Oral Systemic Therapy

Introduction

In moderate to severe atopic dermatitis (AD), treatment with moisturizers and topical corticosteroids and/or topical calcineurin inhibitors is often insufficient at inducing remission. As such, long-term treatment with systemic agents may be required to control disease burden, prevent flares and improve patient quality of life. This module will review oral systemic therapies, including:

• Janus kinase (JAK) inhibitors:
  • Abrocitinib
  • Upadacitinib
  • Baricitinib.
• Systemic immunosuppressants:
  • Azathioprine (AZA)
  • Cyclosporine A (CSA)
  • Methotrexate (MTX)
  • Mycophenolate mofetil (MMF)
  • Tacrolimus.
  • Systemic corticosteroids
• Phosphodiesterase-4 (PDE-4) inhibitor:
  • Apremilast.

The appropriate use of systemic antimicrobials and oral antihistamines will also be discussed, as they are frequently used in clinical practice despite only being efficacious in limited circumstances. Refer to Table 9-1 for an overview of American Academy of Dermatology (AAD) recommendations regarding these treatments.

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Oral Janus Kinase (JAK) Inhibitors

Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are critical intracellular mediators of several cytokine signaling pathways, including T_h2, T_h22, T_h1 and T_h17. They therefore play an important role in the pathogenesis of autoimmune and inflammatory diseases, including AD, which makes them promising therapeutic targets (Figure 9-1). Several JAK inhibitors are being investigated for use in AD. Two agents — the JAK1 inhibitors abrocitinib and upadacitinib — have received FDA approval for use in AD, while the JAK1/2 inhibitor baricitinib has completed multiple phase 3 trials.

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Cibinqo (Abrocitinib)

Abrocitinib is a JAK1-specific inhibitor which received FDA approval for use in the treatment of AD in January 2022. Abrocitinib is indicated for the treatment of adults with refractory, moderate-to-severe AD whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable. The efficacy of abrocitinib for the treatment of AD was tested in three phase 3 trials: the placebo-controlled JADE MONO-1 and JADE MONO-2, as well as placebo- and active comparator-controlled JADE COMPARE.

JADE MONO-1 and JADE MONO-2 were two identical phase 3 trials that assessed the safety and efficacy of abrocitinib monotherapy (no concomitant prescription topical therapy allowed) for the treatment of moderate-to-severe AD in adolescents and adults (aged ≥12 years). Patients received one of two abrocitinib doses (100 mg or 200 mg once daily) or a placebo. At week 12, a significantly greater proportion of patients in both abrocitinib groups achieved EASI-75 and an IGA of 0/1, the co-primary endpoints, compared to the placebo in both JADE MONO-1 and JADE MONO-2 (Table 9-2). In both trials, abrocitinib treatment at either the 100 mg or the 200 mg dose significantly reduced itchiness compared to the placebo, as measured by the proportion of patients achieving a 4-point or greater improvement on the Peak Pruritus Numerical Rating Scale (PP-NRS), which is equivalent to a moderate improvement of itch.

JADE COMPARE was a placebo- and active comparator-controlled phase 3 trial which tested the efficacy of abrocitinib against placebo or the biologic dupilumab for the treatment of moderate-to-severe AD. Patients received abrocitinib 100 mg or abrocitinib 200 mg once daily (with a Q2W subcutaneously injected placebo), 300 mg dupilumab Q2W by subcutaneous injection (after an initial 600 mg dose; and accompanied by a once daily oral placebo), or a once daily oral placebo and a Q2W subcutaneous placebo. At week 16 (Table 9-3), the IGA response of patients in both the 100 mg abrocitinib (36.6%) and 200 mg abrocitinib (48.4%) groups was superior (P<0.001) to the placebo group (14.0%). The proportion of patients achieving the EASI-75 response was also statistically higher (P<0.001) in the 100 mg abrocitinib (58.7%) and 200 mg abrocitinib (70.3%) groups compared to the placebo group (27.1%). With dupilumab treatment, 36.5% of patients achieved an IGA response and 58.1% an EASI-75 response. At the 200 mg dose, abrocitinib was statistically superior to dupilumab in the proportion of patients achieving a clinically significant reduction in itch at week 2 (49.1% vs 26.4%; P<0.001), a key secondary endpoint of the trial, and appeared to be numerically superior to dupilumab at week 16 for improvements in EASI-75 (70.3% vs 58.1%) and IGA outcomes (48.4% vs 36.5%).

In JADE MONO-1/2, abrocitinib was well tolerated overall. Patients in the abrocitinib groups exhibited a numerically greater rate of TEAEs than patients in the placebo group (JADE MONO-1: 69-78% vs 57%; JADE MONO-2: 63-66% vs 54%). The most common TEAEs included nausea, nasopharyngitis, headache and upper respiratory tract infections. In the abrocitinib 200 mg group in JADE MONO-2, a low rate of thrombocytopenia (3.2%) was observed. Serious adverse events were rare (≤4%) and similar across treatment groups, as was the rate of serious infections. No cases of venous thromboembolism or malignancy were reported in either study, and a single sudden cardiac death in JADE MONO-2 was judged to be unrelated to the treatment. In JADE COMPARE, abrocitinib demonstrated a safety profile consistent with that of JADE MONO-1/2.

