Psoriasis in solid organ transplant patients: best practice recommendations from The Medical Board of the National Psoriasis Foundation

Abstract

Background: Treatment of solid organ transplant patients who have psoriasis can be a therapeutic challenge. Biologic and systemic drugs used to treat psoriasis can result in an increase in infections or malignancies.

Objective: We sought to develop a treatment algorithm for organ transplant recipients (OTR) diagnosed with psoriasis vulgaris.

Methods: A systematic literature search for psoriasis treatment in organ transplant patients was performed using MEDLINE and GOOGLE.

Results: In mild-to-moderate disease, topical therapy should be a first-line treatment. In moderate-to-severe disease, first-line treatment is acitretin with narrow band ultraviolet light (NBUVB), NBUVB, or acitretin. Second-line treatment is increasing the current antirejection drug dose. Other systemic or biologic therapies should be reserved for more severe or refractory cases.

Conclusion: No systematic clinical studies have been done to explore psoriasis treatments among affected solid organ transplant patients who have psoriasis, and only a few case reports are available. The algorithm for best practices was developed based on these reports and on the clinical experience and judgment of the Medical Board of the National Psoriasis Foundation. There remains a need for further research on the management of psoriasis in the organ transplant patient population.

Keywords:

• Psoriasis
• solid organ transplant
• National Psoriasis Foundation

Introduction

Psoriasis vulgaris is a chronic immune-mediated inflammatory disease affecting approximately 3% of the US population [1]. Nearly 30,000 solid-organ and 18,000 bone marrow or umbilical cord blood transplants are performed in the US annually [2]. Organ transplant recipients receive immunosuppressive therapies that put them at increased risk of infections and certain malignancies.

As a consequence of the required degree of immunosuppression needed to prevent graft rejection, psoriasis often clears acutely in the immediate post-transplantation period. However, thereafter when patients are transitioned to a maintenance dose of immunosuppression, psoriasis may recur or flare. This also may be impacted by the choice of immunosuppressive medications, the organ transplanted and tolerability for the individual patient.

The oral systemic and biologic treatments used in psoriasis, in addition to the antirejection drugs taken by this group, could potentially increase the risks of infections, malignancy, graft toxicity or drug interactions. The goals of this paper are to provide guidance on treating the psoriasis OTR population.

Methodology

A MEDLINE search was performed from January 1 1970 until June 30, 2016, of the terms ‘psoriasis’, ‘organ transplant’ and the name of the therapy. The articles were evaluated with levels of evidence, previously reported by Shekelle et al. [3]. Category IA evidence consists of data from meta-analyses from multiple randomized controlled trials (RCT). Category IB evidence includes data from at least one RCT. Category IIA includes nonrandomized controlled studies, IIB includes evidence from at least one other type of quasi-experimental study. Nonexperimental studies, comparative studies, correlation studies, case–control studies are Category III. Expert committee reports, opinions and clinical experience from respected authorities are graded Category IV. Limited data are available on the treatment of psoriasis in organ transplant patients as these patients typically are excluded from RCTs.

Results

The research literature on treating psoriasis in organ transplant recipients consists entirely of case series. The lack of systematic clinical research in this area necessarily limits the confidence with which lessons can be derived from the literature as well as any recommendations for treating this population.

I. Topical therapies: evidence IV

Topical therapies should serve an important role in the treatment of psoriasis in OTRs based on their known safety, efficacy and low risk of systemic side effects.

• Topical steroids: Three case reports in organ transplant patients with severe psoriasis showed no response to topical steroids [4–6].

• Combination topical steroids + vitamin D3 analogs: There is no case report in the literature in the OTR population.

• Vitamin D3 analogs: There is no case report in the literature in the OTR population. In the non-OTR psoriasis population, use of topical vitamin D3 can reduce total ultraviolet dose [7] and increase efficacy when used in combination with acitretin [8].

• Topical calcineurin inhibitors (TCI): The FDA has warned against use of TCIs pimecrolimus and tacrolimus in the immunosuppressed population. Therefore, at this time, these should be used only second line.

• Topical retinoids: There is no case report in the literature in the OTR population. In the non-OTR psoriasis population, tazorotene 0.1% gel reduced number of NBUVB treatments versus NBUVB alone [9] which could potentially reduce future skin cancer formation.

• Dithranol: One case report in a patient with a pancreas–kidney transplant showed no response to dithranol in severe psoriasis [4].

II. Retinoid-NBUVB: evidence IV

• Acitretin with NBUVB has the advantage of better efficacy and fewer UVB treatments. Acitretin is a known chemoprotective agent in preventing SCC’s in the psoriasis and OTR populations [10–12].

