Tofacitinib: Pioneering JAK science in psoriatic arthritis
Management of patients with psoriatic arthritis (PsA) remains challenging due to the heterogeneity of its presentation, disease course and severity. At the International Conference of Chinese Rheumatologists 2019 in Hong Kong, Dr Eduardo Mysler of the Organización Médica de Investigación (OMI) in Buenos Aires, Argentina, discussed the importance of early diagnosis and multidisciplinary management of PsA, and reviewed emerging evidence supporting the use of tofacitinib (Xeljanz®, Pfizer), an oral Janus kinase (JAK) inhibitor, in patients with inadequate response to previous treatments.
Challenges in management of PsA
Patients with PsA often present with heterogeneous signs and symptoms that vary by tissue involvement, location, symmetry, timing and severity, potentially making the condition difficult to diagnose and manage early. “Thus, PsA is often misdiagnosed, resulting in delay in appropriate treatment,” said Mysler. [Ann Rheum Dis 2009;68:1387-1394; World J Ortho 2014;5:537-543]
“Early diagnosis and treatment of PsA is crucial because of its clinical and radiographic progression and functional disability associated with advanced disease,” he continued. [Ann Rheum Dis 2015;74:1045-1050; Ann Rheum Dis 2011;70:2152-2154] “Treatment decisions are further complicated by the presence of comorbidities, with up to 42 percent of PsA patients having three or more comorbid conditions.” [J Rheumatol 2013;40:1349-1356]
Multidisciplinary approach to PsA management
Psoriasis is an important early indicator of PsA since an estimated 30 percent of patients with psoriasis may also have PsA. [Ann Rheum Dis 2006;65(suppl 3):iii22-iii24]
“In fact, up to 70 percent of patients with PsA exhibit skin symptoms before developing arthritis, while 15 percent develop joint disease before skin lesions and 15 percent may have simultaneous joint disease and skin manifestations,” said Mysler. [Ann Rheum Dis 2006;65(suppl 3):iii22-iii24] “Skin lesions can also precede the onset of joint symptoms by up to 10 years.” [J Eur Acad Dermatol Venereol 2009;23(suppl 1):3-8]
“However, approximately 50 percent of patients with psoriasis and PsA are undiagnosed,” said Mysler. [Arthritis Care Res (Hoboken) 2014;66:1759-1766] “With cutaneous manifestations being common initial symptoms of PsA, patients are more likely to interact with dermatologists and primary care physicians than other medical specialties at first, highlighting the need for a multidisciplinary approach in the screening and detection of this disease,” stressed Mysler.
“The involvement of dermatologists and primary care physicians in PsA screening and detection presents an opportunity for early diagnosis and treatment to delay disease progression,” he added. [Arthritis Care Res 2014;66:1759-1766; Am J Clin Dermatol 2013;14:377-388]
JAK inhibition an emerging treatment target in PsA
According to the European League Against Rheumatism (EULAR), initial treatment options for patients with PsA include the conventional synthetic disease-modifying antirheumatic drug (DMARD) methotrexate, followed by biologic DMARDs such as tumour necrosis factor (TNF) inhibitors, as well as interleukin (IL)-12, IL-23, and IL-17 inhibitors. [Ann Rheum Dis 2016;75:499-510]
“In the 2019 update of EULAR’s recommendations, the first-in-class oral JAK inhibitor tofacitinib is now considered an option for patients who were refractory to prior treatment options,” said Mysler. [Gossec L, et al, EULAR 2019] “Tofacitinib is the first JAK inhibitor approved for the treatment of PsA in Europe, and it is currently undergoing regulatory review in other countries.” [Ann Rheum Dis 2019;78(suppl 2):1848-1849]
OPAL trial results
The 12-month, double-blind, active- and placebo-controlled phase III OPAL (Oral Psoriatic Arthritis Trial) Broaden trial evaluated the safety and efficacy of tofacitinib in patients with active PsA who previously had inadequate response to conventional synthetic DMARDs and had not received prior TNF inhibitors. [N Engl J Med 2017;377:1537-1550]
Patients were randomized to receive oral tofacitinib 5 mg BID (n=107), oral tofacitinib 10 mg BID (n=104), subcutaneous adalimumab 40 mg Q2W (n=106), placebo with a blinded switch to tofacitinib 5 mg at 3 months (n=52), or placebo with a blinded switch to tofacitinib 10 mg at 3 months (n=53). The primary endpoint was American College of Rheumatology 20 (ACR20) response (ie, ≥20 percent improvement from baseline in the number of tender and swollen joints and ≥20 percent improvement in at least three out of five other important domains) rate at 3 months.
At 3 months, ACR20 response was achieved by 50 percent of patients in the tofacitinib 5 mg group, 61 percent of patients in the tofacitinib 10 mg group, and 33 percent of patients in the pooled placebo group (p=0.01 for 5 mg dose vs placebo; p<0.001 for 10 mg dose vs placebo). The ACR20 response rate was 52 percent for patients receiving adalimumab. (Figure)
The mean change from baseline in Health Assessment Questionnaire–Disability Index (HAQ–DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at 3 months was −0.35 in the tofacitinib 5 mg group and −0.40 in the tofacitinib 10 mg group vs −0.18 in the pooled placebo group (p=0.006 for 5 mg dose vs placebo; p<0.001 for 10 mg dose vs placebo); the value was −0.38 in the adalimumab group. Adverse event rates at 12 months were 66 percent in the tofacitinib 5 mg group, 71 percent in the tofacitinib 10 mg group, 72 percent in the adalimumab group, 69 percent in the placebo group that switched to tofacitinib 5 mg, and 64 percent in the placebo group that switched to tofacitinib 10 mg, respectively.
Similarly significant results vs placebo were observed for tofacitinib in the randomized phase III OPAL Beyond trial, which included patients with active PsA with inadequate response to a TNF inhibitor. In this trial, ACR20 response rates were 50 percent with tofacitinib 5 mg and 47 percent with tofacitinib 10 mg vs 24 percent with placebo (p<0.001 for both comparisons). The mean changes from baseline in HAQ-DI score were −0.39 and −0.35 vs −0.14 (p<0.001 for both comparisons). [N Engl J Med 2017;377:1525-1536]
“Results of the OPAL trials support the use of tofacitinib in patients with PsA who have received prior treatment with either conventional synthetic DMARDs or TNF inhibitors. Another major advantage of tofacitinib is its convenient oral route of administration,” concluded Mysler.