Indian Journal of Drugs in Dermatology

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 5  |  Issue : 2  |  Page : 83--88

Real-world experience on the effectiveness and tolerability of apremilast in patients with plaque psoriasis in India


Shrichand Parasramani1, Jayakar Thomas2, Leelavathy Budamakuntla3, Dhiraj Dhoot4, Hanmant Barkate4,  
1 Dermocosmetology Laser Center Lilavati Hospital, Mumbai, Maharashtra, India
2 Department of DVL, Sri Balaji Medical College and Hospital, Chennai, Tamil Nadu, India
3 Department of Dermatology, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India
4 Medical Services, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India

Correspondence Address:
Dr. Dhiraj Dhoot
B D Sawant Marg, Chakala, Andheri (E), Mumbai, Maharashtra
India

Abstract

Introduction: Apremilast, a phosphodiesterase-4 inhibitor, has been recently approved for the management of plaque psoriasis in India in 2017. However, no real-world experience pertaining to apremilast has been documented. Materials and Methods: A retrospective review of medical records was conducted of all patients across India who were prescribed apremilast for an entire 16 weeks. The primary endpoint was the percentage of patients achieving the Psoriasis Area and Severity Index (PASI) 75 at 16 weeks. The secondary endpoints were as follows: (i) change in mean PASI; (ii) change in mean body surface area (BSA); (iii) percentage of patients who achieved PASI 50, 90, and 100; and (iv) adverse events (AEs) reported. Results: We analyzed the records of 105 patients. Mean age was 41 years and mean disease duration was 6.75 years. All the patients had previously received some forms of systemic treatment. Forty-three patients (41%) achieved ≥ PASI 75 of which four patients (3.8%) and five patients (4.76%) achieved PASI 100 and PASI 90, respectively at week 16. Moreover, 28 patients (26.7%) demonstrated PASI 50 response. Baseline mean PASI score of 14.78 reduced to 4.5 (−69.55%), whereas mean BSA score of 24.4 reduced to 8.24 (−66.3%). Nine patients discontinued apremilast due to adverse effects. Thirty-five patients (33.3%) had one or more AEs, diarrhea being the most common (30.5%) followed by nausea (20.3%). Most AEs were mild to moderate in severity. Conclusion: These results, from a real-world setting in India, confirm the effectiveness and tolerability of apremilast as seen in clinical trials.



How to cite this article:
Parasramani S, Thomas J, Budamakuntla L, Dhoot D, Barkate H. Real-world experience on the effectiveness and tolerability of apremilast in patients with plaque psoriasis in India.Indian J Drugs Dermatol 2019;5:83-88


How to cite this URL:
Parasramani S, Thomas J, Budamakuntla L, Dhoot D, Barkate H. Real-world experience on the effectiveness and tolerability of apremilast in patients with plaque psoriasis in India. Indian J Drugs Dermatol [serial online] 2019 [cited 2020 Sep 19 ];5:83-88
Available from: http://www.ijdd.in/text.asp?2019/5/2/83/272938


Full Text



 Introduction



Psoriasis is an autoimmune skin disorder, which warrants continuing treatment with effective oral drugs with minimum possible adverse effects. The key pathological features of psoriasis are augmented production coupled with partially differentiated epidermis, dermal and epidermal intrusion of leukocytes, and escalated blood flow to the skin. Owing to its debilitating clinical course, psoriasis tends to have a profound adverse impact on psychosocial aspect of the patient.[1] Certain systemic diseases such as psoriatic arthritis (PsA) and cardiovascular diseases also coexist with psoriasis, thus adding to the agony of the patients.[2],[3] All these things translate into increased economic, physical, and psychosocial stress in affected patients.[1]