• Although there are no case reports or studies in the psoriasis OTR population, we recommend NBUVB be used in conjunction with acitretin, rather than monotherapy, whenever possible.

III. Narrow band ultraviolet B (NBUVB): evidence IV

• NBUVB is an effective treatment for psoriasis and has the advantage of avoiding systemic toxicity or drug interactions. Its disadvantage is that there is a risk of inducing skin cancer, especially in Fitzpatrick skin types I–III. NBUVB been shown to have a reduced risk of NMSC versus psoralen with UVA (PUVA). A retrospective study using a Scottish Cancer Registry showed no significant association between NBUVB and BCC, SCC or melanoma [13]. Its use is safest in Fitzpatrick skin types IV–VI.

• The fewest treatments and lowest doses of NBUVB possible should be used to clear psoriasis. Patients should be counseled on minimizing sun exposure to reduce additional ultraviolet exposure.

• No case reports or studies are published regarding use of NBUVB in the organ transplant psoriasis patient population. NBUVB has been shown to be safe and effective in the treatment of cutaneous graft versus host disease following allogeneic bone marrow transplantation [14].

IV. ACITRETIN: evidence IV

• Acitretin is FDA approved to treat psoriasis, but no study exists in the psoriasis OTR population. We recommend acitretin the best systemic choice, because it is not immunosuppressive and can reduce NMSC in the OTR population.

• A single case report in a psoriasis patient who underwent a liver transplant showed use alone and with PUVA [5]. Acitretin was discontinued as a result of elevated triglycerides.

• Acitretin has been shown in a number of studies to reduce the number of SCCs in patients treated with PUVA and in OTRs [10,11]. A review of RCTs on the use of oral retinoids in OTRs was performed. Data from these small numbers of trials suggest that acitretin may reduce NMSCs in the OTR patient [15].

V. Cyclosporine evidence IV

• Cyclosporine (CSA) is an antitransplant rejection therapy and is very efficacious in the treatment of psoriasis, but due to the long-term risks of developing NMSCs and renal side effects, its risks outweigh its benefits for long-term use in the psoriasis OTR population.

• Although there is no case report or study in psoriasis OTR patients, CSA is a potent immunosuppressive agent widely used in organ transplantation. CSA is extremely effective in the treatment of psoriasis and was FDA approved in 1997. Nephrotoxic side effects such as acute azotemia, hypertension, tubular dysfunction or chronic progressive renal disease can occur which limits its long-term use in psoriasis.

VI. Apremilast: evidence IV

• There are no case reports or studies on the use of apremilast in the organ transplant population. The immunosuppressive effects of apremilast are unknown, but as inhibitors to phosphodiesterase 4 can modulate the inflammatory response, the use of apremilast should be third-line until further data are available.

• Apremilast exposure is decreased when administered concomitantly with strong inducers of CYP3A4, ex rifampin, and these combinations may result in reduced clinical response. One needs to reduce apremilast dose if the patient has significant renal impairment [16].

VII. Ustekinumab: evidence IV

• No study or case report in OTRs with psoriasis.

• This class of biologics have also been reported to rarely induce skin cancer or serious infections.

VIII. Secukinumab/ixekizumab/brodalumab: evidence IV

• No study or case report in OTRs with psoriasis.

• Infections and malignancies have been reported with this class of drug.

IX. TNF inhibitors (TNFI)

TNF (tumor necrosis factor) mediates inflammation and modulates cellular immune responses. Inhibitors to TNF affect host defenses against infections and development of malignancies among certain populations.

• Large registries of etanercept [17] and adalimumab [18] in psoriasis and retrospective cohort studies of TNFIs in psoriasis and all other indications for a TNFI do not indicate a higher risk of serious infection [19] or NMSC [20].

• However, the PSOLAR registry showed that ‘other biologics’ (mostly etanercept and adalimumab) had higher risk of infection versus nonbiologics (adjusted hazard ratio, 1.96; CI 95%, 1.57–2.44) [21].

• Use of TNFI’s in OTRs could potentially increase the risk of NMSC or serious infections per label. Therefore this class of drugs should be used third line in the moderate–severe psoriasis OTR population.

(A) Etanercept: evidence IV

• Three case reports involving OTR’s with psoriasis show clinical improvement with no reduction of graft function and no increase in infection or malignancy risks with up to two years follow-up [4–6].

(B) Adalimumab: evidence IV

• No study or case report in OTRs with psoriasis.

(C) Infliximab: evidence IV

• No study or case report in OTRs with psoriasis.

