Update on Oral Molecules

Oral molecules continue to play a significant role in the treatment of psoriatic disease. With advances in the understanding and treatment of psoriasis and psoriatic arthritis (PsA), more targeted treatment options are available to patients. This has changed the way oral molecules are now prescribed, with pre-21st century molecules also not being used as often. This article discusses the latest evidence on the use of oral molecules, from new research on the safety and efficacy of apremilast (Otezla) to the potential for Janus kinase (JAK) inhibitors for the treatment of psoriasis and PsA.

Current Uses of Apremilast

Apremilast was approved by the FDA in 2014 for the treatment of moderate to severe plaque psoriasis and PsA. More recently, apremilast has been used as monotherapy for patients with more moderate psoriasis and in combination with other systemic treatments for more severe disease.

The UNVEIL study, conducted by Linda Stein Gold, MD, and colleagues,¹ supported the use of apremilast as monotherapy among participants with moderate psoriasis. Compared with placebo, more participants receiving apremilast achieved improvements in Physician’s Global Assessment and body surface area after 52 weeks of treatment. In addition, participants who switched from placebo to apremilast at week 16 experienced improvements through week 52. 

The LIBERATE study,² which was a longer-term study for moderate to severe patients, showed improved and maintained Psoriasis Area and Severity Index (PASI) scores among participants who received apremilast during 104 weeks of treatment. In the study, participants were assigned 1:1:1 to apremilast, placebo, or etanercept (Enbrel) for 16 weeks. After week 16, those assigned to placebo or etanercept were switched to apremilast. The data showed that the majority of participants who received apremilast at baseline or were switched at week 16 achieved PASI 75 and maintained response through 104 weeks. In addition, apremilast was found to improve nail and scalp PASI scores through 104 weeks of treatment. Data from both trials confirms long-term efficacy and safety of apremilast, for moderate and moderate to severe patients, and even for patients with psoriasis in difficult to treat areas. 

In addition, new evidence shows that apremilast can be safely combined with biologics and narrowband UV-B phototherapy. A retrospective open-label study, conducted by Samy Metyas, MD, and colleagues,³ included 22 participants with both severe psoriasis and PsA, and showed that adding apremilast to biologic therapy was safe and helped further improve PASI scores. Biologics included in the study were adalimumab (Humira), ustekinumab (Stelara), infliximab (Remicade), golimumab (Simponi), etanercept, and certolizumab pegol (Cimzia). No major adverse events were observed, such as cancer or serious infection, and minor adverse events were consistent with findings from clinical trials, including nausea, diarrhea, and weight loss.  Additionally, participants remained on both therapies for several months, with mean treatment duration of 8 months (range: 1-24 months). 

Jerry Bagel, MD, and colleagues⁴ demonstrated improved efficacy and safety of apremilast when combined with narrowband UV-B. Participants received narrowband UV-B 3 times per week and apremilast 30 mg twice daily for 12 weeks. By week 12, 73% of participants achieved PASI 75, with 45% achieving PASI 90. The only adverse event noted during the study period was an increase in first-degree burns. Dr Bagel noted that apremilast in combination with narrowband UV-B may increase the risk of minor burns and patients should especially be monitored for this adverse event. However, apremilast in combination with narrowband UV-B showed greater efficacy compared with previously reported data with apremilast monotherapy. Perhaps to mitigate the risk of burns, patients who receive narrowband UV-B and take apremilast should have less incremental increase in UV doses if they show signs of burning.

A subanalyses from phase 3 trials with apremilast (ESTEEM 1 and 2)⁵ demonstrated that patients who had longer psoriasis disease duration (>10 years) had a more rapid relapse of their psoriasis after apremilast discontinuation than those who had shorter disease duration (<10 years). Between 70% to 78% of patients with longer disease duration relapsed compared with 22% to 29% of patients with shorter duration of psoriasis. In most patients who relapsed, relapse occurred by 8 weeks after apremilast discontinuation. After reinitiating treatment, most patients did regain their PASI responses. 

Older Molecules

Methotrexate

Approved by the FDA in 1972, methotrexate continues to have a place in the treatment of PsA and psoriasis. However, its use, specifically as monotherapy, has decreased with the advent of biologics and newer oral therapies like apremilast. Today, methotrexate is primarily prescribed for psoriasis patients with Medicare (who have no donut hole coverage) or no insurance, in combination with biologics to boost their efficacy on someone’s psoriasis, as an insurer mandated step therapy to fail prior to starting a biologic, and as a bridge between biologics prior to initiating a different biologic therapy. 

Part of the decline of methotrexate use is due to the superiority of biologics for severe disease and perceived safety of apremilast when treating more moderate disease. In one study,⁶ compared with infliximab, about 40% of participants treated with methotrexate compared with almost 80% of participants treated with infliximab, achieved PASI 75 at week 16. 

In addition, because of hepatoxic, renal toxic, and anemia risks, methotrexate requires extensive, consistent laboratory monitoring—more so than other currently FDA-approved therapies for moderate to severe psoriasis. This is not only inconvenient for the patient, but also increases the total cost of care. Much of methotrexate potential toxicity increases the longer the patient is on therapy.  Today, therefore, methotrexate is often administered as a temporary medication—as a bridge between biologics or in combination with a biologic if a patient is experiencing a sudden disease exacerbation. 