Several conventional and biologic agents are available in India for the management of psoriasis. Apremilast is an oral phosphodiesterase-4 (PDE4) inhibitor, approved by the US Food and Drug Administration in September 2014 and Drug Controller General of India in October 2017. It is indicated for the management of adult patients with psoriasis and active PsA as a twice daily dose.[4] PDE4 regulates the inflammatory response by degrading cyclic adenosine 3',5'-monophosphate (cAMP), an important intracellular second messenger. Thus, the inhibition of PDE4 increases the cAMP level resulting in decreased production of inflammatory mediators and an increase in anti-inflammatory mediators. Apremilast specifically blocks the production of pro-inflammatory cytokines (interferon-ϒ, tumor necrosis factor-α, interleukin-12 [IL-12], IL-17, and IL-23) and increases the expression of anti-inflammatory mediators such as IL-10.[5]

In the landmark clinical trials, apremilast had shown the superiority over placebo with an excellent safety profile [6],[7] and long-term maintenance of efficacy.[8],[9] However, data on real-world patients are scarce.[10],[11],[12],[13],[14] In this cohort, we retrospectively analyzed various clinical data of plaque psoriasis patients treated with apremilast in terms of its efficacy and safety in psoriasis. The patients in our cohort analysis had been previously treated with a systemic agent and switched to apremilast either due to the lack of efficacy or the side effects of the previous treatment.

 Materials and Methods



This was a retrospective, multicenter, observational cohort analysis that examined the results in patients with plaque psoriasis in real-world dermatology practice at seven centers across India. A prevalidated questionnaire was used to conduct this analysis. The questionnaire was designed to assess the efficacy and tolerability of apremilast in the management of plaque psoriasis patients. The survey was conducted during December 2017–August 2018. Only those records were included for analysis, whose data were available for complete 16 weeks.

The primary endpoint was the assessment of clinical response in patients achieving the Psoriasis Area and Severity Index (PASI 75) at 16 weeks after treatment initiation. The secondary endpoints were the assessment of:

Change in mean PASI from baseline to week 16Change in mean body surface area (BSA) from baseline to week 16Percentage of patients who achieved PASI 50, PASI 90, and PASI 100 at week 16Percentage of patients who discontinued the treatmentAdverse events (AEs) reported during the entire course of the therapy.

Statistical analysis

Statistical analysis was done using SPSS (Statistical Package for Social Sciences, IBM SPSS Inc., Chicago, IL, USA) version 15. Continuous and categorical data were expressed in terms of means and percentage, respectively. To compare changes in mean scores at baseline and 16, the Chi-square test was applied. P < 0.05 was considered as statistically significant.

Demographic characteristics as well as previous psoriasis treatments are listed in [Table 1].{Table 1}

 Results



We analyzed the data of 105 patients who were prescribed apremilast for chronic plaque psoriasis. The mean disease duration was 6.75 years. Most of the patients (62%) were male. Most of the patients had received previously some form of antipsoriasis treatment, with methotrexate being the most common (65/105) and biologic therapy in 11 patients. Some of the patients had received phototherapy (15/105) and topical therapy (18/105) as well. Eight patients were treatment naïve.

Efficacy

The primary endpoint was achieved in 43 patients (41%), of which 4 patients (3.8%) and 5 patients (4.76%) achieved PASI 100 and PASI 90, respectively, at week 16. Moreover, 26.7% (n = 28) of patients demonstrated PASI 50–75 response at week 16 [Figure 1].{Figure 1}

The baseline mean PASI score of 14.78 decreased to 4.5 ([−69.55%], P < 0.05), whereas the mean BSA score of 24.4 decreased to 8.24 ([−66.3%], P < 0.05) at week 16 [Figure 2].{Figure 2}

A total of 9/105 patients discontinued treatment, all due to AEs. In detail, two patients experienced worsening of disease within 2 weeks of treatment. Headache, vomiting, and diarrhea were the reasons for discontinuation in two patients each, whereas one patient discontinued due to depression [Figure 3]. After drug discontinuation, five patients were lost to follow-up, another wished no further therapy, and three patients were switched to their previous systemic treatments (methotrexate).{Figure 3}