The FDA prescribing information for abrocitinib includes a black box warning on potential serious adverse events associated with JAK inhibitors as a class, including increased risk for serious infections, higher rates of all-cause mortality, lymphomas and lung cancers and major adverse cardiovascular events, as well as increased incidence of pulmonary embolism and venous and arterial thrombosis.

Dosage and Administration

Abrocitinib is available in three tablet dosage forms: 50 mg, 100 mg and 200 mg. Abrocitinib tablets are taken by mouth, and the recommended dosage is 100 mg once per day. The dosage may be increased to 200 mg daily if an adequate response is not achieved after 12 weeks on the 100 mg daily dose. The 50 mg dose is available for dose adjustments. Abrocitinib should be discontinued if an adequate response is not achieved on the 200 mg daily dose.

Abrocitinib can be used with or without topical corticosteroids and with or without food. It should not be used in in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

Is a dose of abrocitinib is missed, the dose should be taken as soon as possible. However, if less than 12 hours remain before the next dose, the missed dose should be skipped. The original dosing schedule should then be resumed.

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Rinvoq (Upadacitinib)

Upadacitinib is a JAK1-specific inhibitor which is FDA-approved for the treatment of moderate-to-severe active rheumatoid arthritis, active psoriatic arthritis, and, since January 2022, AD. Upadacitinib is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate to severe AD whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable. The efficacy of upadacitinib for the treatment of AD was investigated in multiple phase 3 clinical trials, with results for three trials having been presented at this time: Measure Up 1, Measure Up 2 and Ad Up.

Measure Up 1 and Measure Up 2 were identically designed double-blind trials which assessed the safety and efficacy of two upadacitinib doses (15 mg and 30 mg, once daily) against a placebo for the treatment of moderate-to-severe AD in adolescent and adult patients (aged ≥12 years) The proportion of patients who achieved EASI-75 and a vIGA-AD score of 0/1 at week 16 (the co-primary endpoints) was significantly higher in both upadacitinib groups compared to the placebo in both Measure Up 1 and Measure Up 2 (Table 9-4). A significantly higher proportion of patients in both upadacitinib groups also achieved an improvement in itchiness in both trials, as assessed by a 4-point or greater improvement on the Itch Numeric Rating Scale (Itch NRS).

AD Up was a double-blind, placebo-controlled trial which tested the safety and efficacy of upadacitinib (at 15 mg and 30 mg daily) in combination with topical corticosteroids for the treatment of moderate-to-severe AD in adolescent and adult patients (aged ≥12 years). At week 16, a significantly greater proportion of patients in the upadacitinib 15 mg and 30 mg groups achieved EASI-75, a vIGA score of 0/1, and a 4-point or greater improvement on the Itch NRS, compared to the placebo group.

Upadacitinib was generally well tolerated in the phase 3 AD trials, with a safety profile similar to that observed in prior studies of upadacitinib for rheumatoid arthritis and psoriatic arthritis. During the placebo-controlled phase of Measure Up 1/2, the most common TEAEs were acne, upper respiratory tract infection, nasopharyngitis and headache. Serious AEs occurred at low rates (<3%), and were similar in the placebo and the two upadacitinib groups. Serious infections were rare (<1%), and no deaths or major adverse cardiac events were reported. Safety results from AD Up were consistent with those from Measure Up 1/2.

Like that of abrocitinib, the FDA label for upadacitinib contains a black box warning on potential serious adverse events associated with JAK inhibitors as a class. These include increased risk for serious infections, higher rates of all-cause mortality, lymphomas and lung cancers and major adverse cardiovascular events, as well as an increased incidence of pulmonary embolism and venous and arterial thrombosis.

Dosage and Administration

Upadacitinib is available in two extended-release tablet dosage forms: 15 mg and 30 mg. Upadacitinib tablets are taken by mouth, and should be swallowed whole (without splitting, crushing, or chewing) with or without food. The recommended dose of upadacitinib in children aged 12 and older who weigh at least 40 kg and in adults younger than 65 is 15 mg once per day. The dose can be increased to 30 mg once daily if an adequate response is not achieved, but upadacitinib should be discontinued if an adequate response is not achieved with the higher dose.

Upadacitinib should not be used in in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.

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Olumiant (Baricitinib)

Baricitinib is a potent inhibitor of JAK1 and JAK2 which is currently FDA-approved for the treatment of rheumatoid arthritis and is under investigation for use in AD treatment. The safety and efficacy of baricitinib in AD was investigated in seven phase 3 trials (BREEZE-AD1-7).

