An institution-based non-randomised prospective study to estimate the efficacy and adverse effect profile of apremilast for moderate to severe refractory palmoplantar psoriasis

INTRODUCTION

Psoriasis is an immune mediated genetically determined common dermatological disorder which affects skin, nails, and joints and has various systemic associations. There is evidence that the disease is associated with a high impact on health-related quality of life and considerable cost. There are different types of psoriasis like chronic plaque, inverse, erythrodermic, scalp, nail, drug induced, pustular, guttate etc. Palmoplantar involvement can occur in isolation but often occurs with psoriasis elsewhere in body. Though only small body surface area is affected but because of the disabling sequelae, it carries a definite significance. It also leads to cosmetic disfigurement causing psychological morbidity to the patient. It can occur in the form of scaly plaques or pustular lesions which can present as palmoplantar pustulosis or acrodermatitis continua of Hallopeau. Several topical and systemic treatment are currently available for its management like topical steroids, topical calcineurin inhibitors, coal tar, keratolytic agents, methotrexate, psoralens, NBUVB therapy, cyclosporine, systemic retinoids etc. Each of the treatment options present with its own set of advantages and adverse effect profile.

Apremilast is an orally administered small molecule inhibitor of Phosphodiesterase 4(PDE4). It was approved by USFDA on March 21, 2014 for the management of active psoriatic arthritis in adults. Soon, on September 23, 2014, FDA approved apremilast for treating patients of moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.¹ It has got marketing approval from Drug Controller General of India in 2017. As a result of PDE4 inhibition, the levels of proinflammatory cytokines like TNF-a and IL-23 decrease and those of anti-inflammatory mediators like IL-10 increase.² The absolute bio-availability of apremilast is around 73%. Its concentration in the plasma peaks (Cmax) in a median of around 2.5 hours. Food intake does not affect its clinical activity. Mild to moderate renal dysfunction or moderate to severe hepatic dysfunction do not change the pharmacokinetics of apremilast to a significant level clinically.

However, dose reduction is recommended in those with severe renal dysfunction. ³ The recommended dose of apremilast in adults for psoriasis and psoriatic arthritis is 30mg twice daily. It is started with 10mg morning dose with daily increment of 10mg until day 6 when the recommended dose of 30mg BD for adults is reached and continued as such thereafter. Such dose titration reduces gastrointestinal side effects.

A new nail lacquer formulation for nail psoriasis has also been developed, though not yet available commercially.⁴ The efficacy and safety of apremilast were established through well-conducted clinical trials which showed superior efficacy over placebo. Unlike the clinical trials that followed strict protocols in patient follow-up and treatment plan, the real world data have revealed even better efficacy with the achievement of Psoriasis Area and Severity Index (PASI-75) in half of the studied population.^5,6 Evidence from various clinical studies has established the efficacy of apremilast monotherapy irrespective of previous exposure to the systemic agents.^5-9

Aim and objectives

Aim and objective of current study was to estimate the efficacy and adverse effect profile of apremilast for moderate to severe refractory palmoplantar psoriasis.

METHODS

This institution- based Non-randomised prospective clinical trial was conducted over a period of 3 months from 1 December 2021 to 28 February 2022 in the dermatology department of school of tropical medicine, Kolkata. The study population comprised of moderate to severe palmoplantar psoriasis patients who were refractory to conventional line of treatment, attending the Dermatology OPD. A total of 42 patients were taken in the study.

A written informed was presented to the patients followed by detailed history taking and clinical examination. The diagnosis of palmoplantar was mainly clinical and histopathological confirmation was done wherever applicable. Severity of palmoplantar psoriasis was assessed using Palmoplantar psoriasis area and severity index (PPPASI). It is a point-based system quantifying the area and quantity of palmoplantar psoriasis. It takes into account erythema, induration and desquamation on scale of 0-4, 4 being the most severe. Scores between 2-4 were labelled as moderate to severe and thus included in the study. Refractory cases were the once who did not respond to conventional line of therapy for atleast 3 months or had contraindications for the same.

Inclusion and exclusion criteria

Inclusion criteria for current study were; Patients of age 20-60 yrs, Patients with moderate to severe palmoplantar psoriasis (Measured using PPPASI).PPPASI scores 2-4 were taken, Patients who were refractory to Conventional therapy, Patients who had contraindications for conventional therapy. Severely ill or pregnant patients and those unwilling to participate in the study were excluded.

