatment were 6.8 ± 1.01 and 7.2 ±1.01 respectively and gradual reduction in VAS started from 2nd month onwards of treatment in both the groups compared to pretreatment value (percentage wise). Significant reduction in mean VAS was observed in gr A treatment as compared to gr B treatment (P<0.05) from 2nd month onwards [as shown in [Table 5]]. As depicted in [Figure 5], [Figure 6], [Figure 7], definite clinical improvement was observed after treatment with both regimens. Adverse drug reactions occurred in four patients in each group. In Gr-A (thalidomide + steroid), two patients (13.3%) had dizziness & two patients ((13.3%) had fatigue. In Gr-B (clofazimine+steroid), three patients (20%) had hyperpigmentation & one patient (6.6%) had nausea and vomiting [as shown in [Table 6]]. According to WHO UMC causality assessment system 25% ADRs were probable and 75% were possible [as shown in [Table 7], [Graph 4]]. Adverse drug reactions were self-limiting and did not lead to drop outs. No death was found during the total study period.
Figure 5: Before treatment by Thalidomide

Click here to view
Figure 6: After treatment of Thalidomide

Click here to view
Figure 7: Before and after Clofazimine treatment

Click here to view
Table 6: ADRs Observed in Two Groups

Click here to view
Table 7: WHO-UMC ADR Assessment Scale

Click here to view




 » Discussion Top


Recently, there has been a rising interest in the treatment schedule of ENL which is a severe, chronic and recurrent reaction. There are variable opinions about the treatment of this severe reaction. Steroids have been extensively used for the management of ENL including prevention and treatment of nerve function impairment.[8]

Most of the times, it is difficult to control many cases of ENL with prescribed dose of steroid (prednisolone 40 mg/day). Many patients develop new ENL lesions and there is the chance of steroid dependency in some situations when the steroids are tapered. It is often not realized that addition of an alternative drug; thalidomide or clofazimine may reduce the need for steroids.[9] Further, to reduce the long-term side effects of cumulative dose of steroid, researchers are searching for better steroid based regimen.

In our study population, the mean duration of ENL was 2.09 years which was found to be shorter in contrast to the study done by Nabarro et al.[10] Further our study showed that the mean duration of leprosy was 2.4 years. This suggests the early diagnosis and treatment of leprosy and its reaction in our study population. Steroid nonresponder patients (Gr-A and Gr-B) received the treatment as described earlier. Significant clinical improvement was found in both the treatment groups, but it was found to be significantly better in Group A in comparison to Group B. The RSS value was found to be significantly reduced (P < 0.05) in Gr-A in comparison to Gr-B. The significant reduction in VAS was observed in Gr-A treatment in comparison to Gr-B treatment (P < 0.05), which is in accordance with a study by Kar and Gupta.[11]

In this study, the patients treated with thalidomide had fewer recurrence than those receiving clofazimine which was similar to a study by Kar and Gupta where the recurrence were 17.65%, and 40%, respectively. Similar to our study, patients of a study by Kar and Gupta were weaned off from steroids for a period of 1 month.[11] Both thalidomide and clofazimine when combined with steroid proved to be very effective drug in the management of recurrent/chronic ENL. Clofazimine being a slow acting drug may take a year or even more to make the patient steroid free.[11]

Our study of only 6 month duration may not be sufficient to give opinion about whether treatment with clofazimine and steroids can be a good combination in chronic and recurrent ENL, because of its anti-inflammatory effect and in cases where thalidomide cannot be given. Our study proved that thalidomide is a very effective drug but cannot completely replace steroid in the management of ENL.

The better tolerability to treatment might be due to steroid sparing effect of thalidomide. Further we did not get any neurological side effects of thalidomide which might be due to additional use of steroid or due to short study duration. In the study done by Nabarro et al., there were ten ADRs reported in each group which could be due to longer study period, in contrast to ours.[10] Compared to others, there were no deaths found during our study period. Walker et al. found a mortality rate of 7.9% in patients hospitalized for ENL in Ethiopia, where thalidomide is not available. The shorter study period and small sample size of our study might not be able to conclude about the role of thalidomide for zero mortality.


 » Conclusion Top


Steroid-based combination therapy with thalidomide and clofazimine was found to be effective in the treatment of steroid nonresponder recurrent ENL patients with few tolerable side effects. The recurrence rate of ENL was also less in thalidomide combination than clofazimine combination treatment.

Further work is needed to better define the clinical aspect of the condition and refine the response to treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Kahawita IP, Lockwood DN. Towards understanding the pathology of erythema nodosum leprosum. Trans R Soc Trop Med Hyg 2008;102:329-37.  Back to cited text no. 1
    
2.
Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, et al. Clinical course of erythema nodosum leprosum: An 11 year cohort in Hyderabad, India. Am J Trop Med Hyg 2006;74:868-79.  Back to cited text no. 2
    
3.
Sugumaran DS. Leprosy reactions-complications of steroid therapy. Int J Lepr Other Mycobact Dis 1998;66:10-5.  Back to cited text no. 3
    
4.
Penna GO, Pinheiro AM, Hajjar AL. Translation: Thalidomide : Mechanism of action, side effects and therapeutic use. An Bras Dermatol 1998;73:501-17.  Back to cited text no. 4
    
5.
Marriott JB, Muller G, Dalgleish AG. Thalidomide as an emerging immunotherapeutic agent. Immunol Today 1999;20:538-40.  Back to cited text no. 5
    
6.
Penna GO, Ramos AM, Proenaca N. Translation : Sbd contribution to the review of ordinance 354 August 1997 an bras dermatol 2001 76 632 3. An Bras Dermatol 2001;76:632-3.  Back to cited text no. 6
    
7.
Brown GK, Nicassio PM. Development of a questionnaire for the assessment of active and passive coping strategies in chronic pain patients. Pain 1987;31:53-64.  Back to cited text no. 7
    
8.
Smith WC, Anderson AM, Withington SG, van Brakel WH, Croft RP, Nicholls PG, et al. Steroid prophylaxis for prevention of nerve function impairment in leprosy: Randomized placebo controlled trial (TRIPOD 1). BMJ 2004;328:1459.  Back to cited text no. 8
    
9.
Naafs B. Bangkok Workshop on Leprosy Research. Treatment of reactions and nerve damage. Int J Lepr Other Mycobact Dis 1996;64:S21-8.  Back to cited text no. 9
    
10.
Nabarro LE, Aggarwal D, Armstrong M, Lockwood DN. The use of steroids and thalidomide in the management of Erythema Nodosum Leprosum; 17 years at the Hospital for Tropical Diseases, London. Lepr Rev 2016;87:221-31.  Back to cited text no. 10
    
11.
Kar HK, Gupta L. Comparative efficacy of four treatment regimens in type 2 leprosy reactions (Prednisolone alone, Thalidomide alone, Prednisolone plus Thalidomide and Prednisolone plus Clofazimine). Indian J Lepr 2016;88:29-38.  Back to cited text no. 11
    
12.
Walker SL, Lebas E, Doni SN, Lockwood DJ, Lambert SM. The mortality associated with Erythema Nodosum Leprosum in Ethiopia: Retrospective hospital based study published in PLOS ( Neglected Tropical Diseases 2014;8:e2690.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

Top
Print this article  Email this article
 

    

Site Map | Home | Contact Us | Feedback | Copyright and Disclaimer | Privacy Notice
Online since 20th July '04
Published by Wolters Kluwer - Medknow