Anti-drug antibodies in psoriasis: a critical evaluation of clinical significance and impact on treatment response

TNF inhibitors and anti-p40IL12/23 monoclonal antibodies are efficacious treatments for moderate-to-severe psoriasis. However, the formation of anti-drug antibodies (ADA) with biologics may prevent patients from achieving a full clinical response. ADA have been reported in patients treated with etanercept, infliximab, adalimumab or ustekinumab at rates of 0–18.3%, 5.4–43.6%, 8.8–44.8% and 3.8–5.4%, respectively. Antibodies against etanercept have no apparent effects on clinical response, whereas antibodies against infliximab or adalimumab have been associated with diminished clinical response. The significance of ADA against ustekinumab is yet to be determined. Data regarding management strategies to counteract ADA formation and their effects are limited in psoriasis patients. However, some evidence suggests that concomitant immunomodulators such as methotrexate may suppress ADA development in psoriasis. ADA specific to one biologic do not appear to carry cross-linking potential with other biologic agents. ADA formation needs to be considered as a possible factor contributing to diminished response from biologic agents.     

Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases

ABSTRACT

Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics.

Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab.

Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.     

Current Concepts in Rheumatology,Royal Society of Medicine

Ustekinumab is a fully human monoclonal antibody directed against the p40 subunit shared by interleukin 12 and interleukin 23, two naturally occurring protein regulators that play an important role in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA). In September of 2009, the US FDA approved ustekinumab for the treatment of adult patients with moderate to severe plaque psoriasis. Beginning in November of 2009, Janssen Biotech (formerly Centocor Biotech), the developer of ustekinumab, initiated clinical trials to investigate the efficacy of ustekinumab in the treatment of other inflammatory disorders, including PsA. Phase II and Phase III studies showed both a good safety profile and significant efficacy for ustekinumab in the treatment of PsA, leading to the drug's approval in both Europe and the USA. In an immunotherapy market currently dominated by anti-TNF-α drugs for the treatment of PsA, ustekinumab offers an alternative option for patients with PsA, including those unresponsive to methotrexate and the TNF-α inhibitory agents currently approved for this potentially debilitating disease.     

Secukinumab demonstrates superior efficacy and a faster response in clearing skin in Asian subjects with moderate to severe plaque psoriasis compared with ustekinumab: Subgroup analysis from the CLEAR study

The 52‐week results from the CLEAR (NCT02074982) study showed high and superior efficacy of secukinumab versus ustekinumab in clearing skin and improving patient‐reported outcomes, with comparable safety profile in subjects with moderate to severe psoriasis. Here, we analyzed the efficacy and safety of secukinumab in Asian subjects from the CLEAR study. In this double‐blind, phase IIIb study, eligible subjects with moderate to severe plaque psoriasis were randomized (1:1) to receive s.c. injection of secukinumab 300 mg or ustekinumab as per label. Of 62 subjects included in Asian subanalyses, 23 were randomized to secukinumab and 39 to ustekinumab. A significantly higher proportion of subjects achieved 90% or more improvement in Psoriasis Area and Severity Index (PASI 90) with secukinumab versus ustekinumab at week 16 (78.3% vs 35.9%, P = 0.0010) and at week 52 (60.9% vs 33.3%, P = 0.0196). Similarly, a higher proportion of subjects achieved PASI 100 with secukinumab versus ustekinumab at week 16 (43.5% vs 10.3%, P = 0.0029) and at week 52 (30.4% vs 12.8%, P = 0.0704). The median time to achieve 50% improvement in baseline PASI was 2.8 weeks in the secukinumab group versus 6.3 weeks in the ustekinumab group. The safety profile of secukinumab was in line with the known profile and no deaths occurred. Overall, 95.7% and 84.6% of subjects remained on secukinumab and ustekinumab, respectively. Similar to the core study, secukinumab showed sustained and superior efficacy with faster response versus ustekinumab, and no new or unexpected safety concerns were identified, in Asian subjects with moderate to severe plaque psoriasis.     