In case of treatment, patients were weaned off the previous systemic medications, then they were given starter kit for 7 days. Maintenance dose was 30 mg twice daily for 6 months. Then, follow up was done monthly for 6 months. The investigator’s scoring was done using PPPGA score (Palmoplantar psoriasis physician global assessment) in which the scores were 0,1,2,3 and 4, lower scores indicating good response. Weak response is reduction by 1 score. Moderate and good responses are represented by reduction in scores by 2 and 3 or more respectively. Subject’s scoring was done using DLQI (dermatology life quality index). The score brackets being 0-1, 2-5, 6-10, 11-20 and 21-30. Lower scores indicated good response.

RESULTS

In our study, we had 30 male patients while the rest 12 were females. There were no transgender patients (Table 2). 64% of the patients were Hindus while 12% of them were Muslims, rest 3% belonged to other religions (Table 3). Majority (36%) belonged in the age group of 30-40 yrs, 28% belonged in the group of 40-50 yrs while 12% belonged in the group of 50-60 yrs (Table 4). In terms of residence, 60% belonged to urban areas while rest 40% belonged to rural areas (Table 5). In our study, 42% of patients (17) were good responders where they showed a decrease in PPPGA by 3 or more scores. 31% were moderate responders (12) who showed a decrease in PPPGA by 2 scores. 1 patient did not show any response while 2 patients showed progression of disease despite treatment (Figure 1).

In our study, there was a decrease in the mean DLQI scores of patients with progression of the months. By 1^st month, it dropped to below 15 from 25. By the 3^rd month, it dropped to below 10 while by the 6^th month, it came to near around 5. This showed all over good improvement in the subjective parameter of the disease (Figure 2). In our study, out of 42 patients, 25 of them (60%) showed onset of response by 1^st month, 4 patients (10%) each by the 2^nd and 3^rd month respectively while 1 patient (2%) each showed onset of response by the 5^th & 6^th month respectively. This showed that the speed of response of action varies according to different patients (Figure 3). In our study, majority (55%) of the patients showed no adverse effects while 45% of them showed various adverse effects (Figure 4). Among them, nausea seemed to be the most common adverse effect which was present in 59% of them, followed by dizziness (42%) and diarrhea (21%). Palpitations were noted in 3 patients for which Cardiological opinion was sought. 12% of the patients showed other adverse effects like coryza, weight loss, general feeling of discomfort etc. (Figure 5).

DISCUSSION

Psoriasis is an immune mediated inflammatory papulo-squamous disorder which has various clinical subtypes like chronic plaque, scalp, inverse, guttate, erythrodermic, drug-induced, nail psoriasis etc. Palmoplantar psoriasis is also one such variant in which hyperkeratotic lesions chiefly affect the palm and sole and which causes significant morbidity and disability to the patient as it hampers with their daily activities. Apremilast is a relatively newer drug which is a Phosphodiesterase-4 inhibitor (PDE4) which suppresses production of proinflammatory cytokines like IL-17, TNF-a and IFN-g and promotes production of anti-inflammatory cytokines like IL-10.

