Oral Systemic Therapy for Psoriasis

Introduction

Any practitioner who cares for patients with psoriasis should be familiar with and make use of systemic therapies. These medications are clearly indicated for patients who have diffuse disease where topical treatment or phototherapy is not feasible or for localized activity that has a significant associated disability or loss of quality of life that has not responded to more limited treatment techniques. Nonetheless, surveys suggest that only a fraction of patients with extensive disease are treated with systemic therapy for reasons that remain unclear.

Systemic medications for psoriasis can be broadly classified into oral systemic medications and biologic therapies. Biologics will be reviewed in Biologic Therapy for Psoriasis. There are five oral systemics that are approved in the United States (Table 11-1) and make up the overwhelming majority of the oral systemic therapies used worldwide:

• Methotrexate, the most commonly used and first of these mediations approved for treatment of psoriasis
• Cyclosporine
• Acitretin, a metabolite of the earlier retinoid, etretinate
• Apremilast
• Deucravacitinib.

Other than fumaric acid esters that are commonly used in Germany, no other agent has significant general usage worldwide.

A side effect monitoring chart for these five oral systemics is provided in Table 11-2.

One important point should be made. A very common misnomer, particularly among rheumatologists, is to call these medications “disease-modifying drugs.” This appellation stems from their perceived equivalence to Disease-Modifying Antirheumatic Drugs (DMARD) medications for rheumatoid arthritis (RA) and psoriatic arthritis (PsA). While disease modification is a much clearer concept in inflammatory arthritis based on changes in disease course and permanent damage of joints, there is no evidence for any medication that there is actual disease modification in psoriasis. While oral systemic and biologic medications do, in fact, improve the activity of disease, it is incorrect to refer to any treatment of psoriasis as disease-modifying. Thus, methotrexate, acitretin, cyclosporine, apremilast and deucravacitinib should best be referred to as oral systemic therapies.

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Methotrexate

By far, the most common oral systemic used for psoriasis around the world is methotrexate. Methotrexate was approved for use for psoriasis by the FDA in 1972 but was used commonly for years prior to approval. Its many advantages include being inexpensive, easy to use and generally well tolerated.

Methotrexate is an anti-metabolite medication that was originally used as a chemotherapeutic agent for a variety of cancers. Methotrexate blocks the dihydrofolate reductase system, leading to death of rapidly proliferating cells that require high levels of folic acid. In psoriasis, it was thus concluded for many years that methotrexate inhibited the rapid proliferation seen in epidermal keratinocytes of the psoriatic plaque.

However, in the 1990s, a new possible mechanism was proposed. Methotrexate was shown to increase extra-cellular adenosine production in inflammatory conditions. This increase in adenosine can have significant impact on the activation of local inflammatory cells, including macrophages, dendritic cells and T cells. Thus methotrexate has significant anti-inflammatory effects. With the change in perception that psoriasis is primarily an inflammatory rather than primarily proliferative disease, the adenosine hypothesis for the activity of psoriasis has become generally accepted.

Methotrexate Efficacy

Our understanding of methotrexate therapy for psoriasis is incomplete. Methotrexate came into common usage for more extensive psoriasis in the 1970s, prior to the application of more modern clinical trials methodology to psoriasis trials. Exact measures of psoriasis efficacy did not become available until methotrexate began to be compared with newer medications in the past decade.

The first published randomized trial using methotrexate was a comparison between methotrexate and cyclosporine in 2003. In this trial, an aggressive dosing schedule, but with only 43 subjects treated, resulted in a PASI 75 of 60%. This result, despite a similar study showing a lower Psoriasis Area and Severity Index (PASI) 75 result of 25%, led to a general acceptance that methotrexate worked well in the majority of psoriasis patients.

As methotrexate was studied in trials with biologic treatments, a more consistent picture of efficacy has emerged. In randomized trials comparing methotrexate with adalimumab and infliximab, the PASI 75 result for methotrexate was 36% and 42%, respectively, at 16 weeks. These studies were criticized as underestimating the response to methotrexate due to their short duration and less aggressive dosing of the medication. However, a longer-term, more aggressive dosing schedule was used when methotrexate was compared with infliximab and showed a PASI 75 of 41% at 16 weeks. The general feeling among practitioners is that on a population basis, methotrexate is a moderately effective medication with a PASI 75 of about 40%.

