Case of pityriasis rubra pilaris progressed to generalized erythroderma following blockade of interleukin‐17A,but improved after blockade of interleukin‐12/23 p40

We report herein a case of a 72‐year‐old man with pityriasis rubra pilaris (PRP) that was refractory to conventional therapies. His skin lesions progressed to generalized erythroderma despite anti‐interleukin (IL)‐17A antibody therapy. Topical corticosteroids, emollients, systemic retinoid, methotrexate, cyclosporin and phototherapy yielded no therapeutic response. However, blockade of IL‐12/23 p40 dramatically improved his cutaneous lesions. Complete remission was achieved 4 weeks after the first injection of ustekinumab and maintained for more than 48 weeks. Our data indicate that IL‐12 was associated with the onset of PRP in this patient, rather than IL‐23. IL‐12 is critical for the differentiation of T‐helper (Th)1 cells. Thus, the Th1 pathway may be associated with the onset of PRP.     

Treatment of refractory adult‐onset pityriasis rubra pilaris with TNF‐alpha antagonists: a case series

Background Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis with frequent clinical presentation as erythroderma. Conventional systemic treatment is often unsatisfactory and limited by long‐term toxicity. The use of tumour necrosis factor (TNF) antagonists has been reported previously in single cases, but lacking long‐term follow‐up or comparison between different biological agents. Objectives To assess the long‐term efficacy and safety of TNF‐alpha antagonist, infliximab and etanercept, either in monotherapy or in combination therapy of severe, refractory adult‐onset PRP. Methods Seven patients of adult‐onset PRP, six newly diagnosed type‐I and 1 type‐II, which were resistant or ineligible to conventional systemic treatment, received a single course of infliximab or etanercept therapy, alone or in combination with low‐dose acitretin (>0.25 mg/kg/daily). After complete remission and treatment discontinuation, a follow‐up period of 12 months was evaluated for relapses. Results Six patients obtained complete remission after a single course of anti‐TNF‐alpha therapy: mean therapy duration was 19.3 weeks (range 6–48 weeks). All patients obtained significant clearing (>75% of body surface area) of skin lesions at week 12. Two patients with marked keratoderma developed localized disease recurrence during treatment. During follow‐up, only a single patient, affected by type II PRP, had disease relapse. Conclusions Both TNF‐alpha antagonists proved successful for the treatment of refractory, adult‐onset PRP, yielding complete and persistent clinical responses in type‐I PRP. Infliximab was associated with a more rapid onset of action, while treatment duration was comparable with etanercept. PRP type II warranted long‐term therapy and showed relapse after drug discontinuation.     

Refractory pityriasis rubra pilaris treated with etanercept,adalimumab, or ustekinumab: A retrospective investigation

Pityriasis rubra pilaris (PRP) is a rare, difficult to treat papulosquamous disorder that responds variably to retinoids and immunosuppression. Successful use of biologics for treating PRP has been described in the literature by case reports and a limited number of case series. To provide additional data, we retrospectively analyzed cases of PRP treated with biologics at our institution. We identified seven patients with a clear diagnosis of PRP treated with adalimumab, etanercept, and/or ustekinumab at our institution from January 1, 2014 to April 1, 2017. Six of seven patients had type I, adult acquired PRP, and one had type V atypical juvenile PRP. In response to tumor necrosis factor (TNF)‐α inhibition, two patients had marked responses (>75% improvement in involved body surface area), while three patients failed to show any improvement on a TNF‐α inhibitor. In two cases of PRP refractory to TNF‐α inhibition, ustekinumab resulted in a partial response (<75% improvement) in one patient and no response in the other. Compared to other published data, our cohort was substantially more resistant to treatment with biologics, a finding which may provide valuable perspective for dermatologists managing refractory PRP in the future.     

Excellent response to ustekinumab in a 9‐year‐old girl with severe psoriasis

We report the case of a 9‐year‐old girl with severe plaque psoriasis refractory to multiple topical and systemic therapies. Physical examination revealed extensive, erythematous plaques with overlying thick scales that covered more than 80% of her body surface area, which included the face, scalp, trunk, and limbs. Because of the severity of the disease and lack of treatment response to other systemic therapies, she was treated with ustekinumab. Three weeks after ustekinumab was initiated, her psoriatic lesions fully cleared.     

