Effectiveness and safety of ustekinumab for the treatment of psoriasis; six years of clinical experience

Abstract

Background

This work aimed to investigate the long-term clinical experience with ustekinumab in cases with psoriasis.

Materials and methods

This retrospective cohort research group consisted of cases who presented to the dermatology outpatient clinics between January 2015 and January 2021, diagnosed with psoriasis, and were treated with ustekinumab. Data including gender, age, weight, disease duration, naïve and non-naïve status, psoriasis type, duration of medication, comorbidities, psoriasis area and severity index scores, the causes of treatment discontinuation, and previous treatments were retrospectively reviewed and analyzed.

Results

160 cases with psoriasis were treated with ustekinumab during the research period. Twenty-four patients were excluded. Among 136 cases, 84 (61.8%) were male and 52 (38.2%) were female. We determined 80.55% of the non-naïve cases responded to ustekinumab.

Conclusion

Ustekinumab can be a suitable treatment option for non-naïve and resistant patients. Our data suggest the positive effect persists in cases with favorable responses to the first or second dose of ustekinumab. Also, we determined male cases gave more rapid and more robust responses than female cases, and patients were more willing about continuing the treatment.

Keywords:

• Psoriasis
• ustekinumab
• biologic

Introduction

Psoriasis is a chronic, immune-mediated disease characterized by erythematous scaly patches or plaques that occur mainly on the extensor surfaces of the limbs (1,2). 1 It can be associated with a number of comorbidities; cardiovascular disorders, diabetes, metabolic syndrome and depression (2). However, it can also affect the palms, soles, nails, and intertriginous areas (3). The etiology remains unclear, and treatment is still mostly based on combating acute symptoms (2). Although there are different treatment options for psoriasis, the advent of biologics led to a paradigm shift in psoriasis treatment since they showed excellent efficacy (3). Ustekinumab (CNTO 1275, Centocor Inc, Malvern, PA, USA) is one of the biologics used in treating psoriasis (4,5). It is a monoclonal antibody targeting interleukin (IL)12 and IL-23 and preventing interaction with the cell surface IL12Rβ1 receptor (5). It is used to treat moderate to severe plaque psoriasis, psoriatic arthritis, moderate to severe Crohn disease, or moderate to severe ulcerative colitis (inflammatory bowel disease). The drug is FDA approved for use in moderate to severe plaque psoriasis (Ps), particularly in those patients who are candidates for phototherapy or systemic therapy, aged 6 or older. A 45 mg subcutaneous dose is administered initially (90 mg if body weight is over 100 kg), then 45 mg (or 90 mg) subcutaneously four weeks later, and thereafter 45 mg (or 90 mg) subcutaneously every 12 weeks (4). This study aimed to reflect our long-term clinical experience with ustekinumab while treating psoriasis patients.

Materials and methods

This study was designed as a retrospective single-center study and conducted under the ethical principles reported in the Declaration of Helsinki. It was approved by the İzmir Tepecik Training and Research Hospital Ethical Review Committee (2019/18-17 − 26.12.2019). Patients who presented to the dermatology outpatient clinics of the same hospital between January 2015 and January 2021, diagnosed with psoriasis and treated with ustekinumab, constituted the study group of this retrospective cohort. The patients who did not present to the clinic for follow-up after receiving the second dose of ustekinumab were excluded. Data including gender, age, weight, type of psoriasis, disease duration, duration of medication, first psoriasis area and severity index (PASI) scores, previous treatments, and comorbidities were retrieved from electronic patient folders. These folders also included the 5th, 12th, 24th, 36th, 48th, 56th, 78th, 104th week and 3rd, 4th, 5th, 6th-year PASI scores, the reasons for drug discontinuation, and the patients’ naïve or non-naïve status. These data were also analyzed for study purposes. The patients under 100 kg recieved 45 mg ustekinumab treatment at week 0, 4 and then every 12 weeks. The cases over 100 kg recieved 90 mg ustekinumab treatment at week 0, 4 and then every 12 weeks.

Statistical analyzes were performed using Statistical Package for Social Sciences (SPSS v.24.0, IBM Corporation, Armonk, New York) software. Descriptive statistics were presented as means ± standard deviations (SDs) and ranges [minimum-maximum]. Mann-Whitney U test was used for binary comparisons between groups in the case of non-normally distributed data. The p values were regarded as statistically significant when less than .05.