This consensus was given further credibility with the publication of likely the best trial of methotrexate to date, the METOP trial. In this trial, subjects were aggressively dosed with subcutaneous methotrexate, starting at an initial dose of 17.5 mg weekly. The belief was that it was important to use subcutaneous dosing to give the most consistent absorption of the medication and start with high doses to best understand the maximal potential efficacy of methotrexate. At 16 weeks of therapy, 41% of subjects obtained a PASI 75 response compared to 10% in the placebo group. Moreover, with extended use and a protocol that permitted increasing doses, 45% of patients achieved a PASI 75 at 52 weeks. These results closely follow those of the biologic comparator trials mentioned above. One final question is of great importance when discussing methotrexate. Many clinicians believe that methotrexate needs to be given up to 12 or even 24 weeks to see if a patient will respond sufficiently to the medication. This belief has come into question through an analysis of the adalimumab and briakinumab comparator studies with methotrexate. Investigators have determined that the great majority of patients who will go on to have a PASI 75 response to methotrexate will have at least some (PASI 25) response at 4 weeks of treatment. This finding was consistent whether the protocol had an aggressive or conservative treatment approach to methotrexate. Thus, while it still may be reasonable to follow patients on methotrexate for a few more weeks, if a patient has no early response to methotrexate, it is very reasonable to move on to other, potentially more efficacious, therapies.

Methotrexate Safety

Like efficacy, the safety of methotrexate is not fully understood in dermatology. As there are no long-term clinical trials or good prospective registries to study this issue, a more general discussion is necessary. The safety concerns with methotrexate fall into a number of broad categories:

• Hepatic
• Hematologic
• Other toxicities and intolerances.

All of these issues have a few similar predisposing risk factors. First, since methotrexate is renally excreted, patients with reduced renal function are at greater risk of side effects, probably because the effective dose is increased as excretion decreases. Patients with renal dysfunction, including the elderly or those who are on medications such as NSAIDs that could decrease renal removal of the medication, are at greater risk. Additionally, certain medications, particularly sulfa-based antibiotics that alter the folate synthesis pathway, can significantly magnify the side effects of methotrexate.

Patients treated with methotrexate should be concomitantly treated with folic acid supplementation as well. While the exact dosing, schedule and form of this supplementation is not clear based on clinical trial information, it is generally accepted that at least 1 mg daily of folic acid decreases intolerance side effects and, most importantly, hepatic toxicity in RA patients. It is doubtful that there is a significant alteration in the risk of hematologic toxicity.

Hepatic Toxicity

In dermatology, the side effect of greatest concern is hepatic toxicity. The incidence of this toxicity is unclear in patients with psoriasis but it is probably higher than in inflammatory arthritis patients due to increased alcohol use and obesity with associated non-alcoholic steatohepatitis (NASH) in the psoriasis population. For this reason, alcohol use should be severely limited in patients taking methotrexate and liver function tests should be checked periodically. Patients should be screened for abnormal liver function and hepatitis prior to starting treatment.

The most controversial issue in methotrexate use in psoriasis is the use of liver biopsy. Although the incidence is unclear and is likely very low, there are reported cases of hepatic fibrosis associated with methotrexate with normal liver function tests. In the 1970s and 1980s, it was suggested that regular liver biopsy could identify patients at risk for liver fibrosis related to methotrexate and should be done in all patients. The original proposal was for a biopsy prior to treatment, at 1.5 g of therapy and then every 1 g of continued treatment. It has been suggested that the incidence of hepatic fibrosis is probably lower than initially believed in patients without risk factors. These risk factors are listed in Table 11-3. Thus, the recommendations of the American Academy of Dermatology and the National Psoriasis Foundation have decreased the frequency of recommended liver biopsy. The recommendations are outlined in Figure 11-1. Given the high morbidity associated with liver biopsy, others have recommended the use of tests that lower the pre-test probability of fibrosis in patients with normal transaminases, particularly the amino-terminal peptide procollagen III test. Unfortunately, this test is not available in the United States.

