Abstract
Monotherapy may not be sufficient for the complete control of the psoriatic disease in selected patients. In refractory patients, combining two drugs with different mechanisms of action may result in improved efficacy. Data regarding the combination of biologics and Janus kinase inhibitors are lacking. A 61-year-old man affected by severe chronic plaque psoriasis and peripheral psoriatic arthritis affecting hands and feet, dactylitis, and enthesitis was successfully treated with a combination of upadacitinib and guselkumab. The combination of the two drugs was needed because upadacitinib was effective on psoriatic arthritis, but not on the skin lesions, while responding to guselkumab, which, vice versa, was not effective on psoriatic arthritis. Notably, the patients failed different conventional synthetic and biologic drugs. At a follow-up of 12 months, he had not experienced adverse events or laboratory alterations. Other studies are necessary to confirm the efficacy and safety profile of upadacitinib associated with guselkumab.
Case report
Psoriatic disease is a chronic immune-mediated disease affecting multiple disease domains, including skin, joints, enthesis, bone, nails, and it is nowadays considered a systemic disease for its heterogeneous inflammatory involvement and comorbidities. 1 Approximately 10%–20% of patients have been reported to be multi-resistant to monotherapies with biologic agents.2,3 Refractory patients may potentially benefit from combination therapy, including the association with Janus kinase (JAK) inhibitor and a biologic, because this could increase the effectiveness, but reduce the safety. However, efficacy and safety data regarding the combination of JAK inhibitors and biologics are lacking because randomized controlled trials investigated them only as monotherapies.
We report the case of a Caucasian 61-year-old man affected by psoriatic disease from the age of 30, with involvement of skin, peripheral joints, and entheses, who progressively failed different lines of therapy during the last 20 years, including convectional synthetic DMARDs (methotrexate, ciclosporin, sulfasalazine), biologic DMARDs, (TNF inhibitors, etanercept, adalimumab, infliximab, certolizumab pegol, golimumab, IL-12/IL-23 inhibitor ustekinumab, IL-17 inhibitors secukinumab, ixekizumab and brodalumab, IL-23 inhibitor guselkumab) and targeted synthetic DMARDs, and tsDMARDs (PDE4 inhibitor apremilast, JAK inhibitor tofacitinib).
He was affected by arterial hypertension, effectively treated by ramipril, he had a body mass index of 29.3, and he had been affected by Schonlein–Henoch purpura (flares at the ages of 12, 26, and 37, treated with steroids and mycophenolate.
Guselkumab was started in May 2022, achieving a complete remission of skin lesions (Psoriasis Area Severity Index (PASI) reduced from 38 to 5.2) but a very poor control of arthritis (Disease Activity Index for Psoriatic Arthritis (DAPSA) = 38), so in September 2022, guselkumab was interrupted and replaced with upadacitinib at the dose of 15 mg/day. In the following 3 months, a good response on psoriatic arthritis (PsA) was obtained (DAPSA reduced from 38 to 5.4), but multiple erythematosus and scaling psoriatic plaques reappeared on the trunk and legs, achieving a PASI score of 21 (Figure 1(a)). Skin lesions were burning and were not responsive to topical therapy with calcipotriol/betamethasone dipropionate combination. Moreover, dactylitis of the first digit of the right foot developed. Guselkumab was reintroduced (label dose including the induction) and combined with upadacitinib (15 mg/day). The patient has been informed about the potential safety concerns of this pharmacologic association. A close follow-up, with monthly blood tests, was performed. After 12 weeks, the cutaneous lesions were significantly improved with some residual hyperpigmentation (Figure 1(b)), joint disease activity further improved (DAPSA = 1.07), and a complete resolution of the dactylitis was observed. During the 12-month follow-up, the blood exams were within normal ranges, and adverse events, including infectious, were not reported.
Erythematous and desquamative lesions affecting the back and the upper limbs before (a) and after 12 weeks (b) of the combined therapy with upadacitinib 15 mg/day and guselkumab.
Discussion
Our clinical case draws attention to the possibility of combining a JAK inhibitor with a biological drug only in those selected patients who have a severe form of chronic plaque psoriasis associated with PsA that have multi-failure to many conventional and biological treatments when used as monotherapy. It must be immediately acknowledged that this combination is off-label and that randomized clinical trials are investigating its efficacy and safety, which could potentially expose the patient to an increased risk of infection and/or other safety concerns. We chose IL-23 inhibitor guselkumab because there are long-term data that confirm its safety both in patients with psoriasis and PsA, 4 and it is associated with a low risk of infection, especially of upper respiratory tract infections, but not of opportunistic infections.
Our experience is consistent with that of a recent case series that described the use of different JAK inhibitors in combination with biologics (IL-17 or IL-23 inhibitor) in six patients with recalcitrant psoriasis and PsA, for a short period of time. 5 One of these patients, with PsA in remission, whereas persistent psoriasis on upadacitinib monotherapy, was effectively treated by combining guselkumab with upadacitinib. Nevertheless, guselkumab was stopped after 56 days, and upadacitinib was continued as monotherapy. 5 Dual biologic therapy for recalcitrant psoriasis and PsA has also been occasionally reported. 6 Other case reports described the combination of TNF inhibitor with apremilast, with inconsistent results. 7 Moreover, dual-targeted therapy, combining two biologic agents or biologics with small molecules, has emerged as a novel approach to address this unmet need by targeting multiple inflammatory pathways simultaneously in patients with refractory intestinal bowel disease or extraintestinal manifestations. 8
We are aware that the evidence coming from a single clinical case is very limited, and we are aligned with the GRAPPA guidelines when they state that the combination of JAKi and biologics should be further studied. 9
In conclusion, psoriatic disease can affect several domains, including skin, nails, joints, entheses, dactylitis, and axial skeleton, so it may happen in real life that these domains do not respond well to therapy consistently, and therapy must be adjusted to have complete control over all domains. JAK inhibitor associated with a biologic with a different mechanism of action may result in improved efficacy, but other investigations are needed.
Footnotes
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Gisondi P received honoraria for serving as a speaker at congresses and/or participating to advisory board for Abbvie, Almirall, Amgen, Eli Lilly, Johnson and Johnson, UCB.