Results

Although 160 patients met the inclusion criteria, 24 patients were excluded since they did not present to the clinic for follow-up. Among the 136 cases, only one was younger than 18; all others were over 18. While 84 (61.8%) cases were male, 52 (38.2%) were female. Mean patient age was 48.59 ± 14.79 [14-83]; there was no significant difference between female and male patients regarding mean patient age (49.12 ± 14.77 vs. 48.26 ± 14.88). Mean patient weight was 81.46 ± 15.83 [49-140] kg; while mean patient weight was 76.02 ± 14.46 in females, it was 84.83 ± 15.77 in males. There was plaque psoriasis in 132, palmoplantar psoriasis in 3 cases, and flexural psoriasis in one case. None of the patients developed any severe adverse effects. One female patient had psoriatic arthritis. There were PASI score improvements of at least 75% in 106 (77.9%) cases (i.e. 36 females and 70 males), while no improvement was detected in 30 (22.1%) patients who didn’t reach PASI 75 response. The most common comorbidity was hyperlipidemia (n = 11). While 9 patients had hypertension, 6 patients had diabetes mellitus, 3 patients had end-stage renal disease, 2 patients had mitral valve regurgitation as comorbidities. Hepatitis C virus (HCV) positivity, breast cancer, congestive heart failure, chronic obstructive pulmonary disease (COPD), hypothyroidism, and asthma was detected in one case. Ustekinumab treatment was discontinued in 30 (22.1%) patients because of drug ineffectiveness, and 36 (26.5%) cases were non-compliant with the treatment and outpatient clinic encounters. Ustekinumab treatment was given to 21 cases after using one biological agent, 9 cases after using two biological agents, and one case after using four biologics. We didn’t determine any significant correlations between naive and non naive cases about PASI 75-90-100 responses. All other data are displayed in the tables [Tables 1–4].

Table 1. Information about the patients and medication of ustekinumab.

Parameters	Results
Disease duration	15.64 ± 9.95 years (min 2, max 53)
Duration of medication	23.13 ± 15.93 months in total cases (min 7, max 72) 21.9 ± 13.09 in females 23.88 ± 17.52 in males
Naive cases	100 (73.52%) total 39 (75%) female 61 (72.61%) male
Non naive cases	36 (26.47%) total 13 (25%) female 23 (27.38%) male

Table 2. Information about PASI 75-90-100 responses of all the patients and female and male patients Separately.

Parameters	PASI 75			PASI 90			PASI 100
	Total	Female	Male	Total	Female	Male	Total	Female	Male
Total number	41	12	29	69	24	45	64	22	42
Missed cases	95	40	55	67	28	39	72	30	42
Mean week	5.32	5.08	5.41	6.19	7.83	5.31	8.86	9	8.79
Std.	3.588	2.811	3.905	5.862	8.766	3.267	6.650	6.495	6.806
Minimum (week)	1	1	1	1	1	1	1	4	1
Maximum (week)	16	9	16	36	36	12	36	26	36

Abbreviations: PASI, psoriasis area and severity index.

Table 3. Comparison between male and female cases about time to reach PASI 75-90-100 responses.

PASI	Gender	Number	Week (mean ± std)	p
PASI 75	M	29	5.41 ± 3.9	0.92
	F	12	5.08 ± 2.8
PASI 90	M	45	5.31 ± 3.2	0.68
	F	24	7.83 ± 8.7
PASI 100	M	42	8.79 ± 6.8	1
	F	22	9 ± 6.4

PASI: psoriasis area and severity index; M: male; F: female. ‘Week’ means the duration of receiving PASI75-90-100 responses.

Table 4. Comparision between naive and non naive cases about PASI 75-90-100 responses.

Cases	Naïve (total)	Non naïve (total)	p	Naïve (female)	Non naïve (female)	p	Naïve (male)	Non naïve (male)	p
PASI 75
Response [n (%)]	77 (56.6%)	29 (21.3%)	.4	26 (50%)	10 (19.2%)	.14	51 (60.7%)	19 (22.6%)	1
Not response [n (%)]	23 (16.9 %)	7 (5.1%)		13 (25%)	3 (2.2%)		10 (19.2%)	4 (4.8%)
PASI 90
Response [n (%)]	48 (35.3%)	21 (15.4%)	.33	16 (30.8%)	8 (15.4%)	.22	32 (38%)	29 (34.5%)	.8
Not response [n (%)]	52 (38.2%)	15 (11%)		23 (44.3%)	5 (9.6%)		13 (15.5%)	10 (11.9%)
PASI 100
Response [n (%)]	47 (34.6%)	17 (12.5%)	1	16 (30.8%)	6 (11.5%)	.75	31 (37%)	11 (13%)	1
Not response [n (%)]	53 (39%)	19 (14%)		23 (44.2%)	7 (13.5%)		30 (35.7%)	12 (14.3%)

PASI: psoriasis area and severity index. p < .05 (*) statically significant correlation.

Discussion

There are different treatment modalities for psoriasis, one of them is ustekinumab used for healing moderate-to-severe psoriasis (6,7).

The Active Comparator (CNTO1275/Enbrel) Psoriasis Trial (ACCEPT) showed ustekinumab had a rapid onset of action (6). We obtained similar results in our work. Our data also supported male patients improved faster than female patients. The treatment response rate was also higher in male cases than females. Of note, male patients regularly monitored their visits more compliantly and they were more enthusiastic for their treatment. We also observed that in cases with positive response to one dose or two doses of ustekinumab, this positive effect of this treatment method tended to persist. On the other hand, in patients with an negative response to one or two doses of this treatment method, the possibility of reaching PASI 75 response was decreased.

During the treatment, in our research, our cases did not meet any severe adverse effects. Any adverse events occured in many researchs (6,8,9).