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Hematologic Toxicity

Hematologic toxicity, particularly pancytopenia and myelosuppression, is a frequent concern for patients on methotrexate. Hematologic toxicity comes as both acute and more chronic problems. Acute pancytopenia can occur idiosyncratically in patients first exposed to methotrexate. Smaller initial doses are generally preferred during the first few weeks of exposure. Many practitioners will use a test dose of 5 mg with blood counts measured in 5 to 7 days after this initial dose to try to minimize the severity of this toxicity. Others will simply start with lower doses of 7.5 mg to 10 mg weekly and re-check the blood counts in 2 to 3 weeks prior to increasing the dose. More chronic bone marrow suppression is generally related to problems with renal excretion or pharmacologic suppression related to drug interactions. In either case, both renal function and blood counts should be checked on a regular basis.

Other Toxicities

Methotrexate is associated with other medical issues that are significantly less concerning or less common than liver and hematologic toxicity. The most common side effects are nausea and general constitutional signs in patients taking the medication, usually in the day or two following weekly dosing. While these signs can be improved by additional folic acid supplementation, they may sometimes require stopping methotrexate therapy. Pulmonary symptoms, including rare pulmonary fibrosis, has also been reported but its relationship to methotrexate is still unclear.

Acitretin

Vitamin A derivatives, retinoids, have been used for the treatment of psoriasis since the 1970s. Retinoids are believed to normalize keratinocyte proliferation and maturation and, thus, improve clinical psoriasis in a way that leaves immune function intact. Some data suggest that retinoids do, in fact, decrease neutrophil function, but it is generally accepted that in patients at high risk for infection, retinoids are a relatively safe therapeutic option.

Acitretin Efficacy

The main obstacle to the use of acitretin is its relative ineffectiveness when compared with other systemic options. As with methotrexate, early studies suffered from poor clinical trial analysis. Additionally, the dosing schedule for acitretin was developed to correspond to the earlier retinoid, etretinate. Unfortunately, tolerance to this high-dose acitretin (50 mg daily) was low, making the early studies not representative of real world usage. Early studies suggested that acitretin could reach PASI 75 of 23% but had a mean PASI improvement of 75% in an “as-treated” analysis. This analysis only included subjects who continued on treatment despite a large group that dropped out of the study due to intolerance of the medication. In a prospective analysis of the 25-mg daily dosage, a more typical schedule, had a PASI 75 of 21%, significantly lower than other available treatments.

One way to make acitretin useful from the perspective of efficacy is to combine it with phototherapy. A number of studies have demonstrated that the efficacy of phototherapy increases with the addition of retinoid therapy. While most of these studies were performed with etretinate and Psoralen plus ultraviolet A (PUVA) treatment, ultraviolet B (UVB) and acitretin have a similar effect. It is important not to treat with increasing doses of UVB prior to the patient achieving a steady state of acitretin. Our protocol is to treat with acitretin for a full month prior to starting the UVB. This delay serves two purposes: not only does the patient have a steady state of acitretin prior to starting the UVB, but if the patient is having a response to the acitretin alone, it may not be necessary even to start using the phototherapy.

Acitretin Safety

While the limiting factor for acitretin use is efficacy, there are a number of safety and tolerability concerns that impact this medication. The first and most important safety concern with acitretin is that it is teratogenic. Treatment of women of childbearing potential with acitretin should be completely avoided. While acitretin is water soluble and is not normally stored in the body, it can be reverse metabolized to etretinate, which is fat soluble. This is most prominent when the patient drinks alcohol while taking the medication. Some, including the Food and Drug Administration (FDA) recommendations on acitretin, have argued that it is safe to start a pregnancy 3 years after stopping treatment. While this can be the case, the difficulty in predicting pregnancy at such a great length of time should exclude this medication as a therapeutic option for women with childbearing potential.

The other toxicities of acitretin pertain more to tolerability than safety. Both triglycerides and liver function tests may become elevated, sometimes quite significantly with acitretin. Luckily, medically significant changes are rare and reverse with stopping the medication. Additionally, these laboratory abnormalities are dose dependent. Starting at lower doses has clearly been shown to decrease the number of laboratory abnormalities.