BREEZE-AD1 and BREEZE-AD2, which compared the safety and efficacy of three baricitinib doses (1 mg, 2 mg and 4 mg) to the placebo in patients with moderate-to-severe AD who have topical therapies, demonstrated that a daily 2 mg or 4 mg dose of baricitinib was superior to the placebo in the proportion of patients achieving a validated IGA (vIGA) score of 0/1 at week 16 (Table 9-5).Baricitinib treatment also resulted in a significant and early reduction of itch, assessed by a 4-point or greater improvement on the patient-reported Itch NRS. The long-term efficacy of baricitinib was assessed in BREEZE-AD3, which demonstrated that 40-50% of responders (vIGA 0/1) and partial responders (vIGA 2) at week 16 in both the 2 mg and 4 mg baricitinib groups maintained their response for another 52 weeks.

BREEZE-AD4 tested the safety and efficacy of baricitinib (1 mg, 2 mg, or 4 mg daily) in combination with topical corticosteroids in patients with moderate-to-severe AD who had failed previous treatment with or had contraindication to cyclosporine. At the 4 mg dose, baricitinib resulted in a statistically significant improvement in the proportion of patients achieving EASI-75 and vIGA 0/1, compared to the placebo, and was superior to the placebo at all three doses in reducing patient-reported itchiness on the Itch NRS.

BREEZE-AD5 assessed the safety and efficacy of two lower dose baricitinib regimens (1 mg and 2 mg daily) as a monotherapy for the treatment of moderate-to-severe AD. At the 2 mg daily dose, baricitinib treatment resulted in a significantly higher proportion of patients achieving EASI-75 (30% vs 8% in the placebo group, P<0.001) and vIGA 0/1 (24% vs 5% with the placebo, P<0.001) at week 16. The proportion of patients achieving a 4-point or greater improvement on the Itch NRS at week 16 was increased at both the 1 mg dose (16%, nominal P≤0.05) and the 2 mg dose (25%, P<0.001) compared to the placebo (6%). With the 2 mg baricitinib dose, statistical superiority to the placebo (P≤0.01) was observed by week 2. BREEZE-AD6, an ongoing open-label study in participants who completed BREEZE-AD5, is testing the long-term efficacy of baricitinib in an outpatient, open-label setting over the course of 204 weeks.

BREEZE-AD7 investigated the safety and efficacy of two higher dose baricitinib regimens (2 mg and 4 mg daily) in combination with optional low-to-moderate potency topical corticosteroids for the treatment of moderate-to-severe AD. A significantly higher proportion of patients receiving baricitinib 4 mg daily exhibited a vIGA score of 0/1 compared to those receiving placebo, demonstrating that this dosage regimen, in combination with background topical corticosteroids, can improve signs and symptoms of moderate-to-severe AD.

The safety of baricitinib in the treatment of AD was assessed in eight clinical trials: one phase 2 study and the seven aforementioned BREEZE-AD trials. A pooled safety analysis of these trials, comprising 2,531 patients who received baricitinib for a total of 2,247 patient-years, found that the most common treatment-emergent adverse events (TEAEs) were nasopharyngitis, headache, CPK elevations and diarrhea. TEAEs were numerically more common during the placebo-controlled period in the baricitinib 2 mg (49.3%) and 4 mg (51.0%) groups compared to the placebo (43.2%). The incidence of serious adverse events was not different between the placebo (2.3%) and the baricitinib 2 mg (1.4%) and 4 mg (2.3%) groups. The rate of serious infections was low and similar across treatment groups, and no patients experienced malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events, or tuberculosis.

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Systemic Immunosuppressants

Systemic immunosuppressants are commonly used in dermatology for inflammatory skin disorders, such as:

• Autoimmune blistering disorders
• Granulomatous diseases
• Psoriasis.

These agents are also recommended for adult and pediatric patients with AD who failed to control the signs and symptoms of disease with optimized topical regimens using:

• Emollients
• Topical anti-inflammatory therapies
• Adjunctive methods and/or phototherapy
• In whom contact dermatitis has been considered.

They may also be considered in patients with intense and uncontrolled symptoms and substantially impacted quality of life even with milder or less extensive physical signs of disease. Although few studies directly compare the efficacy of different systemic immunosuppressants in randomized controlled studies, systemic corticosteroids, CSA, MTX, MMF and azathioprine are prescribed most often.

Azathioprine (AZA)

AZA is a purine synthesis inhibitor, preferentially affecting cells with elevated proliferation rates, thus inhibiting B- and T-cell proliferation during inflammatory processes. Although approved by the FDA for rheumatoid arthritis and renal transplant rejection prophylaxis, use of AZA in inflammatory skin diseases, such as AD, is off-label.