Safety assessments

Thirty-five patients (33.3%) experienced at least one or more treatment-related AEs. The most common side effects were diarrhea (30.5%), nausea (20.3%), and headache (15.25%). Most of these gastrointestinal AEs were temporary and resolved over time. In four cases, severity of diarrhea and vomiting led to drug discontinuation. Two patients discontinued due to headache. Overall, most of the reported AEs were mild to moderate in severity and well manageable [Figure 4]. [Figure 5] and [Figure 6] demonstrates clinical images of patients before and after therapy with Apremilast.{Figure 4}{Figure 5}{Figure 6}

 Discussion



Apremilast had demonstrated efficacy and safety in the management of adult patients with plaque psoriasis in landmark clinical trials.[6],[7],[8],[9] However, clinical trial data do not fully reflect the demographically and clinically diverse population of patients treated at different dermatology practices. Hence, it becomes important to determine the treatment patterns and clinical efficacy of different therapies at the point of care for ascertaining real-world patient outcome, designing treatment strategies, and hence, improving patient outcome.

Among previous real-world studies, many provided detailed data including PASI.[13],[14],[15] Vujic et al.[13] and Papadavid et al.[14] highlighted the differences between real-world data and Phase III clinical trial data (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1 and 2).[6],[7] Regarding the mean age in years, patients in our study were of similar age as in ESTEEM 1 and 2 (41 vs. 46 years) but had lower disease duration (6.7 vs. 18.7 years).[6],[7] In addition, less number of patients in our study received prior therapy with biologic (10% vs. 30%) compared to ESTEEM trials. In case of mean PASI, the patients in this study had a lower mean PASI at baseline than those in ESTEEM 1 and 2 (14.78 vs. 18–20, respectively)[6],[7] and higher mean PASI against other real-world studies.[12],[13],[14],[16]

Efficacy

Primary endpoints

The results obtained in the present study are superior than those seen in landmark ESTEEM 1 and 2 trials, where 28.8% and 33% of the patients achieved PASI 75 at the end of 16 weeks, respectively,[6],[7] as compared to 41% of patients achieving the same parameter in the present study. Similar results were reported by Wong et al.[15] and recently published Indian study by Thomas and Srinivasan.[17] However, Papadavid et al.[14] reported an even higher percentage of patients (60%) achieving PASI 75. This may be due to the fact that mean PASI score in that study was 10, as compared to 14.78 in the present study.

Although, due to the retrospective study design, we could not analyze the Dermatology life Quality Index, the majority of the patients continuing the full course of treatment indirectly points toward improvement in patient compliance and quality of life. Overall, the PASI 75 responses reported in various clinical studies at the end of the 16-week treatment with apremilast range from 30% to 50%.[6],[18],[19]

Secondary endpoints

Regarding further secondary endpoints at week 16, 67.61% of the patients achieved at least PASI 50 vs. 58.7% in ESTEEM 1 and 55.5% in ESTEEM 2,[6],[7] 4.76% of patients achieved PASI 90 vs. 9.8% ESTEEM 1 and 8.8% in ESTEEM 2,[6],[7] and even 3.8% of patients reached PASI 100 which was not reported in the ESTEEM trials. Since the population involved in the survey was of moderate psoriasis, our real-life cohort explains the difference rated in response compared with landmark ESTEEM trials where population had severe psoriasis. Thomas and Srinivasan also demonstrated PASI 50 response in 50% of the patients.[17] A similar pattern of higher percentage of patients achieving PASI 90 and 100 was reported in other real-world studies.[14],[15]

Moreover, our patients demonstrated improvement in both mean PASI and BSA assessments at week 16 from baseline. Starting from a baseline of 24.4, mean BSA decreased to 8.24 (−66.3%) and mean PASI score of 14.78 dropped to 4.5 in 16 weeks. This improvement was more than that observed in ESTEEM 1 trial,[6] which reported − 47.8% change/improvement in BSA involvement. It is noteworthy to mention that baseline BSA and PASI in ESTEEM 1 trial were more than that in the present study. Similar results for PASI were reported in a study by Papadavid et al.[14]

In another real-life clinical study of Mayba and Gooderham,[12] a mean baseline PASI score of 10.4 and a mean BSA score of 9.6% were reported, which are low compared to our study but much lower than the ESTEEM trials. Of the 81 patients, 63 were still on apremilast (at the time of publication). Of the patients still on treatment, 37% (23/63) have achieved BSA ≤ 1, with a further 25% achieving 2 ≤ BSA ≤ 3. PASI response was not included.