Also, there are numerous dose-dependent cutaneous toxicities that have been associated with retinoid therapy. The most prominent of these are cheilitis, skin and eye dryness, retinoid dermatitis, “clammy feeling” on the palms and soles and most prominently, hair loss. These “nuisance” side effects are the most common reason for patients stopping acitretin therapy (other than lack of efficacy). The other side effect associated with acitretin, diffuse idiopathic skeletal hyperostosis (DISH), is probably not related to retinoid therapy.

Cyclosporine

Cyclosporine use has been pivotal in the development of psoriasis treatment. It was the first medication that was clearly only immunologically active that demonstrated tremendous efficacy for psoriasis. Cyclosporine, first used for prevention of rejection of solid organ transplants, blocks immune activity by inhibiting activation of the calcineurin pathway, thus preventing T cell activation and proliferation. The use of cyclosporine was the first direct evidence of the success in treating psoriasis by isolated blockade of T cell immunity. While cyclosporine is not commonly used in the United States, it remains an important part of the treatment options for psoriasis, particularly for patients who are most severely impacted by their disease.

Cyclosporine Efficacy

When cyclosporine was first tried for psoriasis, the efficacy results were beyond all other available agents. Dosing of cyclosporine in clinical trials was between 1.25 and 7.5 mg/kg per day. Various studies showed significant improvement of 80% to 90% of patients. Later studies, particularly those comparing cyclosporine with methotrexate, demonstrated PASI 75 of 58% to 71%. Moreover, these results were rapid with clinically significant improvement in as little as 4 weeks of treatment. Trials have also suggested that this response can be maintained while lowering the dose of cyclosporine. Thus, cyclosporine was, and is, believed to be the most predictably effective oral medication for psoriasis and an important medication for short-term use, particularly for the most severely affected patients.

Cyclosporine Safety

Unfortunately, while cyclosporine is an effective medication, its use is limited by multiple safety concerns that make it difficult to use. These concerns include immunosuppression, renal toxicity, cardiovascular toxicity and a myriad of laboratory abnormalities. Additionally, there are numerous drug interactions that must be considered whenever using cyclosporine.

Since cyclosporine works primarily by suppressing T cells, one would expect that it would lead to an increased likelihood of infection and even certain cancers. In psoriasis patients, it has clearly been demonstrated that the incidence of squamous cell carcinoma of the skin is increased with extended use of cyclosporine. This is particularly true in patients who have been treated with PUVA therapy. Caution should be taken in patients with a history of phototherapy or excessive sun exposure. While this finding cannot necessarily be generalized to infections and other forms of cancer, they do raise questions about the use of cyclosporine in populations at greater risk.

The most frequent concern with cyclosporine therapy is nephrotoxicity. Renal function abnormalities associated with cyclosporine can be both acute and chronic. In the relatively rare acute case, elevations of serum creatinine will be seen within 1 to 4 weeks of starting cyclosporine therapy. This acute change is not always dependent upon the dose of cyclosporine. If the serum creatinine rises by more than 30% over baseline, it is important to stop therapy. These changes in renal function are largely reversible.

Chronic renal toxicity associated with cyclosporine use is more common and may not be reversible. The likelihood of chronic renal changes is dependent upon time of exposure to the medication as well as the dose used. With continuous use of over 4 years, over 70% of patients had significant changes in their serum creatinine. Even with stopping the medication, many of these patients did not return to normal. In fact, patients with increased risk of renal toxicity, including older patients, those with diabetes and those on chronic nonsteroidal anti-inflammatory agents (NSAID) therapy, may be at increased risk for cyclosporine-associated toxicity. Due to long-term concerns of irreversible renal toxicity, it is recommended that cyclosporine use be limited to 1 year.

Cardiovascular toxicity, particularly elevation of blood pressure, is another significant concern with cyclosporine therapy. As with renal toxicity, this is most commonly seen in patients at greater baseline risk, particularly the elderly. Blood pressure should be monitored frequently early in the course of therapy and consistently throughout therapy with cyclosporine. If needed, cyclosporine-induced hypertension can be treated, particularly with calcium channel blockers.