Two placebo-controlled studies assessed the safety and efficacy of AZA in the treatment of AD. The first enrolled adults with moderate to severe AD despite optimum topical corticosteroid therapy. At week 12, patients treated with AZA reported a 37% improvement in AD, as measured by Six Area, Six Sign Atopic Dermatitis (SASSAD) score, compared with 20% improvement in the placebo group. Significant improvements were observed in:

• Patient-reported itch
• Area of involvement
• Global severity assessment
• Quality of life.

The second study enrolled adult patients with severe AD and found a reduction of 26% in SASSAD score in the AZA group compared with 3% reduction in the placebo group. Significant improvements were also observed in:

• Pruritus
• Sleep disturbance
• Disruption of work/daytime activity.

These studies demonstrated the efficacy of AZA as systemic monotherapy in the treatment of adult AD. Efficacy of AZA is also supported in pediatric patients. Overall, the AAD recommends AZA for patients with refractory AD or with disease having a significant psychosocial impact on the patient or family.

Safety

The most common adverse effects associated with AZA treatment include:

• Nausea
• Vomiting
• Other GI symptoms.

Other adverse effects may include:

• Headache
• Hypersensitivity reactions
• Elevated liver enzymes
• Leukopenia.

History, physical examination and laboratory monitoring may be appropriate before and during treatment with AZA, depending on the patient. AZA metabolism is dependent on thiopurine methyltransferase (TPMT) activity level, and genetic polymorphisms in TPMT result in patients having different susceptibilities to AZA toxicity. Therefore, baseline TPMT activity level testing is strongly recommended before initiating AZA treatment. Use should be avoided in those with low or absent TPMT activity. Although TPMT enzyme activity varies between patients, with greater activity protecting against the risk of myelotoxicity, its level of activity will not alter the risk of GI intolerance or hypersensitivity syndrome. Regular monitoring of blood cell counts and liver enzymes is essential while patients are taking AZA, regardless of TPMT status. Monitoring guidelines for the use of AZA are shown in Table 9-6.

Dosage and Administration

AZA is taken orally once daily. Most studies choose a dosage range between 1 and 3 mg/kg/day. Gradually increasing dose may be beneficial since many patients experience intolerable nausea and vomiting at higher doses, leading to discontinuation of treatment. Dosage may be based according to TPMT activity level. Full clinical benefit may not be observed for up to 12 weeks of treatment. Once clearance or near-clearance is achieved and maintained, AZA should be tapered or discontinued; remission can then be maintained with emollients and topical agents. Concomitant usage with phototherapy is not advised, especially UVA, because of an increased risk of photocarcinogenicity.

In children, an optimal treatment regimen has not been established, but the most common dosage given is 2.5 to 4.0 mg/kg/day. As in adults, TPMT levels should be measured at baseline and repeated as necessary.

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Cyclosporine A (CSA)

Discovered in the 1970s, CSA is often the first-choice systemic treatment in patients with moderate to severe AD. It acts as an immunosuppressant through the inhibition of T cells and IL-2 production. Although originally used as a graft anti-rejection medication, it has demonstrated therapeutic efficacy in several immune-mediated skin diseases. In AD, CSA is recommended as an effective off-label treatment for patients with an inadequate response to optimized topical treatment. Therapeutic effectiveness is typically experienced within 1 to 6 weeks of treatment initiation. In a placebo-controlled study of patients with severe AD, CSA treatment resulted in a mean decrease in total body severity assessment of 55%, compared with an increase of 4% in the placebo group. Mean score for extent of disease decreased by 40% in patients who received CSA, compared with an increase of 25% in those who received placebo. As such, CSA was demonstrated to be beneficial in the treatment of AD compared with placebo.

In a randomized controlled study of canines with AD, the efficacy and safety of CSA was compared with methylprednisolone for 4 months. Although there was no difference in reduction from baseline in lesion or pruritus scores, a significantly better overall assessment of efficacy was obtained in CSA-treated animals (76% vs 63% responses excellent or good). CSA-treated animals presented with a higher frequency of gastrointestinal (GI) disorders. A second 4-month canine study compared CSA with methylprednisolone for AD. In the 2 months following treatment, 87% of animals treated with methylprednisolone relapsed after a mean period of 27.9 days, compared with 62% of CSA-treated animals after a mean period of 40.7 days, a significant difference.

The safety and efficacy of CSA was compared with MTX in a randomized non-inferiority trial of 97 patients with moderate-to-severe AD. Eligible patients were randomized to receive either oral MTX (15 mg/wk) or CSA (2.5 mg/kg/day) for 8 weeks. The primary endpoint of the trial was SCORAD-50 (50% improvement in the SCORing Atopic Dermatitis index). Secondary endpoints included EASI-50 and SCORAD-50 at each visit. At week 8, MTX was inferior to CSA, with 8% of patients in the MTX group achieving SCORAD-50 compared with 42% in the CSA group. Doses of MTX and CSA were then increased to 25 mg/wk and 5 mg/kg/day, respectively, for the following 16 weeks. At week 20, 92% of patients in the MTX group and 87% of patients in the CSA group achieved EASI-50. Treatment-related adverse events were more frequent in the CSA group.

