Tacrolimus, a calcineurin inhibitor used in atopic dermatitis as a therapeutic option in psoriasis. The literature reviewed from 2020 to 2024 indicates that topical tacrolimus is effective for the treatment of mild-to-moderate psoriasis with a good safety profile. This drug mechanism involves the inhibition of T-cell activation, which is believed to be very important in the disease process of psoriasis. Clinical trials and observational studies have evidenced marked improvements in the PASI scores, combined with reduced erythema, scaling, and induration. Besides, tacrolimus is well-tolerated with very minimal systemic absorption and fewer adverse effects compared to traditional therapies. However, its efficacy in plaque psoriasis may be limited because of the drug’s vehicle, which can provide a barrier to penetration in thickened lesions. Studies on formulation, optimization, and combination regimens continue to enhance efficacy. In genera,l tacrolimus offers a very useful therapeutic modality in the management of psoriasis of sensitive skin sites. Overall, this is an alternative to corticosteroids with fewer side effects and showing comparable efficacy.

Tacrolimus, Calcineurin inhibitor, Atopic dermatitis, Psoriasis, Sensitive areas, Systemic absorption, Vehicle.

Psoriasis is a chronic inflammatory skin disease of autoimmune origin, which is characterized by atypical differentiation and hyperproliferation of keratinocytes associated with an imbalanced inflammatory response.[1] It affects approximately 2-3% of the population worldwide and is highly heterogeneous in its form,s with plaque psoriasis being the most prevalent form.[2] There are interactions of genetic predisposition, environmental triggering, and imbalanced immune functioning, particularly T-cells and cytokines such as tumor necrosis factor-alpha, interleukin-17, and interleukin-23. These cytokines push the inflammatory cascade forward to produce the typical symptoms of psoriatic lesions, including erythema, scaling, and induration.[3]

Topical therapies remain the cornerstone in the management of psoriasis, especially in its mild to moderate forms. Corticosteroids are among the most used drugs owing to their anti-inflammatory and immunosuppressive properties. However, their long-term use is associated with significant adverse effects, including skin atrophy, striae, and tachyphylaxis, especially on sensitive areas like the face, genitals, and intertriginous zones.[4] This has been a reason for interest in alternative treatments that offer effective disease control with a better safety profile. Tacrolimus belongs to the class of calcineurin inhibitors, which are conventionally used in the therapy of atopic dermatitis but currently have expanding indications in the management of psoriasis.

Tacrolimus exerts its effect by inhibiting calcineurin. This results in the prevention of nuclear translocation of NFAT, which is one of the major transcription factors in the production of pro-inflammatory cytokines such as IL-29.[5] Here, the rationale given directly relates to T-cell activation as part of the psoriatic inflammatory cascade. Although basically formulated for atopic dermatitis, the use of tacrolimus for psoriasis has become popular, especially inverse and facial psoriasis, due to its immune-suppressive action devoid of corticosteroid-related side effects.[6]

Its therapeutic potential in psoriasis was realised first in sites where conventional treatments carried a greater risk of complications. Sensitive areas are particularly at risk of corticosteroid side effects, and hence, the non-steroidal nature and negligible systemic absorption of tacrolimus make it very useful.[7] Recent research from 2020 to 2024 has extended knowledge about the drug tacrolimus in treating the disease by assessing efficacy, safety, and patient-reported outcomes for different psoriatic subtypes and severities.[8]

Table 1: Summary of Advancements of the study over the years

Tacrolimus Advancements in Psoriasis
New topical formulations of tacrolimus have been developed that are intended for higher efficacy and fewer systemic adverse effects. Such new formulations are planned to better target the affected skin areas, thereby reducing systemic exposure to the drug.[9]

Recent literature has shed light on the effectiveness of topical tacrolimus in various forms of psoriasis, such as plaque psoriasis and psoriasis vulgaris. Further research is needed regarding optimal concentration and application regime that would yield better results.[10]

Ongoing research includes long-term safety, skin cancer risk, and other adverse effects of tacrolimus.[11] This covers the interaction of the drug on the intervention with other treatments concerning overall patient health.[12]

There is increasing interest in combining tacrolimus with other therapies, including phototherapy or systemic agents, to achieve better outcomes in the treatment and management of more severe degrees of psoriasis.[13]

This means that the progress in knowledge concerning the genetic and molecular basis of psoriasis is now being translated into more personalized approaches to treatment, including tailoring tacrolimus according to individual patient profiles and disease characteristics.[14]

Study Design: The systemic study and meta-analysis were done to evaluate the efficacy and safety of tacrolimus in psoriasis. This study was performed in accordance with the PRISMA guidelines for the whole process of the study. A detailed literature search was conducted using databases for related studies published from January 2020 to August 2024.