Cyclosporine

Cyclosporine, another potentially toxic older oral medication, was a common medication used to treat severe psoriasis in the 1990s. A study from 1991 showed 65% of patients receiving 5 mg/kg/day of cyclosporine achieved clear or almost clear skin after just 8 weeks of treatment.⁷ Today, it is predominately used as a short therapy agent for severe flaring psoriasis crisis management. Its fast efficacy makes it suitable for patients with severe flares and those who are becoming or have erythrodermic psoriasis and need a quick response to treatment. However, patients receiving cyclosporine require close and consistent laboratory monitoring. Cyclosporine is associated with nephrotoxicity, interstitial fibrosis, and renal tubular atrophy over time. Hypertension, skin cancers, lymphoproliferative disorders, hypomagnesemia, hyperkalemia, hyperlipidemia, nausea, headache, fatigue, myalgias, hand tremors, paresthesias, sensitivity to hot and cold in distal extremities, gingival hyperplasia, and hypertrichosis are other risks. In addition, cyclosporine interacts with multiple medications, and because of this is not an option for many patients—even those in need of severe crisis management.

JAK Inhibitors for Psoriasis

JAK (Janus kinase) inhibitors appear to be a promising treatment option for various skin diseases. JAKs are a part of the tyrosine kinase (TYK) pathway. Once activated, JAKs phosphorylate tyrosine residues in the cytoplasmic region of the receptor, which then create docking sites for their corresponding members of molecules that function both as signal transducers and nuclear transcription factor activators for molecules (called the STAT family). There are 4 JAK pathways: JAK1, JAK2, JAK3, and TYK2. Specific JAK pathways are required for embryonic development, hemopoietic differentiation, innate and adaptive immunity, and inflammatory response. The theory is that blocking, for example, the JAK1 pathway, which is responsible for IL-4 and IL-13 inflammation, would inhibit inflammatory responses due to these cytokine elevations. 

Tofacitinib (Xeljanz), which is now considered a pan JAK inhibitor, is approved for rheumatoid arthritis, PsA, and ulcerative colitis. A phase 3 study of tofacitinib⁸ administered at 5 mg and 10 mg twice daily demonstrated efficacy among participants with psoriasis and PsA, with more improvement seen among those receiving 10 mg twice daily. Tofacitinib is assumed to improve PsA and its other FDA-approved indications by blocking IL-12 and 23, which is inhibited by interrupting the JAK2-TYK2 pathway. However, as a pan JAK inhibitor, tofacitinib also interrupts other JAK pathways, interfering with hematopoietic differentiation, growth hormone production, and other aspects of both innate and adaptive immunity. Therefore, patients receiving tofacitinib require regular monitoring of lymphocyte counts, neutrophil counts, hemoglobin, routine liver tests, and lipid parameters. 

Conclusion

Oral psoriasis treatment options and their uses have changed dramatically in the 21st century. While 20th century medications, like methotrexate and cyclosporine are still used, their use is limited to more specific psoriasis manifestations. Apremilast, a 21st century addition to the psoriasis armamentarium, seems to be finding a niche to treat more moderate psoriatic disease, and sometimes in conjunction with other therapies for more severe disease. These uses allow clinicians to develop targeted treatment options for patients that address disease severity and improve quality of life. n

Dr Green is an associate clinical professor of dermatology at George Washington University School of Medicine in Washington, DC.

Disclosure: Dr Green has been a speaker, consultant, and investigator for AbbVie, Amgen, Celgene, Leo, Lilly, Novartis, Ortho Dermatologics, Sienna, and Sun Pharma. 

References

1. Gold LS, Bagel J, Lebwohl M, et al. Efficacy and safety of apremilast in systemic- and biologic-naïve patients with moderate plaque psoriasis: 52-week results of UNVEIL. J Drugs Dermatol. 2018;17(2):221-228.

2. Reich K, Goodfield M, Green L, et al. Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment in the LIBERATE Study. Presented at: the 75th Annual Meeting of the American Academy of Dermatology; March 3-7; Orlando, FL. 

3. Metyas S, Messian R, Gettas T, Asfahani L, Quisomorio A. Combination therapy of apremilast and biologic agent as a safe option of psoriatic arthritis and psoriasis. Presented at: 2016 ACR/ARHP Annual Meeting; College of Rheumatology and America; November 11-16, 2016; Washington, DC.

4. Bagel J, Nelson E, Keegan BR. Apremilast and narrowband UVB combination therapy for treating moderate-to-severe plaque psoriasis. Presented at: 2016 Fall Clinical Annual Meeting; October 20-23, 2016; Las Vegas, NV. 

5. Van Voorhees A, Sofen H, Weaver J, Circulli J, Wang Y, Warren RB. Symptom relapse following apremilast discontinuation is related to longer disease duration at treatment initiation in patients with moderate to severe psoriasis. Presented at: 2018 American Academy of Dermatology Annual Meeting; February 16-20, 2018; San Diego, CA. 

6. Barker J, Hoffman M, Wozel G, et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1). Br J Dermatol. 2011;165(5):1109-1117.

7. Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis — results of a multidose, double-blind trial. N Engl J Med. 1991;324(5): 277-284.

8. Bachelez H, van de Kerkhof PC, Strohal R, et al; OPT Compare Investigators. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet. 2015;386(9993):552-561.