Safety

Potential adverse effects with CSA are well established and include:

• Infection
• Nephrotoxicity
• Hypertension
• Tremor
• Hypertrichosis
• Headache
• Gingival hyperplasia
• Increased risk of:
• Skin cancer
• Lymphoma.

Patients receiving CSA should therefore be monitored for these potential complications. Because of drug interactions, caution should be used when using CSA in patients using other systemic medications. Monitoring guidelines for the use of CSA are shown in Table 9-7.

CSA is safe for use in children. As with adults, the lowest effective dose should be used.

Dosage and Administration

Oral CSA is typically administered twice daily, preferably at the same time each day for maximum benefit. Dosage ranges from 3 to 6 mg/kg/day in adults, and typically higher doses are required in AD than for psoriasis. Initiating CSA at 3.5 mg/kg/day provides a good balance of efficacy, safety and tolerability. Higher initial doses are reported to result in more rapid disease control and improved quality of life measures, including pruritus and sleep disturbance; these efficacy benefits may be offset by a worse safety and tolerability. However, initial and maintenance doses should be individualized to the patient, taking into consideration disease severity, concomitant medications and comorbidities. Once clearance or near-clearance is achieved and maintained, CSA should be tapered or discontinued. Maintenance or remission can then be achieved with emollients, topical agents, phototherapy and/or other systemic immunosuppressants that are better tolerated long-term, eg, MTX or AZA.

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Methotrexate (MTX)

MTX is an antimetabolite that blocks folic acid metabolism, thus interfering with the synthesis of purines and pyrimidines. It is also thought to negatively affect T-cell function. It is currently approved by the FDA for several disorders, including dermatologic conditions such as psoriasis, but is used off-label in the treatment of AD. Several studies assessed the efficacy of MTX in the treatment of AD, with inconsistent methods and dosing regimens. As such, the true efficacy of MTX in refractory AD is unknown. One open-label, dose-ranging study administered MTX for 24 weeks in adult patients with moderate to severe AD, followed by a 12-week follow-up period. At week 24, MTX reduced disease activity by 52% from baseline according to six area, six sign atopic dermatitis (SASSAD) scoring, with mean disease activity remaining at 34% from baseline at the end of follow-up. A second trial randomized patients to receive either MTX or AZA for 24 weeks. At week 12, both groups experienced comparable clinical improvement. A third trial found that administration of low-dose MTX (10 to 25 mg/wk) in adult patients with AD improved scoring of atopic dermatitis (SCORAD) and Dermatology Life Quality Index (DLQI) measurements. In all three trials, MTX appeared safe and effective in controlling AD. However, additional trials are required to determine optimal MTX dosing regimens. As discussed previously, a non-inferiority trial has assessed the efficacy and safety of CSA vs MTX. At week 8, MTX was inferior to CSA, with 8% of patients in the MTX group achieving SCORAD-50 compared with 42% in the CSA group.

Safety

The safety profile of MTX is well-established in other indications, and the adverse effects are thought to be similar in patients with AD. Fatigue and muscle weakness are common adverse effects, typically occurring within 24 hours of patients taking their weekly dose. Oral administration is associated with nausea and other GI symptoms that can be mitigated through parenteral administration. Severe adverse effects can occur, including bone-marrow suppression and pulmonary fibrosis. Bone-marrow suppression often resolves following discontinuation of treatment. Due to the risk of pulmonary fibrosis, patients with pulmonary diseases may not be candidates for treatment. Monitoring guidelines for the use of MTX are shown in Table 9-8.

To reduce the risk of hematologic and GI toxicity, folic acid supplementation is recommended in all patients with AD taking MTX. A starting dose of 1 mg/day of folic acid is suggested, with possible escalation up to 5 mg/day, depending on medical needs; however, 5 mg/day of folic acid might reduce the efficacy of MTX.

Few prospective studies have assessed the safety and efficacy of MTX in children with AD. In a retrospective chart review of 47 children receiving MTX for severe AD, mean IgA at the 3- to 5-month follow-up improved from 4.25 to 2.8, with further improvement to 1.9 in those patients who continued therapy beyond 10 months. Improvement was also observed in the Children’s Dermatology Life Quality Index (CDLQI), where it decreased from 14.4 at treatment initiation to 7.5 at the 3- to 5-month follow-up, with further improvement to 6.6 in those who continued MTX past 10 months. Treatment with MTX was well tolerated. These results are consistent with those from pediatric patients with psoriasis, in whom MTX was also shown to be an effective and well-tolerated treatment. As with adults, the lowest effective dose should be administered to reduce the risk of adverse effects.