In our study, 42% of patients were good responders while 31% were moderate responders, wherein they showed reduction in the PPPGA scores by 2 or 3 and more respectively by the end of 6 months. In a study conducted by Stander et al out of 6 patients with severe and refractory PPP, all patients showed improvements in their PGA scores from their baseline of 3 or 4 to 1 (almost clear) or 0( clear) after 12 weeks of use.¹⁰ Among patient related outcome measurements, there was significant reduction in mean DLQI of the patients from baseline of 25 to less than 15 after 1^st month, less than 10 after 3^rd month and around 6 at the end of 6^th month in our study. These indicators provide a more comprehensive view of the impact that psoriasis and its treatment can have on patients. ¹¹ The durability of improvement in PROs requires longer term monitoring and analyses beyond 32 weeks as shown in the study by Thaci et al. ¹¹ A study by Bissonnette et al suggests apremilast may have a role in the treatment of moderate to severe palmoplantar psoriasis.¹² In a report by Eto et al. 3 patients with palmoplantar pustulosis achieved near complete symptom resolution after 2 weeks while being followed for 8 months.¹³ In our study, adverse effects were reported in 55% of the patients. More than a single adverse effect was present in the same patient in some cases. Nausea and dizziness were the most common which were present in 59% and 42% of those affected, followed by diarrhea and headache in 21% and 17% respectively. Secretory diarrhea, nausea and vomiting were thought to be induced by PDE4 inhibition; a similar mechanism is implicated in caffeine-induced diarrhea. ¹⁴ In a study by Crowley et al 21.9% patients sustained weight loss >5% of their baseline body weight.¹⁴ PDE inhibition can affect other organ systems like adipose tissue, which may contribute to weight loss, this was shown in a study by Zhang et al.¹⁵ Nausea induced by PDE-4 inhibitors appears to be triggered by central and peripheral mechanisms as shown in a study by Li et al.¹⁶ This adverse effect has been associated with lack of selectivity of PDE-4 inhibitors for the different isoforms (A,B,C,D) expressed in different cell types.¹⁶ Specifically, the PDE-4 isoform is expressed in neurons of the area postrema, where the chemoreceptor trigger zone that links with the vomiting centre is located. The increase in intracellular levels of cAMP in neurons of area postrema ultimately triggers the emetic response as shown in the study by Raker et al.¹⁷ Among these non-pharmacological interventions, frequent smaller meals as well as limited liquid intake during meals may help reduce the sensation of nausea as described in a study by Langley et al.¹⁸ A phase 4, multicentre, randomised controlled trial in patients with low BSA involvement (5-10% BSA) known as Evaluating Apremilast in a phase IV trial of efficacy and safety in patients with moderate plaque psoriasis (UNVEIL) demonstrated significantly better patient satisfaction with the safety, efficacy and convenience of apremilast compared with placebo.¹⁹ In studies of patients taking biological agents and small molecule inhibitors like apremilast, latent TB reactivation is not associated with apremilast use. ²⁰

Limitations

Limitations of current study were; we enrolled 42 patients in our study which was conducted over a period of 3 months. A larger sample size would provide more comprehensive details about the efficacy and adverse effect profile of the drug compared to our smaller sample size. Also, a longer study period could have provided more insight into the long-term effect of the drug on remission of the disease and whether any more relapses occurred while taking the drug. Also, any long-term adverse effect could have been observed in greater detail. The tools used for assessing response were the Physician Global Assessment and DLQI, both of which are observer dependent and subjective in nature. This could have led to bias in assessing the results. Inclusion of a more Objective nature study tool can lead to more clarity and perfection in the results.

CONCLUSION

Palmoplantar psoriasis though affects comparatively a smaller area of the body, has a huge impact on the normal daily functioning of the patient causing significant disability and psychological trauma to the patient, especially the cosmetic disfigurement. Several topical and systemic treatment are available like topical steroids, keratolytic agents, topical calcineurin inhibitors, methotrexate, PUVA therapy, cyclosporine etc. Apremilast is a novel PDE-4 inhibitor in this regard which requires minimum blood monitoring and is safe to use in patients with other comorbidities. In our study, we have found several beneficial results of its use in palmoplantar psoriasis. A total of 42 patients of palmoplantar psoriasis were taken in our study. Majority (42%) showed good response at the end of 6 months wherein there was reduction in the PPPGA by 3 or more scores followed by 31% who showed moderate response in which there was reduction in PPPGA by 2 scores.1 patient showed disease progression while 2 had progression of disease. Mean DLQI of the patients was also decreased starting from a baseline of 25 to <15 by the end of 1^st month to <10 by the end of 3^rd month to near about 5 by the 6^th month. This shows beneficial effect of the drug in most patients as has been seen in other studies and trials too. The drug showed early onset of action by 1^st month in majority (60%) of the patients while 1 patient each had onset of action by the 5^th and 6^th month respectively. Majority of the patients (55%) did not show any adverse effect to the drug. However, among those who showed, more than 1 adverse effect was sometimes present in the same patient. Nausea and dizziness being the most common adverse effects present in 59% and 42% of those affected respectively. Palpitations were present in 5 patients for which Cardiological opinion was sought. But none of the patients had to be discontinued from our study and all completed the 6 months course of apremilast. Thus, Apremilast is emerging as a potent systemic agent for the management of palmoplantar psoriasis and its further research in other forms of psoriasis is also highly recommended. It has negligible serious adverse effects with minimum blood monitoring. It can be combined with other systemic agents like methotrexate and psoralens also.