Laboratory abnormalities with cyclosporine go beyond changes in creatinine. Elevations in triglycerides and magnesium levels are the most common findings. While these are rarely acute issues, changes in dose of cyclosporine may be needed. Hypertrichosis and gingival hyperplasia may be associated with cyclosporine use, forcing cessation of therapy.

A significant concern with cyclosporine are drug interactions that can be dangerous. Cyclosporine is metabolized by the P450 system and is an inhibitor of the same hepatic pathway. Drugs that inhibit the P450 system, such as macrolide antibiotics, calcium channel blockers and grapefruit juice, can increase cyclosporine levels. Drugs that increase the P450 system, conversely, can decrease cyclosporine levels. Other drug interactions of concern include increased renal toxicity when combined with other nephrotoxic medications. Therefore, great care must be taken when using cyclosporine in patients who may be on multiple medications.

The final note on cyclosporine safety is its use in pregnancy. While cyclosporine has been associated with low birth weights and pre-term delivery, due to its use in organ transplantation there is significant experience with this medication in pregnancy compared to other systemic medications for psoriasis. Cyclosporine does not seem to be teratogenic and many healthy babies have been delivered to women taking this medication. Thus, for women who are actively flaring from psoriasis with severe disease and require systemic therapy, cyclosporine is often considered the treatment of choice.

Apremilast

Apremilast is an oral treatment that was approved by the FDA in 2014 for the treatment of adults with active PsA. Apremilast was subsequently approved for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

As previously discussed, apremilast is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, which modulate proinflammatory and anti-inflammatory mediator production.

Apremilast Efficacy

The efficacy of apremilast in the treatment of plaque psoriasis was evaluated in two large pivotal phase 3 randomized, placebo-controlled studies in patients who were also candidates for phototherapy and/or systemic therapy (ESTEEM 1 and ESTEEM 2). Approximately 1,250 patients were randomized to receive either apremilast 30 mg twice daily or placebo for the first 16 weeks, followed by a maintenance phase from weeks 16 through 32, in which placebo patients were switched to apremilast 30 mg twice daily through week 32 and a randomized withdrawal phase for responders from week 32 to week 52 based on their initial apremilast randomization and PASI 75 response.

Treatment with apremilast resulted in significant improvements in plaque psoriasis as measured by PASI scores at week 16 (primary endpoint). Clinical improvement, as measured by sPGA scores of clear to almost clear, was also demonstrated in both studies (Table 11-4). The median time to loss of PASI 75 response among the subjects re-randomized to placebo at week 32 during the treatment withdrawal phase was 5.1 weeks.

At week 52 in ESTEEM 1, 61% of patients who had been randomized to the apremilast arm at week 32 demonstrated a PASI 75 response. Among patients re-randomized to placebo who subsequently lost PASI 75 and re-started apremilast, 70.3% regained PASI 75 response after re-starting treatment. Apremilast 30 mg BID treatment demonstrated meaningful improvements in difficult-to-treat areas affected by plaque psoriasis, such as nail and scalp psoriasis.

In ESTEEM 2, primary outcomes were consistent with those from ESTEEM 1. Apremilast significantly improved signs and symptoms of psoriasis, including scalp, nails palms, and soles compared with placebo at week 16.

Results from the 52-week analysis of the ESTEEM program suggest that early responses seen with apremilast treatment in multiple efficacy endpoints of plaque psoriasis, including difficult to treat areas, are durable over time.

The recommended initial dosage titration, intended to reduce the GI symptoms associated with initial therapy, for apremilast for the first 5 days of starting treatment is shown in Table 6-2. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on day 6.

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Apremilast Safety

Long-term safety and tolerability profiles in ESTEEM 1 and 2 were consistent with previously-reported long-term data from apremilast clinical trial programs in PsA. No new or unexpected adverse events (AEs) were reported for patients treated with apremilast compared with placebo at week 16. The most frequently reported AEs during the placebo-controlled period and the long-term 52-week apremilast-exposure period were diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache and headache. Most of these AEs occurred during the first 2 weeks of treatment and tended to resolve with continued dosing.