Dosage and Administration

MTX is available in tablet form as well as in solution for intramuscular or subcutaneous injection. Although bioavailability is better when administered as an injection, patients typically prefer taking tablets. The typical fixed dose for patients with AD ranges between 7.5 and 25 mg weekly. Dosing should be individualized to the patients to achieve and maintain disease control. One approach is to use a weight-based dosing strategy with a starting dose of 0.25 mg/kg/wk, and titrate up to as high as 0.5 mg/kg/wk in patients who tolerate lower doses well but have suboptimal efficacy. Maximum effect is typically observed 10 weeks into treatment. If no benefit is observed after 12 to 16 weeks on a sufficient dose (≥15 mg/wk), then patients should consider discontinuing treatment. As with other systemic treatments, once clearance or near-clearance is achieved and maintained, MTX should be tapered to the lowest possible dose for maintenance and prevention of flares in patients with chronic persistent or relapsing disease. MTX may successfully be discontinued in patients with less frequent moderate to severe flares. In such patients, remission can potentially be maintained with emollients and optimized topical therapy and/or phototherapy.

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Mycophenolate Mofetil (MMF)

MMF is an antimetabolite that blocks purine biosynthesis through inhibition of inosine monophosphate dehydrogenase. This blockage selectively inhibits B- and T-cell proliferation, since other cells can compensate for this inhibition. It is approved by the FDA for solid organ transplant rejection prophylaxis and is used off-label for AD. The AAD recommends MMF as an alternative, variably effective therapy for the treatment of refractory AD.

In one study, 55 adult patients with severe AD were treated with CSA for 6 weeks, followed by a switch to MMF in 24 patients for 30 weeks. Both groups of patients were monitored for 12 weeks post-treatment. During the first 10 weeks after a switch to MMF, SCORAD measurements were better for patients who continued with CSA, and seven patients in the MMF group required a limited oral corticosteroid course. Efficacy equalized thereafter, with comparable adverse effects. Upon treatment discontinuation, clinical remission lasted longer in the MMF treatment group.

Safety

MMF has a good safety profile and is generally well tolerated. The most common adverse effects are:

• Nausea
• Vomiting
• Abdominal cramping.

GI symptoms, headache and fatigue are not dose-dependent and do not typically affect compliance. Rare adverse effects include hematologic and genitourinary symptoms. As evidenced by MMF use in patients with organ transplantation, there is an increased risk of serious infections in AD patients being treated with MMF.

As it is considered a relatively safe alternative systemic therapy, pediatric patients with AD may be treated with MMF, albeit with variable and sometimes minimal efficacy. Patients as young as 2 years old were treated with MMF for severe AD, without significant hematologic, hepatic, or infectious sequelae. Longer-term safety data in children is not yet available. Monitoring guidelines for the use of MMF are shown in Table 9-9.

Dosage and Administration

MMF is given twice daily and is available as tablets, capsules and oral suspension. Although there are no official guidelines for dosing MMF, as there is insufficient data to make recommendations, doses typically range from 0.5 to 3.0 g/day. Typically, maximal doses of 3 g/day are needed to see any demonstrable clinical benefit. The suggested dose of MMF is 40 to 50 mg/kg/day in young children and 30 to 40 mg/kg/day in adolescents.

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Tacrolimus

Oral tacrolimus—a calcineurin inhibitor—is approved for use in the United States for prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. Use of oral tacrolimus in AD is off-label. Currently, there is insufficient data to recommend the use of oral tacrolimus in the management of AD. Both tacrolimus and pimecrolimus are available in topical formulations, which are FDA approved for AD.

Systemic Corticosteroids

Corticosteroids are natural products of the adrenal gland that are frequently used in the treatment of AD because they can rapidly improve clinical symptoms, temporarily suppressing the disease. Although their efficacy in the treatment of AD is generally well accepted, there are few reports to support this in the literature. In one placebo-controlled study, the efficacy of prednisolone, CSA and placebo were compared in patients who also received primary topical treatment (eg, topical steroids and emollients). Only one of 21 patients receiving prednisolone achieved stable remission (75% improvement in baseline SCORAD score) after 2 weeks of oral steroid therapy and a 4-week follow-up period, compared with six of 17 patients in the CSA group. Additionally, the trial was discontinued due to a high number of withdrawals due to exacerbations of AD (n = 15/38). Indeed, AD patients treated with systemic corticosteroids commonly experience rebound flares or worsened disease severity upon discontinuation of systemic corticosteroids. A recent systematic review of the safety and efficacy of systemic corticosteroids in AD concluded that use of systemic steroids should be limited to short courses as a bridge to steroid-sparing therapies.

Use of systemic steroids should generally be avoided and their continuous or chronic intermittent use in AD is discouraged. The AAD only recommends their consideration for acute usage as transitional therapy in severe, rapidly progressive, or debilitating cases in adults and children with AD while nonsteroidal immunomodulatory agents or phototherapy are being initiated.