The works NCT02684370 (UltIMMa-1) and NCT02684357 (UltIMMa-2) founded PASI 75 response was 70% and 69.7% at the 12th week. In UltIMMa-1, PASI 90 response was 42% at week 16 and 44% at week 52, while PASI 100 response was 12% at week 16 and 21% at week 52. In UltIMMa-2, PASI 90 response was 47.5% at week 16 and 50% at week 52. This research also founded PASI 100 response was 24% at week 16 and 30.3% at the 52nd week (10). In our work, the mean duration for reaching PASI 75, PASI 90, and PASI 100 response was less than 10 weeks. These data proved that our cases healed rapidly and efficiently with ustekinumab.

In the PHOENIX 1 work, the authors compared the outcomes of ustekinumab 45 mg (n = 255), ustekinumab 90 mg (n = 256) and placebo (n = 255) (5). They founded the maximum efficacy was determined at week 24 in both ustekinumab 45 mg and 90 mg groups. They also founded PASI 75 response was reached by 191 of 251 (76.1%) cases in the 45 mg group and by 209 of 246 (85%) cases in the 90 mg group and approximately half of the cases in both 45 mg and 90 mg ustekinumab groups obtained at least a 90% improvement (i.e. PASI 90) at week 28. Approximately one-third of the patients in both ustekinumab groups reached PASI 100 response at week 12. On the other hand, half of the cases in the ustekinumab 45 mg group and 71% in the ustekinumab 90 mg group achieved PASI 100 response at week 28. In the PHOENIX 2 study, nearly half of the cases reached PASI 90 response at week 12, which was maintained at week 28 (11). One-fifth of the patients reached PASI 100 response at week 12, which persisted in the ustekinumab 45 mg group at week 28. One-third of the ustekinumab 90 mg patients reached PASI 100 at the 28th week. The results of PHOENIX 1 and 2 indicate that treatment with ustekinumab 45 mg or 90 mg leads to a rapid and significant improvement in patients with moderate-to-severe psoriasis. Our findings are consistent with these studies.

Our data also proved ustekinumab was effective in both non-naïve and naïve cases. Generally, ustekinumab was effective in 80.55% of all non-naïve patients. This figure was 76.92% for non-naïve female cases and 82.6% for non-naïve male cases. These data suggest ustekinumab is a reasonable treatment method for non-naïve patients. Nontheless, comparing the treatment responses revealed ustekinumab was more effective in naïve patients than non-naïve patients. In the PHOENIX2 study, 38.4% of the patients in the 45 mg ustekinumab group (n = 409), 36.5% of the cases in the 90 mg ustekinumab group (n = 410) and 38.8% of the cases in the placebo group (n = 411) were previously treated with a biologic (i.e. etanercept, alefacept, efalizumab, infliximab and adalimumab). At week 28, only 12.1% of the PASI 75 responders were previously treated with at least one biologic (12).

In another work comparing etanercept and ustekinumab groups, patients in the former group who failed to respond to treatment after 12 weeks were switched to 90 mg of ustekinumab. After 12 weeks, 48.9% achieved PASI 75 and 23.4% achieved PASI 90 (13). In the ACCEPT work, 50 etanercept group patients who did not have a physician global assessment (PGA) score of less than 3 at week 12 were switched to the ustekinumab group (14). This research showed that most cases responded favorably to ustekinumab after failing to respond to other biologics, but the response rates were relatively lower than primary treatments. Our findings are consistent with these studies.

In the meta-analysis work of Sbidian et al. it is founded that ustekinumab was superior to certolizumab; adalimumab and ustekinumab were superior to etanercept. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti-IL23 drugs (risankizumab and guselkumab) except tildrakizumab showed a higher proportion of patients reaching PASI 90 than ustekinumab and three anti-TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab, secukinumab, infliximab, ixekizumab, and tildrakizumab were more effective than etanercept. Secukinumab, ixekizumab, brodalumab, risankizumab and bimekizumab were more effective than ustekinumab. They didn’t found any serious adverse events during ustekinumab treatment (15).

In conlusion, our data suggest ustekinumab has very few side effects, and clinicians can use ustekinumab safely in cases with various comorbidities.Also, ustekinumab can be an appropriate treatment option for non-naïve cases. This affirmative effect persists in cases with favorable responses to the first or second dose of ustekinumab. Whereas, in patients with a negative response to the first or the second dose, the possibility of obtaining PASI 75 response decreases significantly. Also, male cases give more potent and more rapid responses to this treatment than female cases, and they are more willing about using ustekinumab than female patients. Since long-term real-life clinical data regarding the treatment of psoriasis with ustekinumab are rare, we believe our data will significantly contribute to the literature.

Author contributions

Both authors contributed to the writing of the original report.

Acknowledgements

M. Gönülal and D.D. Balcı organized the study. M. Gönülal, D.D. Balcı, A. Öztürk S. Doğan recruited the patients. M. Gönülal and D.D. Balcı performed the statistical analyses. M. Gönülal, D.D. Balcı, A. Öztürk S. Doğan wrote the manuscript. M. Gönülal, D.D. Balcı, A. Öztürk S. Doğan provided helpful criticism and approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data has been received in İzmir Tepecik Training and Research Hospital.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.