X. Methotrexate: evidence IV

• MTX is an effective systemic drug for psoriasis, and it is not a potent immunosuppressant in low dosages. Its use in the OTR patient is limited by its risks to the transplanted organ. It can cause cumulative toxicity in a liver transplant patient, and systemic toxicity may result due to impaired excretion in a kidney transplant.

• A single case report in a liver transplant patient with psoriasis showed use in low dose 5 mg/week. It was discontinued due to increased liver enzymes [5].

XI. PUVA: evidence IV

• A single case report in a liver transplant patient with PsO who was treated with retinoid and psoralen with ultraviolet A (rePUVA). The treatment was discontinued due to the development of bullous pemphigoid [5].

• PUVA is well documented to increase NMSC and melanoma risk. Therefore, its use in the OTR psoriasis population is contraindicated.

Discussion

Patients who have received organ transplants are prescribed immunosuppressive agents to prevent graft rejection. Systemic or biologic drugs for psoriasis have not been evaluated in this patient population in psoriasis trials. Patients with OTRs are already at increased risk of skin cancers and infections, and therefore, the goal of psoriasis therapy should be to minimize this risk.

Ten members of the medical board of the NPF answered four questions in a survey asking about preferences of therapy in this population, and this helped create four treatment algorithms.

Table 1. Therapy for mild-moderate psoriasis in OTR population.

Topical therapy	Topical corticosteroids
First line	Combination agents (calcipotriol/betamethasone)
	Vitamin D analogs (calcipotriol, calcipotriene)
Second line	Tacrolimus ointment or pimecrolimus cream (Preferably used short, not long-term, can be used if failure of other topicals or for areas that are intolerant to topical steroids)
	Tazarotene
	Tar-based therapy

Topical therapy for psoriasis, due to its reduced systemic risks is an appropriate starting therapy for psoriasis OTR patients with mild-to-moderate skin disease (Table 1). Although case reports in the OTR population with severe psoriasis did not show efficacy, it is likely that positive response is underreported. Therefore, we believe many patients with mild/moderate disease should benefit from topical agents. The package inserts of both TCIs ‘shortened the time to skin tumor formation in an animal photocarcinogenicity study.’ However, only the package insert of tacrolimus ointment said ‘it is prudent for patients to minimize or avoid natural or artificial sunlight exposure.’ Margolis et al. published a lack of association between exposure to these drugs and skin cancer in adults [22]. There is insufficient evidence in the epidemiologic literature to infer whether TCIs do or do not cause malignancy [23]. Since further studies need to be performed to clarify this issue, these compounds should be considered second-line topical therapy.

In the clinical context of an immunosuppressed OTR patient, acitretin, which is not immunosuppressive and has chemoprotective properties, with NBUVB is our first-line systemic choice (Table 2).

Table 2. First-line therapy for moderate–severe psoriasis in OTR population.

Therapy	Comment
Acitretin and NBUVB	NBUVB best used in Fitzpatrick skin types III-VI
NBUVB alone	If acitretin not indicated or intolerant. Addition of topical tazarotene 0.1% gel or vitamin D3 analogs may increase efficacy and decrease overall UV exposure
Acitretin	In combination with topical calcipotriol increases efficacy. Avoid with severe liver or renal dysfunction or uncontrolled hyperlipidemia

The choice of therapy for psoriasis will also depend on the organ transplanted. Methotrexate with its known cumulative liver toxicity would be relatively contraindicated in liver transplant patients. As it is excreted via the kidneys, it should be used with caution in patients with insufficient renal function. In renal transplant patients, cyclosporine or apremilast would be less likely used. Acitretin is contraindicated for the women of childbearing potential. It should be avoided in patients with moderate-to-severe liver dysfunction, severe renal dysfunction or uncontrolled hyperlipidemia [2].

In the psoriasis nonimmunosuppressed population, the combination of acitretin and UVB has been published in one RCT, two open label studies and one retrospective investigation. Results demonstrated better efficacy and fewer UVB treatments in the combination group [12]. Some studies show NBUVB as effective as PUVA in PsO, but others do not [24]. Overall the increased risk of skin cancers with PUVA outweighs any clinical benefit over NBUVB in the OTR population (Table 3).

Table 3. Contraindicated for psoriasis in OTR population.

Therapy	Comment
PUVA	May increase NMSC risk

NBUVB, which is also associated with lower skin malignancy risk than PUVA, would be a safer choice. In patients who fail to adequately respond to acitretin alone or with topicals, the combination of acitretin with NBUVB would be an effective systemic combination. This combination would have the lowest risk of immunosuppression and would potentially lower overall ultraviolet exposure.