In ESTEEM 1 and 2, discontinuation rates for diarrhea and nausea were each <2% in the apremilast 30 mg BID group through week 52. No serious AEs of diarrhea and nausea were reported in all groups through 52 weeks. No clinically meaningful changes in laboratory measurements compared with placebo were observed. In a pooled analysis of ESTEEM 1 and 2, exposure-adjusted incidence rates for major adverse cardiac events, serious infections including systemic opportunistic infection, or malignancies were comparable between placebo and apremilast treatment groups.

Treatment with apremilast may be associated with an increase in adverse reactions of depression. During the psoriasis clinical trials, 1.3% of patients with psoriasis treated with apremilast reported depression or depressed mood compared with 0.4% treated with placebo. 0.1% of patients treated with apremilast discontinued treatment due to depression or depressed mood compared with none in placebo-treated patients. Depression was reported as serious in 0.1% of patients exposed to apremilast compared with none in placebo-treated patients. Suicidal ideation and behavior were reported in 0.1% of patients on apremilast compared with 0.2% of patients receiving placebo. One patient receiving placebo committed suicide, while one patient who received apremilast attempted suicide.

Apremilast is also associated with decreases in body weight. In clinical studies, body weight loss of 5% to 10% was reported in 12% of patients taking apremilast and in 5% of patients taking placebo. Physicians should monitor body weight regularly, evaluate unexplained or clinically significant weight loss and consider discontinuation of apremilast.

Deucravacitinib

Deucravacitinib is an orally administered, first-in-class Tyrosine Kinase 2 (TYK2) inhibitor that received FDA approval in 2022 for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Deucravacitinib binds and inhibits TYK2, a tyrosine kinase from the Janus kinase (JAK) kinase family, which also includes with JAK1, JAK2 and JAK3. JAK kinases are effectors of the JAK/STAT signaling pathway (Figure 6-6) which regulates important physiological processes, including immune cell function and hematopoiesis. Unlike JAK1/2/3, which contribute to both immunological and hematopoietic functions, TYK2 appears to only participate in immune regulation, mediating IL-12, IL-23 and type I interferon signaling. Consistent with this observation, deucravacitinib does not appear to be associated with serious adverse events (including cytopenia, dyslipidemia, gastric perforation, thromboembolic events and infections) which may occur with use of JAK1/2/3 inhibitors such as tofacitinib, baricitinib and ruxolitinib. The prescribing information for deucravacitinib notes that it is currently unknown whether TYK2 inhibition may be associated with known or potential adverse events of JAK inhibition.

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Deucravacitinib Efficacy

The efficacy of deucravacitinib for the treatment of plaque psoriasis was assessed in two 52-week, multicenter, randomized, double-blind, placebo- and comparator-controlled companion trials, POETYK PSO-1 and POETYK PSO-2. POETYK PSO-1 and POETYK PSO-2 enrolled adult (≥18 years of age) patients with moderate to severe plaque psoriasis (PASI ≥12, sPGA ≥3 and affected BSA ≥10%) and randomized them 2:1:1 to deucravacitinib 6 mg daily, placebo, or apremilast 30 mg twice a day (titrating apremilast from 10 mg to 30 mg twice a day during the first 5 days of treatment).

In both trials, the first 16 weeks comprised the placebo- and apremilast-controlled period, followed by an 8-week apremilast-controlled period in which patients in the placebo group were switched over to deucravacitinib until week 24. The remaining 28 weeks differed by trial. In POETYK PSO-1, these weeks represented a maintenance period, in which patients in the deucravacitinib group continued the treatment and those in the apremilast group either remained on apremilast (if they had achieved PASI 50) or were switched to deucravacitinib (if they had not achieved PASI 50). In POETYK PSO-2, these weeks represented a maintenance and randomized treatment withdrawal period: patients on deucravacitinib who had achieved PASI 75 were re-randomized (1:1) to deucravacitinib or placebo and patients on apremilast were assigned to either the placebo (if they had achieved PASI 75) or deucravacitinib (if they had not achieved PASI 75).