Safety

Systemic corticosteroids have major adverse issues that limit their short- and long-term use. Possible adverse effects include:

• Hypertension
• Glucose intolerance
• Gastritis
• Weight gain
• Serious infections
• Venous thromboembolism
• Decreased bone mineral density and increased fractures
• Adrenal suppression
• Sleep disturbances
• Emotional lability.

Pediatric patients experience decreased linear growth while exposed to systemic corticosteroids.

Long-term use of systemic corticosteroids should be avoided and necessitates:

• Blood pressure monitoring
• Ophthalmologic examination
• Hypothalamic-pituitary-adrenal axis suppression testing
• Bone-density evaluation in adults
• Growth-velocity measurement in children.

Additionally, long-term treatment may require antibiotic prophylaxis for opportunistic infections and vitamin D and calcium supplementation. Children on long-term systemic corticosteroid treatment may require booster immunization protocols.

Dosage and Administration

The most commonly administered oral systemic corticosteroids to treat patients with AD are prednisolone and prednisone. Dosage is based on body weight, with most providers using a dosage range between 0.5 and 1.0 mg/kg. A gradual taper over 2 to 4 weeks is recommended to reduce the risk of adrenal suppression and rebound flares. Regardless, systemic corticosteroids are not disease-modifying, and worsening of disease should be expected upon discontinuation.

Conclusions

In summary, the potential short- and long-term adverse effects of systemic corticosteroids largely outweigh the benefits. Although immediate improvement may be noted by patients and physicians, other oral systemic or biologic medications have comparable or superior efficacy (e.g., CSA and dupilumab) and better safety and tolerability profiles (e.g., dupilumab, MTX and AZA) and should be considered instead of systemic corticosteroids.

Oral Phosphodiesterase-4 (PDE-4) Inhibitors

Apremilast

Inflammation associated with elevated PDE activity is an important aspect of AD and allergic disease. Increased PDE-4 activity leads to decreased intracellular levels of cyclic adenosine monophosphate (cAMP), which impacts the production of inflammatory cytokines, such as IL-4, IL-5, IL-10, IL-13, and prostaglandin E2. PDE-4 inhibitors therefore increase intracellular cAMP and disrupt the inflammatory process characteristic of AD.

Apremilast is a topical PDE-4 inhibitor that has also been studied for the treatment of:

• Asthma
• Psoriasis
• Psoriatic arthritis
• Obstructive pulmonary disease.

Although approved in the United States for the treatment of psoriatic arthritis, there is limited support for the treatment of patients with AD, and apremilast is not approved by the FDA for use in AD. A Phase 2 trial was conducted in adults 18 years of age or older, comparing placebo with apremilast 30 mg daily and 40 mg daily. Compared with placebo, apremilast 30 mg daily had no significant effect on change from baseline on Eczema Area and Severity Index (EASI) score, percentage of participants who achieved a 50% improvement in EASI score, or a score of 0 (clear) or 1 (almost clear) and a ≥2-point reduction from baseline in static Physician’s Global Assessment of Acute Signs at 12 weeks. Although the 40 mg dose significantly improved percentage change from baseline in EASI score (-10.98 PBO vs -31.57), no difference was observed in the other measures. Moreover, the 40 mg dose was associated with a high rate of treatment-emergent adverse effects and was discontinued by the Data Safety Monitoring Board. Thus, apremilast is not recommended for the treatment of AD.

Systemic Antimicrobials

Patients with AD are at a higher risk for infections due to a variety of factors, including:

• Skin-barrier dysfunction
• Decreased expression of anti-microbial peptides
• Aberrant toll-like receptor signaling and innate immunity
• Increased colonization with Staphylococcus aureus in lesional and non-lesional skin
• Use of topical and/or systemic immunosuppressing medications.

S aureus can be cultured from approximately 5% of the general population; this is increased to >90% in AD patients. There is an increasing body of research demonstrating the role of microbiome in the pathophysiology of AD. However, most AD patients with S aureus colonization do not show increased morbidity due to the colonization per se. Moreover, it has not been conclusively determined whether shifts in S aureus and microbiome are the proverbial “chicken” or the “egg.” That is, immune dysregulation and barrier disruption may drive the microbiome shifts as an epiphenomenon, with only modest relative contributions in AD pathogenesis.

Although many studies have assessed the efficacy of systemic antibiotics in decreasing S aureus colonization in AD patients, data are limited regarding the impact of these treatments on AD outcomes. One Cochrane review of three studies involving 103 patients found that systemic anti-staphylococcal medications were only warranted in AD patients with frank infections, but not in AD alone. The treatment of uninfected skin is controversial for a variety of reasons: although colony counts are initially reduced in patients treated with antibiotics, they return to previous levels within days to weeks of treatment discontinuation; incomplete irradiation of S aureus may contribute to bacterial resistance; S aureus antigens may persist for prolonged periods despite elimination. Moreover, S aureus counts dramatically decrease and microbial diversity increases after treatment with topical and/or systemic anti-inflammatory treatments alone. As such, the AAD only recommends the use of antibiotics in the treatment of AD patients with clinical evidence of bacterial infection. In those scenarios, the antibiotics should be used to treat the infection, not the AD. Thus, antibiotics should be administered in addition to standard treatment for AD, rather than a substitute.