Tazarotene 0.1% gel in combination with NBUVB showed a faster response and significantly lower median cumulative UV exposure than UVB alone [9]. More cautious increments of UVB dosing are needed as retinoids increase erythemogenicity. Several studies showed that vitamin D3 analogs, when used after NBUVB, also reduce the total ultraviolet dose [7]. Therefore, based on these studies, the addition of tazarotene 0.1% gel or a topical vitamin D to NBUVB would be a favorable combination therapy. This would potentially increase NBUVB efficacy and minimize ultraviolet exposure in patients at risk of NMSC.

Topical calcipotriol with acitretin had a statistically significant effect on PASI score compared to acitretin alone. The combination resulted in a significantly lower cumulative dose of acitretin [25]. A Korean study showed that at 12 weeks, 40% of patients using topical calcipotriol with acitretin achieved complete clearance versus 15% in the acitretin monotherapy group [8]. Second-line therapy for moderate-to-severe psoriasis would be to suggest to the transplant surgeon to increase the current dose of antirejection drugs or switch to mTOR inhibitors (Table 4).

Apremilast is a novel orally active compound that modulates multiple inflammatory pathways through targeted PDE4 enzyme inhibition. No studies or case reports are available with its use in the OTR population.

There are no case reports with the use of ustekinumab, secukinumab, ixekizumab or brodalumab in the psoriatic OTR. Based on limited data, it appears that these may be tried in the organ transplant population as a third-line choice for severe refractory psoriasis (Table 5).

Table 4. Second-line therapy for moderate-to-severe psoriasis in OTR population.

Therapy	Comment
Suggest to transplant surgeon to increase current dose antirejection drugs (CsA, tacrolimus, mycophenolate mofetil (MMF)) or switch to mTOR inhibitors (sirolimus and everolimus)	CsA avoid in renal transplants Tacrolimus preferred over CsA Tacrolimus with MMF instead of azathioprine (which is photosensitizing) mTOR inhibitors switch is instituted no less than 6 months post-transplant in recipients with stable graft function

There are several case reports of etanercept use in psoriatic organ transplant patients, and no allograft dysfunction was reported in any of the three cases [4–6]. A randomized, controlled, investigator-blinded pilot study showed that the combination of etanercept dosed at half the standard psoriasis dose 25 mg S/Q once per week plus acitretin 0.4 mg/kg/day was as effective as etanercept 25 mg twice per week, and more effective than acitretin alone in plaque psoriasis [26]. The advantage with this regimen is that one can achieve equal efficacy with less immunosuppression. Given a potentially increased risk of NMSC development with TNFI, it is advisable to add acitretin, when possible, to TNFIs to attempt to reduce the risk of NMSC. There is no case report of psoriasis patients with organ transplants on adalimumab or infliximab. Based on this limited data, etanercept, adalimumab or infliximab can be used as third line therapy in refractory moderate-severe psoriasis (Table 5).

Table 5. Third-line therapy for moderate-to-severe/refractory psoriasis in OTR population.

Therapy	Comment
Apremilast	Avoid with strong CYP3A4 inducers and severe renal impairment
Ustekinumab	PSOLAR data indicate low risk of infections and cancer in nontransplant psoriasis population
Secukinumab, ixekizumab, or brodalumab	Lack of data for IL-17 inhibitors
Etanercept, adalimumab, or infliximab	TNFI’s may increase SCC risk therefore adding acitretin when possible is advised
Methotrexate	Avoid in liver transplant patients, caution in renal transplant patients

In summary, each patient with psoriasis has to been treated individually based on history, severity, comorbidities and risks factors. Decisions on psoriasis treatments should ideally be made after communication with the patient’s organ transplant physician, as these patients require a team effort for optimal care. Consider the risks and benefits of treatment prior to initiating therapy and closely monitor this high-risk group for signs and symptoms of infection or malignancy, especially considering the hazards of combining multiple immunosuppressive agents. After consultation with the transplant team, ensure vaccines such as herpes zoster prophylaxis, are administered or updated prior to initiating additional immunosuppressive psoriasis therapy [27]. For a patient who develops a new infection, perform or refer them for a prompt and complete diagnostic work up and initiate appropriate antimicrobial therapy. Patients who are immunosuppressed as a result of organ transplantation should always be screened carefully for skin cancers and degree of actinic damage before starting psoriasis therapy. Full body skin examinations should also be part of routine follow-up in these patients.

Disclosure statement

No potential conflict of interest was reported by the authors.