Ustekinumab for the treatment of psoriasis

Management of psoriasis over the last decade has changed significantly with the introduction of biological therapies. Ustekinumab is a first-in-class biological agent, inhibiting the action of IL-12 and IL-23, and has provided further evidence for the role of Th1 and Th17 lymphocytes in the pathogenesis of psoriasis. Efficacy has been clearly demonstrated in three Phase III clinical trials. Week 12 Psoriasis Area and Severity Index (PASI) 75 was observed in 66.4–75.7% of patients with PASI 90 achieved in 36.7–50.9%. This marked clinical response is also reflected in a significant improvement in quality of life. The most recent Phase III clinical trial has demonstrated the superior efficacy of ustekinumab (regardless of dosing regimen) compared with high-dose etanercept at week 12. Long-term efficacy has been demonstrated over 148 weeks with 64–76% of patients maintaining PASI 75. The role of ustekinumab in the treatment of psoriatic arthritis has shown some benefit in Phase II clinical trials. Phase III clinical trials are pending and will provide further guidance on management of concurrent disease. The currently available safety data are on the whole reassuring, although ongoing vigilance remains central to the detection of rare or late sequelae.     

Ustekinumab in psoriasis: Five‐year real life experience from a single tertiary centre

The efficacy and safety of ustekinumab have been demonstrated in randomized clinical trials; however, there are few real‐life data evaluating ustekinumab. This observational, retrospective follow‐up study included 33 patients with moderate to severe psoriasis vulgaris. Patients were > 18 years old and received at least 16 weeks of ustekinumab. The efficacy of treatment was evaluated as PASI50, PASI75, and PASI90 response rates at 16, 28, 52, 76, and 100 weeks. Side effects associated with ustekinumab were recorded. Of 33 patients, 24 (72.7%) had received 45 mg ustekinumab and 9 (27.3%) 90 mg ustekinumab. At the 16th week of the treatment, 97% of the patients had PASI50, 57.6% had PASI75, and 33.3% had PASI90 response rates. At 16, 28, 52, 76, and 100 weeks, PASI50, 75, and 90 responses were generally higher in naive to biologics and in the 45 mg group than in nonnaive to biologics and in the 90 mg group but the differences were not statistically significant. In conclusion, ustekinumab is an effective and safe treatment option for patients with moderate to severe psoriasis vulgaris. It seems to be more effective in naive to biologics and patients with normal weight.     

Ultrasound in gastroenterology

Crohn’s disease (CD) is an inflammatory bowel disease whose precise etiology is still unknown, and therefore a causal therapy is not yet available. Studies showing the overexpression of IL-12 and IL-23, polymorphisms in genes encoding those cytokines and their receptors and genome-wide association studies have linked Crohn’s pathogenesis with IL-12/23 pathway. Ustekinumab is a novel therapeutic IgG₁ kappa monoclonal antibody that modulates Th1 and Th17 function, by blocking the p40 subunit of both IL-12 and IL-23 and preventing the interaction with their receptors on T cells, natural killer cells and antigen-presenting cells with established efficacy in psoriasis. This review will mainly focus on the available evidence on the role of ustekinumab in moderate-to-severe CD. The potential role of this biologic in the armamentarium of CD therapy is discussed.     

Varicella zoster virus meningitis under ustekinumab because of plaque psoriasis

Ustekinumab, a monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)‐12 and IL‐23, is approved in the USA and Europe for moderate to severe plaque psoriasis. There are concerns that biologic treatments like ustekinumab may lead to an increased rate of infections. We report a 77‐year‐old woman who developed varicella zoster virus meningitis 8 weeks after initiation of ustekinumab therapy because of plaque psoriasis. She presented clinically with sudden onset of fatigue, vertigo, nausea and epileptic seizures. Investigations of the cerebrospinal fluid revealed 522/3 cells, lactate 2.9 mmol/L, protein 232 mg/dL and 2.4 × 10³ varicella zoster virus. After 3 weeks of therapy with acyclovir she recovered. We conclude that infection by varicella zoster virus has to be considered as a differential diagnosis in patients with newly developing neurological or psychiatric abnormalities under immunosuppressive therapy.