Dear Editor, Despite the availability of highly efficacious biologics, psoriasis still remains an area of medical need.1 2 In particular, manifestations of the disease in different organs (skin, joints) may respond differently to the same treatment,1 3 providing rationale for combination treatments. However, experience with concomitant biological treatment is very limited due to safety concerns and high cost.4 5 6 7 8 9 In this report we describe our experience of 16·2 patient years of treatment with ustekinumab combined with an antitumour necrosis factor‐α agent for recalcitrant psoriasis with psoriatic arthritis (PsA) (Table 1). Characteristics of the patients CSA, ciclosporin A; MTX, methotrexate; PUVA, psoralen–ultraviolet A; UVB, ultraviolet B. Characteristics of the patients CSA, ciclosporin A; MTX, methotrexate; PUVA, psoralen–ultraviolet A; UVB, ultraviolet B. Patient 1 is a 67‐year‐old man who developed psoriasis and PsA (peripheral arthritis and spondyloarthropathy) at the ages of 24 and 55 years, respectively. He could not complete the treatment with methotrexate due to nausea and hepatotoxicity. Combination of ciclosporin A (400 mg daily) and methotrexate 5 mg weekly was unsuccessful, and therefore treatment with infliximab (5 mg kg−1 every 8th week) was initiated. After six infusions his Psoriasis Area and Severity Index (PASI) decreased from 18·2 to 10·1, but there was no effect on his arthritis [pain visual analogue scale (VAS) 7·2/10]. Infliximab was changed to etanercept and subsequently to adalimumab, which were efficacious on his arthritis, but not the skin (PASI fluctuating between 10 and 16). Attempts to combine adalimumab with acitretin and methotrexate did not improve the efficacy, and ustekinumab 90 mg (every 12th week) combined with etanercept 50 mg weekly was started. He achieved a satisfactory clinical response (PASI < 1·8, pain VAS < 5, no swollen joints) but developed flares of herpes zoster after injections of ustekinumab, which were controlled only partially with prophylactic valaciclovir (500 mg). The dose of etanercept was eventually reduced to 25 mg weekly, which reduced the flares of zoster and still provided adequate control of PsA and psoriasis (VAS < 4·5, PASI < 1·8). Patient 2 is a 39‐year‐old man with psoriasis and PsA since the age of 21 years and a history of Gilbert–Meulengracht syndrome and hepatitis B. Methotrexate was tried but discontinued due to lack of efficacy, severe nausea and concerns of hepatic comorbidities. He was treated with adalimumab, which was discontinued because of alopecia, and subsequently with etanercept (50 mg weekly titrated to 100 mg weekly) for 3 years with satisfactory effect on PsA, but with only a moderate efficacy on the skin. Because of high psoriasis activity (PASI 11·2, Dermatology Life Quality Index 21), ustekinumab (90 mg every 12th week) was added and this resulted in excellent disease control (PASI reduction to 1·6, pain VAS < 1). Etanercept was reduced to 25 mg weekly without compromising the clinical efficacy. However, the patient developed a retrotonsillar abscess while treated with combination therapy. It was successfully treated by incision and intravenous antibiotics and no other adverse events were noted. Patient 3 is a 49‐year‐old woman with psoriasis and PsA since age 19 years. Comorbidities included obesity, type II diabetes, hypertension, hypercholesterolaemia, chronic obstructive lung disease and chronic lymphoedema of both legs complicated with recurrent erysipelas. Prior antipsoriatic treatment comprised methotrexate (discontinued due to leucopenia) and ciclosporin A (discontinued due to hypertrichosis and uncontrolled hypertension). Acitretin with psoralen–ultraviolet A and efalizumab were not efficacious, whereas infliximab (500 mg every 6th week), adalimumab and etanercept produced only short‐lived responses. In 2009 she was treated with 90 mg ustekinumab every 12 weeks with excellent effect on the skin (PASI decrease from 30 to 1·2) but not on PsA (pain VAS 5·4/10, C‐reactive protein elevation to 64 mg L−1). Ustekinumab was combined with adalimumab 40 mg every other week and the patient achieved good partial remission for 25 months, when she experienced increased activity in psoriasis and arthritis. Adalimumab was discontinued and replaced by golimumab 100 mg every 4 weeks, which resulted in adequate control of the disease (PASI < 1, pain VAS < 2/10). During the combination treatment she had two episodes of erysipelas of the lower legs and one episode of bacterial pneumonia, which responded well to standard antibiotic therapy. Patient 4 is a 44‐year‐old obese woman with psoriasis and PsA since age 16 years. Between 2005 and 2007 she received multiple systemic therapies (methotrexate, ciclosporin, etanercept and infliximab), which did not provide sufficient disease control. In 2007 she received adalimumab (40 mg every other week) and obtained a satisfactory clinical response (decrease in PASI from 17·1 to 3·2 and in VAS score for joint pain from 8/10 to 3/10). Adalimumab was discontinued after 2 years due to pregnancy. Psoriasis flared after delivery (PASI 15·0) and she developed severe PsA (VAS score 7/10). Adalimumab was reintroduced but failed to control skin symptoms, even at a dose of 40 mg weekly. She responded well to combination therapy with ustekinumab (90 mg every 12th week) and adalimumab 40 mg every other week (PASI between 0 and 3, joint pain VAS < 3) for 18 months, when adalimumab was replaced by certolizumab 200 mg every other week because of flare of arthritis. No adverse events were reported during the treatment with biologics and the patient has been well controlled on this treatment. Combination of an antitumour necrosis factor‐α agent and ustekinumab may be beneficial in patients with psoriasis and PsA who do not respond to biologics in monotherapy. However, we noted a higher risk of infectious complications – relapsing herpes zoster (patient 1) and retrotonsillar abscess (patient 2) – which were probably related to the treatment.10 The relation between infections and biologics in patient 3 is less clear, as this patient had a history of recurrent skin infections. Importantly, there were no opportunistic infections. To our knowledge this is the first long‐term observational study documenting the effects of biologics given in combination for psoriasis. Cuchacovich et al.11 described a synergistic effect of ustekinumab and etanercept in a 38‐year‐old man who was treated for 11 months without any adverse events. Similar to our patients, the main reason for giving the biologics in combinations was differences in drug activity towards cutaneous psoriasis and PsA.3 The fact that these two classes of antibodies show additive efficacy supports the hypothesis that the immunopathogenesis of the cutaneous and articular manifestations of psoriasis may be dissociated from each other. Funding sources: none Conflicts of interest: R.G. has been an investigator, paid speaker and advisory board member for Pfizer, AbbVie, Janssen, Lilly, MSD and Celgene.
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Gniadecki et al. (2015) studied this question.
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