Add methotrexate to current regimen.

The effectiveness in managing psoriasis has vastly improved since the emergence of biologic medications. However, biologic drugs tend to lose efficacy with extended use (Levin et al. 2014). Although the specific mechanism that causes the clinical decline is not completely understood, evidence suggests that an immune-mediated mechanism is partially responsible. Biologic drugs are recognized by the immune system as foreign and elicit a helper T-cell-dependent humoral response that leads to the development of antidrug antibodies (ADAs) (van Schouwenburg et al. 2013). ADAs are considered to be either neutralizing or non-neutralizing. Neutralizing ADAs bind to the drug’s active site and prevent it from interacting with its end target. Non-neutralizing ADAs may form immune complexes with the drug, thereby increasing drug clearance (Jullien et al. 2015). Nonetheless, both neutralizing and non-neutralizing ADAs likely alter the bioavailability, excretion, binding sensitivity, and ultimately the efficacy of biologic medications. In order to maximize the utility of biologic agents, additional studies must be conducted to find effective methods of reducing biologic drug immunogenicity and identifying risk factors for loss of response.

Patients experiencing a loss of effect from biologic agents are managed differently depending on the severity of recurrence. A topical corticosteroid may be adequate if less than 3% of the body surface area (BSA) is affected. Apply the topical steroid BID for 2 weeks and alternate with a steroid-sparing agent BID for 2 weeks and repeat as needed. If recurrence involves more than 3% BSA, add methotrexate (7.5–25 mg weekly) to the patient’s current medication regimen for 3–6 months. If symptoms do not improve, consider switching to a different biologic agent with a long-term drug survival (e.g., ustekinumab).

The theory that concurrent methotrexate use can be used to overcome loss of efficacy is supported by retrospective studies of infliximab and adalimumab. Vermeire et al. demonstrated that simultaneous methotrexate use reduces the risk of ADA formation (Vermeire et al. 2007). The group of patients using infliximab with concurrent methotrexate had a lower incidence of ADA formation (46%) compared to the infliximab monotherapy group (73%). Lower serum infliximab levels were also seen in patients not simultaneously using methotrexate. The evidence for concomitant methotrexate use in minimizing loss of biologic effect appears reassuring, although further studies are needed to clarify the exact mechanism and proper dosage.

In a 52-week randomized control trial, 71% of participants treated with adalimumab obtained a 75% reduction in their Psoriasis Area and Severity Index score (PASI 75) after 16 weeks (Menter et al. 2008). During the study, 9% of patients developed anti-adalimumab antibodies (AAAs). Forty-three percent of AAA-positive participants lost clinical response by week 52. In the 3-year open-label extension study, 83% and 76% of participants who received uninterrupted adalimumab therapy maintained PASI 75 at week 100 and week 160, respectively (Gordon et al. 2012). Asahina et al. further demonstrated the correlation of AAAs and poor clinical response. Patients with AAAs fared worse with significantly lower PASI 75 response (23% vs. 73% in AAA-positive patients vs. AAA-negative patient, respectively), PASI 50 response (39% vs. 87%), and PASI 90 response (0% vs. 52%) at week 16 and week 24 (Asahina et al. 2010).

The long-term efficacy of ustekinumab has been well established in two long-term studies (PHOENIX 1 and PHOENIX 2) (Kimball et al. 2013; Langley et al. 2015). In the PHOENIX 2 study, 63.1% and 72% of participants achieved a PASI 75 response by week 12 when administrated 45 mg or 90 mg of ustekinumab, respectively (Papp et al. 2008). About 5% of the participants developed anti-ustekinumab antibodies. Of note, from the group who attained PASI 75, only 2% of participants were found to have anti-ustekinumab antibodies. In contrast, 13% of patients with partial response were found to have anti-ustekinumab antibodies. The authors also noted that partial responders had trough serum drug levels two to three times lower than PASI 75 responders. To further assess the long-term efficacy of ustekinumab, participants who achieved PASI 75 at week 40 were given an every-12-week maintenance treatment to complete 244 weeks of treatment. Approximately 80% of the patients maintained a PASI75 response through 244 weeks of therapy (Papp et al. 2013).