Data Sources and Search Strategy: Specifics of the search strategy are as follows: we searched PubMed, MEDLINE, Embase, Cochrane Library, and clinical trial registries for studies evaluating the use of tacrolimus in psoriasis, using the following MeSH terms and keywords: “Tacrolimus,” “psoriasis,” “calcineurin inhibitors,” and “topical treatment.” We only included English language publications. Reference lists from the included studies and reviews related to the subject were also screened manually for further eligible studies.

Inclusion Criteria
Studies would be included in the review if they met the following criteria:

Population: Adults or children with any form of active psoriasis, e.g., plaque, guttate inverse, or facial, as confirmed by clinical examination or biopsy.

Intervention: Topical tacrolimus given as monotherapy or in combination with other treatments.

Comparison: Comparisons with placebo or other topical agents (such as corticosteroids, vitamin D analogs) or systemic therapies.

Outcomes: Outcomes of interest include studies related to the efficacy of tacrolimus, including but not limited to PASI score, physician global assessment, and symptom improvement; safety, including adverse events and tolerability; and patient-reported outcomes such as quality of life measures.

Study Design: Randomized controlled trials (RCTs), observational studies, cohort studies, and case series of at least 10 participants.

Exclusion Criteria
Studies that met one or more of the following were excluded:

Non-psoriatic indication: In which tacrolimus was used for any indication other than psoriasis, including atopic dermatitis.

Lack of sufficient data: Studies that did not present comprehensive efficacy and safety data in psoriasis.

Duplicate publication: Duplicate, conference abstract without full data, reviews, editorials, or comments.

Preclinical animal or in vitro studies: There was no human involvement in these studies.

Small sample size: Case reports or case series were excluded if the number of participants was below 10 to avoid the potential bias due to small sample effects.

Data Extraction: Data was extracted onto a standard form by independent reviewers in pairs. Any discrepancies were resolved through discussions among reviewers.

Extracted data were not limited to the following but included Study Characteristics: Author, year of publication, country, study design, sample size, duration of follow-up. Participants’ characteristics: age, sex, type and severity of psoriasis, history of treatments.

Intervention details: Tacrolimus formulation (ointment, cream), dosage, frequency of use, treatment duration.

Outcomes: Outcomes were defined as the change in PASI score and the proportion of participants achieving PASI 50/75/90.

Quality assessment All included RCTs were assessed using the Cochrane Risk of Bias tool. For observational studies, the Newcastle-Ottawa Scale was used.

Data Synthesis and Analysis
Data extracted from the selected studies were synthesised narratively and, where appropriate, pooled using meta-analysis. Heterogeneity was assessed using the I² statistic, and random-effects models were used if significant heterogeneity was detected. Sensitivity analysis explored the influence of study quality and sample size on pooled estimates. Subgroup analyses by psoriasis subtype, formulation of tacrolimus, and study design were pre-planned.

Outcome Measures
The primary endpoint was the change in Psoriasis Area and Severity Index score from baseline to the end of the treatment period. Secondary endpoints include physician global assessment, patient-reported outcomes (e.g., Dermatology Life Quality Index), and the incidence of adverse events.

Carroll et al. (2005) conducted a study in which the researchers wanted to determine how well 0.1% tacrolimus ointment, combined with 6% salicylic acid gel, would treat plaque psoriasis. The 30 subjects in their 12-week, left-right comparative study had symmetric plaque-type psoriasis, wherein adults were randomly assigned to either the combination treatment or a vehicle control alongside 6% salicylic acid gel. The primary measure of outcome was the change in erythema, scale, and thickness sum scores from baseline to the end of active treatment.[15]

Of the 30 participants, 24 completed the trial. The combination treatment was well tolerated and demonstrated greater improvement in the sum score of the treated plaques compared with the control at weeks 1, 2, and 8, reaching statistical significance (P<.05). Efficacy of the regimen was confirmed by both investigator and subject assessments.