In both POETYK PSO-1 and POETYK PSO-2, the co-primary endpoints were PASI 75 and sPGA score of 0/1 (clear/almost clear) with at least a 2-point improvement from baseline in sPGA for deucravacitinib compared to placebo at week 16. A number of secondary efficacy endpoints were also assessed, including PASI 90 and DLQI.

In POETYK PSO-1, a total of 666 patients were randomized: 332 to deucravacitinib 6 mg daily, 166 to placebo and 168 to apremilast 30 mg twice daily. As shown in Figure 11-2, at week 16 the PASI 75 response rate was significantly higher with deucravacitinib (58.4%) than with placebo (12.7%, P <0.0001 against deucravacitinib [co-primary endpoint]) or with apremilast (35.1%, P <0.0001 against deucravacitinib), as was the sPGA 0/1 response rate (deucravacitinib: 53.6%; placebo: 7.2%; apremilast: 32.1%; P <0.0001 against deucravacitinib for both placebo [co-primary endpoint] and apremilast). The superiority of deucravacitinib against apremilast was maintained at week 24 with respect to both PASI 75 (deucravacitinib: 69.3%; apremilast: 38.1%; P <0.0001) and sPGA 0/1 (deucravacitinib: 58.7%; apremilast: 31.0%; P <0.0001). Significantly higher PASI 90 and DLQI 0/1 response rates were observed with deucravacitinib than with placebo at week 16 and apremilast at week 16 and 24. The responses were durable; at week 52, 65.1% of patients in the deucravacitinib and 68.3% in the placebo-to-deucravacitinib switch group showed a PASI 75 response, while 52.7% and 53.8% of patients in the deucravacitinib and placebo-to-deucravacitinib switch group, respectively, showed an sPGA 0/1 response.

A total of 1,020 patients were randomized in POETYK PSO-2: 511 to deucravacitinib 6 mg daily, 255 to placebo, and 254 to apremilast 30 mg twice daily. A total of 885 patients (456 in the deucravacitinib, 212 in the placebo, and 217 in the apremilast group) completed 16 weeks of treatment. At week 16 (Figure 11-3), deucravacitinib treatment resulted in significantly higher PASI 75 rates (53.0%) compared to the placebo (9.4%, P <0.0001 against deucravacitinib [co-primary endpoint]) and apremilast (39.8%, P = 0.0004 against deucravacitinib). The sPGA 0/1 response rate at week 16 (Figure 11-3) was also significantly higher with deucravacitinib (49.5%) compared to both the placebo (8.6%, P <0.0001 against deucravacitinib [co-primary endpoint]) and apremilast (33.9%; P <0.0001 against deucravacitinib). At week 24 (Figure 11-3), deucravacitinib demonstrated superiority to apremilast with respect to PASI 75 (58.7% with deucravacitinib versus 37.8% with apremilast; P <0.0001) and sPGA 0/1 (49.8% with deucravacitinib and 29.5% with apremilast; P <0.0001). In accordance with the results from POETYK PSO-1, patients in the deucravacitinib group also showed significantly higher rates of PASI 90 and DLQI 0/1 compared to the placebo and apremilast at week 16 and apremilast at week 24 (Figure 11-3). Among the deucravacitinib-treated patients who achieved a PASI 75 response at week 24, 80.4% of those re-randomized after week 24 to continue deucravacitinib and 31.3% of those re-randomized to switch to placebo maintained a PASI 75 response at week 52.

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Deucravacitinib Safety

The rates of adverse events were generally similar between treatment groups in POETYK PSO-1 and -2. Because their design involved switching patients between regimens in different phases of these two studies, safety results were expressed in exposure-adjusted incidence rates (EAIR) per 100 person-years (PY).

During the entire 52-week course of POETYK PSO-1, treatment-related adverse events (TRAEs) occurred with an EAIR/100 PY of 33.1, 45.2, and 46.9 in the deucravacitinib, placebo and apremilast groups, respectively. Serious AEs had an EAIR/100 PY of 7.5, 19.2 and 5.2 among patients in the deucravacitinib, placebo and apremilast group, respectively. The most common AEs included (in order of incidence): nasopharyngitis, upper respiratory tract infection, headache, diarrhea, nausea, arthralgia, cough, hypertension, psoriasis, dyspepsia and myalgia.