ACKNOWLEDGEMENTS

Authors would like to thank all faculties and colleagues who supported the study.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

REFERENCES

1. 1. Otezla FL. an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis and plaque psoriasis. Am health Drug Benefits. 2015;8:105-10.
2. 2. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83:1583-90.
3. 3. Product monograph 2017: Otezla (apremilast) tablets 10 mg, 20 mg and 30 mg. Available at: https://media.celgene.com/cpntent/uploads/sites/23/Otezla-Product -Monograph-english.pdf. Accessed on 20 November 2022.
4. 4. Kushwaha AS, Repka MA, Narasimha Murthy S. A novel apremilast nail lacquer formulation for the treatment of nail psoriasis. AAPS Pharm Sci Tech. 2017;18:2949-56.
5. 5. Papadavid E, Rompoti N, Theodoropoulos K, Kokkalis G, Rigopoulos D. Real World data on the efficacy and safety of apremilast in patients with moderate to severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2018; 32:1173-9.
6. 6. Wong TH, Sinclair S, Smith B, Fraser C, Morton CA. Real world, single-centre experience of apremilast for the treatment of moderate to severe psoriasis. Clin Exp Dermatol. 2017;42:675-6.
7. 7. Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al. Efficacy and safety of apremilast, an oral Phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis over 52 weeks: A phase III, randomised controlled trial. Br J Dermatol. 2015;173:1387-99.
8. 8. Reich K, Gooderham S, Green L, Bewley A, Zhang Z, Khanskaya I, et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate to severe plaque psoriasis: 52 week results from a phase IIIb, randomised, placebo-controlled trial. J Eur Acad Dermatol Venereol. 2017;31:507-17.
9. 9. Armstrong A, Levi E. Real-world clinical experience with apremilast in a large US retrospective cohort study of patients with moderate to severe plaque psoriasis. J Drugs Dermatol. 2017;16:1240-5.
10. 10. Stander S, Syring F, Ludwig RJ, Thaci D. Successful treatment of refractory palmoplantar Pustular Psoriasis with Apremilast: a case series. Front Med. 2020;7: 543944.
11. 11. Thaci D, Kimball A, Foley P. Apremilast, an oral Phosphodiesterase 4 inhibitor, improves patient reported outcomes in the treatment of moderate to severe psoriasis: results of two phase III randomised controlled trials. J Eur Acad Dermatol Venereol. 2017; 31(3):498-506.
12. 12. Bissonnette R, Haydey R, Rosoph LA. Apremilast for the treatment of moderate to severe palmoplantar psoriasis: results from a double-blind, placebo-controlled, randomised study. J Eur Acad Dermatol Venereol. 2018;32(3):403-10.
13. 13. Eto A, Nakao M, Furue M. Three cases of palmoplantar pustulosis successfully treated with apremilast. J Dermatol. 2019;46(1):e29-30.
14. 14. Crowley J, Thaci D, Joly P. Long term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for >=156 weeks from phase 2, phase 3, randomised, controlled trials. J Am Acad Dermatol. 2017;77(2):310-7.
15. 15. Zhang R, Maratos-Flier E, Flier JS. Reduced adiposity and high-fat diet induced adipose inflammation in mice deficient for Phosphodiesterase 4B. Endocrinology. 2009;150(7):3076-82.
16. 16. Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol. 2018;9:1048.
17. 17. Raker VK, Becker C, Steinbrink K. The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Front Immunol. 2016;7:123.
18. 18. Langley A, Beecker J. Management of common side effects of Apremilast. J Cutan Med Surg. 2018;22:415-21.
19. 19. Strober B, Bagel J, Lebwohl M. Efficacy and safety of apremilast in patients with moderate plaque psoriasis with lower BSA: week 16 results from the UNVEIL study. J Drugs Dermatol. 2017;16(8):801-8.
20. 20. Hagberg KW, Persson R, Vasilakis-Scaramozza C. Herpes Zoster, Hepatitis C, and Tuberculosis risk with Apremilast compared to biologics, DMARDs and Corticosteroids to treat psoriasis and psoriatic arthritis. Clin Epidemiol. 2020;12:153-61.