Based on this small sample size, the authors concluded that 0.1% tacrolimus ointment, combined with 6% salicylic acid gel, is an effective modality of treatment for plaque psoriasis. The magnitude of the observed effect was sufficient to attain statistical significance and thus indicates a promising therapeutic approach.

Thapa et al. (2014) discussed the efficiency of tacrolimus-loaded LCNs as topical delivery systems for the treatment of psoriasis-like skin inflammation. Chronic and relapsing features of the disease in 2-3% of the global population, developing an efficient delivery system for tacrolimus is of significant interest.[16]

In this study, the authors characterized two types of nanoparticles: one based on monoolein and the other on oleic acid added to monoolein. The nanoparticles had sizes of 149.1 nm and 204.3 nm, respectively, with an entrapment efficiency of tacrolimus exceeding 99%. The study demonstrated that the use of LCNs significantly increased both the permeation and retention of tacrolimus in the skin.

Results obtained from in vivo studies showed that tacrolimus-loaded LCNs were much more effective in reducing the psoriasis-like skin inflammation in comparison with the tacrolimus dissolved in propylene glycol. Such findings may suggest the use of LCN as an alternative delivery system to improve the therapeutic efficacy in the treatment of psoriasis.

Lebwohl et al. (2004) investigated the efficacy and tolerability of 0.1% tacrolimus ointment for the treatment of facial and intertriginous psoriasis, both of which are different from other forms of psoriasis in terms of sensitive locations.[17]

Details of the Study
Design: An 8-week, randomized, double-blind, vehicle-controlled, multi-center trial.

Participants: 167 and age 16 years or older.

Intervention: Topical application of tacrolimus ointment 0.1% or vehicle to active psoriatic lesions twice daily.

Assessment: Physician’s global assessment and a 6-point scale measuring psoriasis severity.

Results
Early Improvement: By day 8, a significantly greater proportion of subjects receiving tacrolimus had cleared or achieved excellent improvement, 24.8%, compared with vehicle, 5.8% (P = .004).

End of Study: At 8 weeks, 65.2% of the tacrolimus group and 31.5% of the vehicle group were clear or almost clear (P < .0001).

Adverse Events: Rates were comparable between the tacrolimus and vehicle groups.

The efficacy and safety of tacrolimus ointment 0.1% demonstrated that this could serve as a therapeutic modality in psoriasis affecting facial and intertriginous sites, where topical corticosteroids might result in adverse effects.

Rallis et al. (2005) investigated the efficacy of 0.1% tacrolimus ointment in treating genital and facial psoriasis.[18]

Study Details
Objective: To assess the efficacy of 0.1% tacrolimus ointment in psoriasis affecting the anogenital region and face.

Participants: 10 patients with chronic genital and facial psoriasis poorly controlled by topical corticosteroids.

Treatment: Application of 0.1% tacrolimus ointment twice a day for 10 days.

Follow-up: Every 3 weeks over a period of 12 weeks.

Assessment: The severity of the psoriasis was evaluated according to erythema, scaling, infiltration, and lesional extent on a 0-3 scale. One overall severity score was calculated. Patient-reported outcomes on efficacy, safety, and tolerance were also collected using a 0-5 scale.

Clinical Assessment: Patients were assessed at the start and at weeks 3, 6, 9, and 12. The decision for further application was made based on clinical response only.

Results
Initial Improvement: There was marked improvement in all cases within the first week of treatment without any drug-related side effects.

Recurrences: During the 12-week follow-up study, recurrences were observed in 15 patients.

Final Assessment: The 0.1% tacrolimus ointment was safe and effective in the treatment of genital and facial psoriasis. Good efficacy, safety, and tolerance were reported.

Topical 0.1% tacrolimus ointment may thus present a promising new modality for the treatment of genital and facial psoriasis, resulting in significant clearing without significant side effects. Further studies are necessary to determine optimal dosage and long-term maintenance.