Safety

Most of the patients (33.3%) in our cohort had at least one AE, which is lower than the numbers reported in the ESTEEM trials (79%) but in concordance with Papadavid et al.[14] where 30% of the patients experienced side effects. Such differences between real-life and trial patients are not uncommon and probably due to more rigorous follow-up schedules, methods of data acquisition, and a different mindset of physicians and patients, during clinical trials, with a stronger focus on possible AE. This is also evidenced by high number of AEs reported in placebo-treated patients, i.e., 57% in the ESTEEM 1 trial.[6]

The most common AEs in the present study were diarrhea and nausea, and these findings were corroborated in various clinical studies.[6],[7],[14],[15] The incidence of diarrhea in the present study is higher than that found in ESTEEM 1, i.e., 17.3%[6] but in similar line with a study by Mayba and Gooderham [12] and Kishimoto et al.[20] The high rate might be attributed to recall bias, as the patients were counseled on the possibility of these AEs and then questioned about them on the follow-up visit (every 3–4 months).

The total drug discontinuation rate in the present study was 8.5% which was comparable to other studies. The most common reason for the discontinuation was the side effect profile in our study. Captivatingly, the most common reason reported for such drug discontinuation in these studies was drug failure, even though apremilast was used in combination with other systemic agents in most of the studies.[12],[14] In the present survey, therapy was discontinued owing to AEs and not due to drug failure, although it was used as monotherapy. This finding carries weightage, as it will help to further strengthen the efficacy of apremilast. The major reason cited for the high rates of drug discontinuation in ESTEEM trials (due to AEs) was stringent observance in these clinical trials as compared to real-world studies.[12],[14]

An additional remarkable outcome of the present survey was that a greater number of patients had been exposed to systemic drugs before they were started on apremilast therapy. This finding is in disparity with that of the real-world study by the American Association of Dermatologists, i.e., Long-term Documentation of the Utilization of Otezla® in Patients With Plaque Psoriasis Under Routine Conditions study [11] and ESTEEM trials [6],[7] both of which reported about 50% of the patients being treatment naïve. Thus, from the findings of the present survey and the above-mentioned trials and real-world clinical studies, it is safe to conclude that apremilast is effective in both, treatment naïve and patients who have already taken systemic drugs.

Finally, on a closing note, the vivacious role of patient counseling in improving the adherence of patient to therapy needs to be strengthened further. It is vital to remove the procrastinations of the patients regarding symptom relief with drug use, by sensitizing their expectations with that of real-world experiences.[21]

A summary of the real-world studies is mentioned in brief in [Table 2].{Table 2}

The present analysis outcomes will be an important fortification to the current meager real-world data. To the best of our knowledge, the present survey is the first real-world experience of apremilast use in plaque psoriasis in India.

There were a few limitations in the present analysis. Due to retrospective design, the possibility of selection bias cannot be ruled out. Second, the sample size of the present study was very less, which hampers the overviewing of results to larger population. Moreover, in the end, quality of life was not studied, which would have added more value to the results.

 Conclusion



The results of this study verify those of previous publications. Apremilast is an effective treatment in plaque psoriasis management armamentarium, capable not only to induce clinically meaningful responses but also to keep it under control in the long run. The effect of therapeutic combinations should be further researched to confirm additional impact on responses or AEs. Nonetheless, this report has brought insights into apremilast treatment among Indian psoriasis sufferers.[22]

Acknowledgment

We would like to acknowledge Dr. Abhishek De, Dr. Gajanan Pise, Dr. Prashant Palwade, and Dr. Shwetha Rahul for providing data for this analysis. We would also like to acknowledge Dr. Gaurav Deshmukh and Dr. Harshal Mahajan for their contribution toward manuscript writing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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