Management of Enthesitis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: Enthesitis is a key pathological and clinical feature of psoriatic arthritis (PsA) in children and adults. Enthesitis is typically assessed clinically using several validated enthesitis scoring systems that have been used in clinical trials. Enthesitis treatment response has been reported as change in the total enthesitis score or the proportion of patients who achieved complete resolution. The majority of trials in PsA did not require patients to have enthesitis at study entry since enthesitis was evaluated only as a secondary outcome. Despite the inherent limitations of the clinical assessment of enthesitis, imaging of the entheses using ultrasound or magnetic resonance imaging has rarely been used in clinical trials to assess response to treatment of enthesitis. This systematic review summarizes existing evidence regarding pharmaceutical and nonpharmaceutical interventions for enthesitis in patients with PsA to facilitate an evidence-based update of the Group for Research and Assessment in Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for PsA. METHODS: We performed a systematic literature review to identify 41 randomized clinical trials that reported enthesitis treatment response in patients with PsA. For each intervention, the response effect size was summarized and the quality of evidence was graded. Recommendations were then formulated for the various pharmacological and nonpharmacological therapies. RESULTS: We included 41 randomized clinical trials in our review and graded each intervention. CONCLUSION: Several classes of systemic conventional and advanced therapies and local measures were recommended for active enthesitis in patients with PsA.

Improvement from ixekizumab treatment in patients with psoriatic arthritis who have had an inadequate response to one or two TNF inhibitors.

OBJECTIVE: To evaluate the efficacy of ixekizumab (IXE), a monoclonal antibody selectively targeting interleukin-17A, in patients with inadequate response to one or two TNF inhibitors (TNFi). METHODS: A phase 3 study (SPIRIT-P2; NCT02349295) randomized patients with PsA with inadequate response or intolerance to one or two TNFi to receive 80-mg IXE every 2 weeks (n = 123) or every 4 weeks (n = 122) after a 160-mg starting dose or placebo (PBO; n = 118) through week 24. This post hoc analysis used data from inadequate responders to one or two TNFi, measuring the percentage achieving: ≥50% improvement in ACR response criteria (ACR50) and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100), ACR50, improvement in HAQ-Disability Index (HAQ-DI) ≥0.35, minimal disease activity (MDA), European League Against Rheumatism (EULAR) Good Response Criteria [improvement in Disease Activity Score 28 CRP (DAS28-CRP) >1.2], and Disease Activity in PsA (DAPSA) ≤14. RESULTS: There were no significant differences in baseline characteristics between inadequate responders to one and two TNFi. At week 24, significantly more patients irrespective of previous TNFi experience receiving IXE than PBO achieved ACR50, HAQ-DI ≥0.35 improvement, MDA, EULAR good response, and DAPSA ≤14, and significantly more patients with inadequate response to one TNFi receiving IXE than PBO achieved ACR50 and PASI 100. Improvement persisted in all measures through week 52. CONCLUSION: IXE improved the signs and symptoms of PsA in a population of difficult-to-treat patients with inadequate response to one or two TNFi.

Efficacy and Safety of Ixekizumab in Patients with Psoriatic Arthritis and Inadequate Response to TNF Inhibitors: 3-Year Follow-Up (SPIRIT-P2).

PURPOSE: Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A. The objective of this study was to assess the long-term efficacy and safety (to week 156) of ixekizumab in patients with active psoriatic arthritis and inadequate response or intolerance to one or two tumor necrosis factor inhibitors. METHODS: In the SPIRIT-P2 study (ClinicalTrials.gov ID: NCT02349295), patients were randomized to placebo or ixekizumab 80 mg every 4 weeks (IXE Q4W) or every 2 weeks (IXE Q2W) following a 160-mg starting dose. During the extension period (weeks 24-156), patients maintained their original ixekizumab dose, and placebo patients received IXE Q4W or IXE Q2W (1:1). Exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) are presented. RESULTS: Of 363 patients enrolled in the study, 310 entered the extension period. In all patients treated with IXE Q4W and IXE Q2W at week 0, responses persisted to week 156. At week 156, clinical responses (observed) in patients treated with IXE Q4W and IXE Q2W were assessed [American College of Rheumatology (ACR) response criteria and minimal disease activity (MDA) criteria]: 84 and 85% showed 20% improvement (ACR20); 60 and 58% showed 50% improvement (ACR50); 35 and 47% showed 70% improvement (ACR70), respectively; and 48 and 54% showed MDA. Placebo patients re-randomized to ixekizumab also demonstrated sustained efficacy, as measured by ACR and MDA responses. In the All Ixekizumab Exposure Safety Population (n = 337), with 644 PY of ixekizumab exposure, treatment-emergent adverse events (TEAEs) were reported by 286 patients (44.4 IR). The most common TEAEs were upper respiratory tract infection (9.80 IR), nasopharyngitis (8.2 IR), sinusitis (6.2 IR), and bronchitis (4.5 IR). Serious adverse events were reported by 42 (6.5 IR) patients (included 3 deaths and 10 infections). CONCLUSION: In this 156-week study of ixekizumab, improvements in signs and symptoms of psoriatic arthritis and the safety profile remained consistent with those in previous reports. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02349295.

Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid arthritis aged < 65 years and those ≥ 65 years of age.

OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) aged < 65 years and those ≥ 65 years who were enrolled in the GO-FURTHER study. METHODS: In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, patients with active RA were randomized to intravenous (IV) golimumab 2 mg/kg + MTX or placebo + MTX at weeks 0 and 4, then every 8 weeks thereafter (with crossover to golimumab at week 16 [early escape] or week 24 [per-protocol]). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology (ACR) 20/50/70 response criteria. Efficacy and adverse events (AEs) were monitored through 2 years. Efficacy and AEs were summarized for patients aged < 65 years or ≥ 65 years; AEs were also summarized for patients < or ≥ 70 years and patients < or ≥ 75 years. RESULTS: In GO-FURTHER, 592 patients were randomized to receive placebo (n = 197) or golimumab (n = 395), 515 were aged < 65 years and 77 were ≥ 65 years. At week 24, ACR20 response rates were greater for golimumab + MTX patients compared with placebo + MTX for patients < 65 years (61.6% vs 31.3%, p < 0.001) and those ≥ 65 years (69.5% vs 33.3%; p < 0.01). Infections were the most common AE through week 112 (51.6% in patients < 65 years; 55.3% in patients ≥ 65 years); upper respiratory infections were the most common infection in patients < 65 years (13.2%) and those ≥ 65 years (11.8%). Serious AEs occurred in 17.7% in patients < 65 years and 25.0% of patients ≥ 65 years and included malignancies, pneumonia, fractures, acute pancreatitis, cellulitis, and bacterial arthritis. CONCLUSIONS: In GO-FURTHER, ACR response rates were similar between patients < 65 years and patients ≥ 65 years within each treatment group. AEs in elderly patients were similar to the known safety profile of IV golimumab. Immunosenescence is known to increase the risk of infections in the elderly. Elderly patients had a numerically higher incidence of serious infections. Six malignancies occurred in golimumab-treated patients, all in patients < 65 years. TRIAL REGISTRATION: clinicaltrials.gov: NCT00973479 . Registered September 9, 2009.

4-year results from the RAPID-PsA phase 3 randomised placebo-controlled trial of certolizumab pegol in psoriatic arthritis.

OBJECTIVE: To report the efficacy, patient-reported, radiographic and safety outcomes of 4 years' certolizumab pegol (CZP) treatment in patients with psoriatic arthritis (PsA). METHODS: RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to Week 24, dose-blind to Week 48 and open-label (OL) to Week 216. Patients were randomised 1:1:1 to either placebo or CZP 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W) (following 400 mg at Weeks 0/2/4). Patients randomised to CZP continued their assigned dose in the OL period. Patients randomised to placebo were re-randomised to CZP 200 mg Q2W or 400 mg Q4W (post-loading dose) at Week 16 (early escape) or after the double-blind phase. We present observed and imputed data; missing values were imputed using non-responder imputation (NRI) for categorical and last observation carried forward (LOCF) for continuous measures. RESULTS: 409 patients were randomised; 20% (54/273) of Week 0 patients randomised to CZP had prior anti-tumour necrosis factor (TNF) exposure; 67% (183/273) completed 216 weeks. By Week 48, 60.4% of patients achieved Disease Activity Index for Psoriatic Arthritis low disease activity or remission, which was maintained; 66.3% achieved these outcomes at Week 216 (NRI). At Weeks 48 and 216, 39.2% of patients achieved minimal disease activity (NRI). 75% reduction in Psoriasis Area and Severity Index responses were 65% and 52% at Weeks 48 and 216 (NRI). Total resolution rates for enthesitis, dactylitis and nail psoriasis, at 4 years, were 71%, 81% and 65%, respectively (LOCF). Structural damage progression was low over 4 years' treatment. No new safety signals were identified after Week 96. CONCLUSIONS: CZP efficacy in treating PsA was maintained over 4 years, in patients both with and without prior anti-TNF exposure, with no new safety signals identified.

Rituximab versus cyclophosphamide for ANCA-associated vasculitis.

BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Abatacept: a costimulatory inhibitor for treatment of rheumatoid arthritis.

T cell costimulation is believed to be crucial in orchestrating immune responses that lead to inflammation and destruction in rheumatoid arthritis (RA). Abatacept is a novel recombinant CTLA4Ig fusion protein that selectively modulates costimulation via interrupting the CD28:CD80/86 pathway, resulting in downregulation of T cell activation and multiple ensuing effector mechanisms. Abatacept has been shown to be efficacious, either when given alone or in combination with methotrexate, in patients with active RA, including anti-TNF failures. Improvements in clinical signs and symptoms, slowing of radiological progression, and enhancement in patient function and pain have been reported in clinical trials. Infusions were well-tolerated with a favourable safety profile similar to placebo and no appreciable immunogenicity. Abatacept is the first in a new class of biological response modifiers called costimulatory blockers.