Brune et al. (2007) conducted an open-label trial of 0.1% tacrolimus ointment in pediatric patients with facial and intertriginous psoriasis.[19]

Details of the Study
Objective: To investigate the efficacy of tacrolimus ointment 0.1% for the treatment of facial or inverse psoriasis in children.

Subjects: Eleven Patients with facial or intertriginous psoriasis aged between 6 years to 15 years were included for this study.

Design: A 6-month, single-center, open-label trial was performed.

Assessment Time: Baseline, 30 days, 90 days, and 180 days.

Assessment: Improvement was assessed by the physician’s global assessment of improvement, a 6-point rating scale for signs of disease erythema, infiltration, desquamation, and an overall severity score.

Results
Initial Improvement: All patients showed either clearing or excellent improvement with tacrolimus ointment within the first 30 days of treatment.

Statistical Significance: Each sign of the disease (erythema, infiltration, desquamation) and overall severity score improved significantly.

Adverse Events: The only adverse event reported was severe itching in one patient, without any other remarkable side effects.

Some of the indications revealed that tacrolimus ointment, 0.1%, was a very effective, well-tolerated therapeutic option for facial and intertriginous psoriasis in children, serving as a very promising alternative to corticosteroids, which may be associated with adverse effects in these sensitive sites.

The calcineurin inhibitor tacrolimus is one that is usually used for atopic dermatitis but has recently gained increasing importance as an alternative treatment in psoriasis and sensitive skin areas like the face and intertriginous regions (Del et al., 2013).[20] Recent studies from 2020 to 2024 have reinforced its potential efficacy and safety profile in the management of psoriasis although some limitations persist (Dé et al., 2001).[21]

The principal advantages of tacrolimus for the treatment of psoriasis are that it is a non-steroidal drug and only minimally absorbed systemically. In contrast corticosteroids, though quite effective have a high risk for atrophy of the skin and other side effects particularly in long-term therapy and in sensitive areas of the skin (Remitz et al., 1999). [22] It exerts its therapeutic effect by inhibiting the activation of T cells through calcineurin-NFAT-a pathway which is significant in the inflammatory process of psoriasis. This targeted approach minimizes the systemic side effects often seen with corticosteroids. (Baveja et al., 2022).[23]

Clinical improvement, defined as significant reductions in Psoriasis Area and Severity Index scores, has been documented in several clinical trials and observational studies with topical tacrolimus (Wang et al., 2014).[24] In these, a reduction in erythema, scaling, and induration confirms that tacrolimus has the potential to control mild to moderate psoriasis effectively (Pischon et al., 2018).[25] Besides this, tacrolimus is well-tolerated: side effects are relatively uncommon and less severe compared to those associated with traditional therapies. This favorable safety profile is of advantage in those patients requiring treatment for extended periods or in patients with psoriasis in sensitive areas (Bayliffe et al., 2004).[26]

Despite these advancements, it is crucial to consider the limitations of the current evidence. Many studies have small sample sizes, which can impact the generalizability of the findings. Additionally, the long-term safety and efficacy of tacrolimus in psoriasis, especially in comparison to newer systemic or biologic therapies, remain areas for further research (Gomes et al., 2023).[27]

Recent developments
Recent improvements in the use of tacrolimus for psoriasis also concern formulation and delivery systems that enhance its efficacy while reducing its side effects. Newer topical formulations, including combinations with other agents or newer nanocarriers, showed better skin penetration and provided site-specific action, thereby giving better clinical responses. Further research into the mechanism of action of tacrolimus has also revealed its ability to modulate immune responses; this can be beneficial in controlling inflammation and improving skin health in psoriasis patients. Other current investigations also involve its use in combination with either biologics or other systemic treatments to maximize outcome and management of the patient.

Efficacy
Literature review indicates that topical tacrolimus proves to be effective for the treatment of mild-to-moderate psoriasis, and many studies confirm significant improvements in PASI scores. Clinical trials and observation studies have shown consistent reduction of erythema, scaling, and induration, which are key features of psoriasis. The improvement can be statistically significant, and it confirms that tacrolimus is a viable alternative to corticosteroids, particularly on sensitive areas like the face and intertriginous zones.