In POETYK PSO-2, the TRAE EAIR/100 PY over the 52 weeks of the trial was 40.2 in the deucravacitinib group, 42.4 in the placebo group and 99.6 in the apremilast group. Serious AEs occurred with an EAIR/100 PY of 4.3, 2.5 and 2.8 among patients who received deucravacitinib, placebo and apremilast, respectively. In order of incidence, the most common AEs observed during the 52-week course of the trial were nasopharyngitis, upper respiratory tract infection, headache, diarrhea, arthralgia, increased blood creatine phosphokinase, pharyngitis, hypertension, psoriasis, rhinitis, sinusitis, back pain, nausea, abdominal disease and gastroesophageal reflux disease.

Overall, incidences of AEs and serious AEs were comparable between treatment groups in both POETYK PSO trials, and rates of discontinuation due to AEs were lower in the deucravacitinib group. Rates of malignancy and cardiovascular disease were similar across treatment groups and comparable to the general population, and deucravacitinib treatment did not meaningfully affect laboratory parameters typically affected by JAK1/2/3 inhibitors, including lymphocytes, neutrophils, platelets and cholesterol. A slight increase in nonserious (mild-to-moderate and localized) herpes zoster and other viral infections was noted. The prescribing information for deucravacitinib recommends monitoring patients for signs of infection (Table 11-2) and discontinuing treatment if a serious infection develops.

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2020 Joint American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) Guidelines for the Treatment of Psoriasis with Systemic Nonbiologic Therapies

The current joint AAD-NPF guidelines on the use of systemic nonbiologic therapies for the treatment of psoriasis were released in 2020. Separate recommendations are provided for each systemic nonbiologic agent, including:

• Methotrexate: Recommended for the treatment of moderate to severe psoriasis in adults. The guidelines also note that methotrexate is less effective than the biologic agents adalimumab and infliximab for cutaneous psoriasis. To enhance efficacy and lower cumulative doses of both treatments, methotrexate can be combined with narrow-band UVB therapy.
• Acitretin: The guidelines state that acitretin can be recommended as monotherapy for the treatment of plaque psoriasis and for the treatment of erythrodermic, pustular and palmar-plantar psoriasis. They further state that acitretin can be combined with broadband UVB for plaque psoriasis and can be recommended as combination therapy with PUVA for psoriasis.
• Cyclosporine: Recommended for patients with severe, recalcitrant psoriasis. The guidelines also state that cyclosporine can be recommended for the treatment of erythrodermic, generalized pustular and/or palmoplantar psoriasis, as well as a short-term interventional therapy in patients who experience a flare-up while on systemic therapy.
• Apremilast: Recommended for the treatment of moderate to severe psoriasis in adults.

More information and further recommendations can be found in the current AAD-NPF Guidelines.

Conclusion

Oral medications for psoriasis have been used for decades. They remain an important part of treatment regimen for psoriasis. While methotrexate, acitretin, cyclosporine, apremilast and deucravacitinib all have use in psoriasis patients, they have distinctly different roles in treatment. Methotrexate is the standard for oral medication for good efficacy with potential for long-term tolerability when used with caution. Acitretin is probably the least effective of the oral medications but does not have significant impact on the immune system. While it cannot be used in women of childbearing potential, those patients that respond may be treated safely for extended periods. Cyclosporine is usually reserved as an emergency treatment for those patients in the midst of severe flares. With predictable efficacy but significant long-term safety concerns, cyclosporine is rarely used for long-term control of the disease. Apremilast is a versatile option but has only moderate efficacy in psoriasis. Deucravacitinib is the most recently approved oral systemic therapy for psoriasis, and while initial results show marked efficacy, more clinical experience may be needed to elucidate its role in the treatment spectrum of patients with psoriasis. In addition to deucravacitinib, a number of JAK inhibitors have entered phase 2 and phase 3 clinical trials for psoriasis. With the development of novel oral systemic therapies, it remains to be seen whether biologic immunotherapies, originally developed to replace oral treatments, will remain as prominent for psoriasis treatment.