Eczema herpeticum is an infection with herpes simplex virus that occurs in patients with multiple chronic inflammatory skin disorders. AD is the skin disorder most strongly associated with eczema herpeticum. Prior to the use of acyclovir, the mortality rate for patients with untreated eczema herpeticum was between 10% and 50%. However, a retrospective study of 1331 pediatric patients found that no deaths occurred from eczema herpeticum when treated with systemic antiviral therapy. As such, the AAD recommends the prompt initiation of systemic antiviral agents for the treatment of eczema herpeticum. Patients with eczema herpeticum commonly have superimposed bacterial skin infections, and some authors recommend combined treatment of eczema herpeticum with oral antivirals and antibiotics. Earlier initiation is associated with shorter hospital stays.

Systemic Antihistamines

Histamine is secreted as part of the immune response and stimulates local blood vessels and nerves. Histamine type 1 (H1) receptors are found on multiple immune cell types, including T-cell subsets and dendritic cells. H1 receptors have a clear pathogenic role in immediate hypersensitivity reactions and urticaria. A role for H1 receptors was demonstrated in mouse models of AD, but not in humans.

Pruritus is one of the most important drivers of disease-burden and poor quality of life in AD patients. Anti-H1 receptor blocking anti-histamines are often used as an adjunctive treatment in AD patients. However, antihistamines have not been shown to be effective treatments of itch in AD and the AAD does not recommend their general use in AD treatment.

The efficacy of both sedating and non-sedating anti-H1 blocking antihistamines in AD treatment has been studied in a number of trials, with the preponderance of evidence showing no benefit. In a review of 16 trials published in the period from 1966 to 1999, non-sedating antihistamines were found to be ineffective for management of AD. Sedating antihistamines were suggested to be useful only because they inhibit central H1 receptors, thereby sedating patients who have poor sleep secondary to uncontrolled itch. In this scenario, the antihistamines act as a sedative, but have not been found to improve itch per se. Similarly, a meta-analysis of 42 trials of topical AD treatments and 10 trials of oral AD treatments demonstrated that topical antihistamines were less effective than either topical corticosteroids or topical calcineurin inhibitors, while oral antihistamines had no effect on pruritus. A study in infants aged 12 to 24 months demonstrated that, while cetirizine-treated patients had less urticaria, there was no improvement in overall AD control.

Adverse effects of oral antihistamines depend on the individual medication and the medical history of the patient. Before an oral antihistamine is prescribed, it is good practice to consult the product information and drug reference material. Common adverse effects of oral antihistamine use are:

• Undesired sedation and a hangover-like effect
• Impaired cognition
• Anticholinergic symptoms like:
  • Xerostomia
  • Tachycardia
  • Blurry vision
  • Urinary retention
  • Weight gain.

Use of high doses of sedating antihistamines is a risk factor for serious injuries owing to sedation, altered sensorium, dizziness, orthostasis, etc. In addition, a recent study implicated chronic use of antihistamines as the strongest observed risk factor for the development of attention deficit hyperactivity disorder in childhood AD, irrespective of AD severity.

Based on currently available evidence, the AAD does not recommend the general use of antihistamines in the treatment of AD. Intermittent short-term use of sedating antihistamines may be helpful in the management of sleep loss caused by pruritus, but their use in pediatric patients may impact academic performance and in elderly patients, may impact cognition and should therefore be minimized. Systemic antihistamines may also be beneficial in AD patients with overlapping histaminergic disorders like:

• Urticaria
• Dermatographism
• Rhinoconjunctivitis.

That is, these overlapping disorders may cause pruritus and trigger the itch-scratch cycle. Thus, treatment of these histaminergic disorders with antihistamines may mitigate this potential trigger of itch.

Other Oral Systemic Therapies Not Recommended for AD

There is insufficient data to make recommendations regarding the use of several other oral systemic treatments, including:

• Theophylline
• Papaverine
• Montelukast.

These were used to treat other conditions, including allergic diseases, but have yet to demonstrate sufficient efficacy in patients with AD. Theophylline is a methylxanthine drug used to treat:

• Wheezing
• Chest tightness and shortness of breath caused by asthma
• Other lung diseases.

Papaverine is an opium alkaloid antispasmodic drug typically used to treat visceral spasm and vasospasm, but that may also provide itch relief in patients with AD. Montelukast is a leukotriene receptor antagonist used to treat symptoms of seasonal allergies and in the maintenance treatment of asthma.