The main advantageous use of tacrolimus is the treatment of inverse psoriasis and facial psoriasis, where corticosteroids are often poorly used because they lead to epidermal thinning and other adverse drug reactions. Such literature roles of tacrolimus in those specific fields are supported in reviewed literature outlining the capabilities of the treatment of psoriasis with minimal complications (Mittal et al., 2016).[28]

Safety Profile
Given its negligible systemic absorption, tacrolimus is well-tolerated compared to the side effects seen with the long-term use of corticosteroids. This offers a very favorable safety profile, especially in patients who require chronic treatment or have psoriasis affecting sensitive areas. Recent publications confirm findings of low rates of adverse events and lower severity compared to traditional therapies. This enhances its acceptability as a therapeutic choice in patients at risk of corticosteroid-induced side effects.

Formulation and Delivery
Recent development efforts have geared towards enhancing the efficacy and delivery of tacrolimus with new formulations. Development of novel delivery systems includes nanoparticles loaded with tacrolimus and microneedle patches to increase drug penetration and retention within the skin. Advanced drug delivery systems are thus designed to overcome pitfalls related to the vehicle of the drug, which, in some conditions, is not able to penetrate properly, particularly in thickened psoriatic plaques. These formulation developments mark significant steps toward the optimization of tacrolimus therapy and better patient outcomes.

Limitations and Future Directions
Despite these promising results, several limitations remain that must be addressed. Many of the studies that had been reviewed were small, reducing the generalizability of the results. For example, while tacrolimus is very promising, further studies on its long-term safety and efficacy are called for. There is a dire need, especially for studies to address the possibility of skin malignancy and other adverse effects with which this drug has been associated in its long-term use.

However, while tacrolimus is effective in the management of mild-to-moderate psoriasis, its efficacy in severe plaque psoriasis may be limited. Current studies are focused on investigating combination regimens and optimized formulations that may give further improvements in the therapeutic response with this agent in more severe cases. Ongoing research investigating the use of tacrolimus in combination with other therapies, including phototherapy or systemic agents, may provide for broader strategies in the management of psoriasis (Rivard et al., 2006).[29]

We are seeing the development and relevance of personalized medicine approaches in the treatment of psoriasis. The latest progress could be recorded to include tailor-made patient formulations and treatments based on unique profiles and disease patterns. This, therefore, forms a basis for personalized medicine approaches with the objective of ensuring maximum therapy while reducing adverse effects, thereby increasing the usefulness of tacrolimus in treating psoriasis.

Tacrolimus is one of the important alternatives in the treatment of psoriasis, and it may be applied to sensitive regions where the use of classic corticosteroids is contraindicated. Its mechanism of action, safety profile, and recent improvements in pharmaceutical formulations make it effective in treating mild-to-moderate psoriasis. Even though current evidence already supports its indication as an alternative to corticosteroids, research studies should not be discontinued, considering the limitations and needs for strategy optimization. The future of tacrolimus in psoriasis treatment is one of continuous innovation and personalized approaches, thus offering more efficient and safer treatment options to the patients (Ortonne et al., 2006).[30]

Not applicable

Corresponding Author:
Mansi Srivastava
Independent Researcher, Department of Content
medtigo India Pvt Ltd, Pune, India
Email: srivastavamansi811@gmail.com

Co-Authors:
Raziya Begum Sheikh
Independent Researcher, Department of Content
medtigo India Pvt Ltd, Pune, India
Email: raziya.pharma@gmail.com

Samatha Ampeti
Department of Pharmacology
Kakatiya University, University College of Pharmaceutical Sciences, Warangal, TS, India
Email: ampetisamatha9@gmail.com

Shubham Ravindra Sali
Independent Researcher, Department of Content
medtigo India Pvt Ltd, Pune, India
Email: shubhamsali42@gmail.com

Sonam Shashikala B V
Independent Researcher, Department of Content
medtigo India Pvt Ltd, Pune, India
Email: venkateshsonams@gmail.com

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation, and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

Not applicable

Not applicable

None

https://doi.org/10.63096/medtigo3061114

Mansi S, Raziya BS, Samatha A, Shubham RS, Sonam SBV. A Critical Review of Tacrolimus for Psoriasis: Mechanisms, Efficacy, and Clinical Outcomes. medtigo J Pharmacol. 2024;1(1):e3061114. doi:10.63096/medtigo3061114 Crossref