Successful Treatment of Severe Psoriasis in an Adolescent with Ustekinumab

Psoriasis is a chronic, inflammatory, immune‐mediated disease. Approximately 30% of patients have disease onset before age 18 years. Psoriasis in children and adolescents may be difficult to control, with subsequent poor quality of life and psychosocial consequences. We describe the case of a 12‐year‐old boy with severe, refractory, chronic plaque psoriasis for 6 years. Various therapeutic regimens including different topical corticosteroids, topical vitamin D analogs, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin, and combination therapies showed only partial or transient responses with frequent relapses. Because anti‐interleukin‐12/23 agents have been successfully used in adults with psoriasis, ustekinumab was initiated and our patient showed a rapid, excellent, sustained response. No recurrence or flares have been observed after 33 months of follow‐up. This case illustrates that ustekinumab may be an effective and safe therapeutic option in adolescents with psoriasis.     

Efficacy comparison of ustekinumab between anti‐tumor necrosis factor‐α drug‐naïve and anti‐tumor necrosis factor‐α drug‐resistant Japanese psoriasis cases

Ustekinumab is highly efficacious for psoriasis; however, it has not been fully clarified whether previous failure in anti‐tumor necrosis factor‐α (TNF‐α) therapy affects the treatment response with ustekinumab. Therefore, we evaluated the efficacy of ustekinumab in anti‐TNF‐α‐naïve and anti‐TNF‐α‐resistant cases and compared the clinical efficacies of adalimumab and ustekinumab in biologic naïve cases. Thirty‐five patients with plaque psoriasis who showed resistance to conventional therapies were enrolled; 26 patients, who had never been treated with biologics, were allocated to ustekinumab or adalimumab; nine patients who failed to achieve psoriasis area and severity index (PASI) 50 at week 16 with one or two TNF‐α antagonists were switched to ustekinumab. The end of the study was defined as 52 weeks after starting the first biologic for anti‐TNF‐α‐naïve patients and after switching to ustekinumab for anti‐TNF‐α‐resistant patients. The primary outcome measurement was the percentage of patients achieving PASI75 at week 16. In patients treated with ustekinumab, 87.5% of anti‐TNF‐α‐naïve and 77.8% of anti‐TNF‐α‐resistant cases achieved a PASI75 response at week 16, and no statistically significant difference was found between the treatment response rates (P = 0.60). When comparing the treatment efficacy of ustekinumab and adalimumab among anti‐TNF‐α‐naïve patients, there was also no statistically significant difference in PASI75 achievement rates (87.5 vs. 83.3%, P = 0.79). Our study suggests that ustekinumab can be considered as a first‐line biologic for psoriasis and a rescue therapy for anti‐TNF‐α‐resistant cases.     

A child with CARD14-associated papulosquamous eruption (CAPE) successfully treated with ustekinumab

CARD14-associated papulosquamous eruption (CAPE) is a rare inflammatory skin eruption that can have features of psoriasis, pityriasis rubra pilaris, and erythroderma. This skin condition is known for its resistance to topical or conventional systemic therapies. Successful treatment of CAPE with anti-IL-12/IL-23 and IL-17 inhibitors has been reported. We present a case of a 2-year-old girl with CAPE who was successfully treated with ustekinumab.     

Systemic therapies of pityriasis rubra pilaris: a systematic review

Pityriasis rubra pilaris (PRP) is a rare papulosquamous disorder. Treatment is challenging; the armamentarium consists of topical corticosteroids, phototherapy, classic systemic treatments such as retinoids or immunosuppressive drugs, and most recently biologicals. However, the relative effectiveness of therapies is unclear. Our objective was to review the published literature on systemic treatment of PRP. A systematic review was conducted on PubMed and the Cochrane Library up to 5 September 2017. Studies evaluating any systemic treatments of PRP (except for historical treatments) were included. Overall, 182 studies met the predefined inclusion criteria, and reported on 475 patients and 652 courses of treatment. 42.0 % (225/514) of all patients treated with retinoids achieved an excellent response (isotretinoin: 61.1 % [102/167], etretinate: 47 % [54/115], and acitretin: 24.7 % [43/174]) compared to an excellent response rate of 33.1 % (53/160) with methotrexate. Therapy with biologicals was successful in 51.0 % of patients (71/133) (ustekinumab: 62.5 % [10/16], infliximab: 57.1 % [28/49], etanercept: 53.3 % [16/30], and adalimumab: 46.4 % [13/28]). This review balances effectiveness, side effects, experience, and drug costs in order to suggest a treatment regimen starting with isotretinoin as first‐line, methotrexate as second‐line and biologicals as third‐line treatment for this difficult‐to‐treat dermatosis.     

Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: a retrospective,multicentre study in a clinical setting

Background Both the safety and efficacy of biologic therapy may be affected in the presence of highly prevalent chronic viral hepatitis. Objectives To evaluate the safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and concomitant chronic viral hepatitis. Methods This was a retrospective, multicentre study. Twenty‐five patients with psoriasis and concurrent hepatitis C virus (HCV) (20 patients) or hepatitis B virus (HBV) (five patients) infection who had received at least one biologic agent (etanercept, 21 treatments; adalimumab, four; ustekinumab, four; infliximab, two) were included. Clinical, imaging and laboratory data were recorded. Results In the case of HCV infection, the majority of the patients did not exhibit increases in their viral load or serum liver tests. Aspartate aminotransferase, alanine aminotransferase and gamma glutamyl transpeptidase were doubled from the baseline measurement in only one patient treated with etanercept. Two other cases exhibited viral load increases during the follow‐up period. In total, 18 of the 26 treatments achieved a 75% improvement in their Psoriasis Area and Severity Index (PASI 75) score during the follow‐up period. Two patients treated with etanercept were diagnosed with hepatocellular carcinoma. In the case of HBV infection, all of the patients were being treated with antiviral therapy, and none presented significant variations in viral load or serum liver enzymes. All patients achieved a PASI 75 during follow‐up. Conclusions Biologic therapy was effective and safe for the majority of our patients with HCV and HBV infection, although there may be a risk of reactivation or aggravation. We describe the first cases to receive ustekinumab. The use of biologics should be limited to those cases in which the risk–benefit ratio is justified.     

Clinical efficacy of platelet rich plasma in combination with methotrexate in chronic plaque psoriatic patients

Psoriasis affects up to 3% of the world's population or more than 125 million people. There is an urgent need for new treatment strategy, as up to 50% of patients are not satisfied with current therapies. We evaluated the combined efficiency of platelet rich plasma (PRP) and methotrexate (MTX) in the management of patients with plaque psoriasis. Twenty‐one patients with chronic plaque psoriasis were recruited in the study. Sixteen patients were assigned into combinational treatment group (PRP + MTX) and monotherapy group (MTX alone) consisted of five patients. All patients in combinational therapy received autologous PRP in their first sitting and subsequently followed with folitrax‐15 for 4 weeks, while patients in monotherapy group received only folitrax‐15, all patients received intra‐lesional injections. Digital photograph, Psoriasis Area Severity Index (PASI) score and adverse events were recorded at weeks 0, 4, 8, 12 and 16 and were evaluated by three investigators independently. Patients treated with PRP/MTX showed substantial improvement in term of reduction in erythema, induration and desquamation at each visit and was effectively cleared off psoriasis at week 16. Combination treatment of PRP with MTX was well tolerated by all patients without any serious adverse events.     

Ustekinumab treatment for hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a follicular occlusive inflammatory skin disease that occurs in the axilla, groin, buttocks and vulval region. Control of the intractable inflammation is a primary goal of HS treatments. Benefit of anti‐tumor necrosis factor (TNF) antibodies against HS have been reported, and adalimumab has been approved for HS in Europe, the USA and Japan. However, the alternative therapies for anti‐TNF antibodies have not been established yet. We experienced a case of HS which developed during the infliximab treatment for Crohn’s disease (CD) and was well managed by ustekinumab (UST). We reviewed the articles relating to ustekinumab treatments for HS. Twenty‐four HS patients, 16 women and eight men, have been treated with ustekinumab. The average age was 35.7 ± 10.8 years (mean ± SD). All were of Hurley stage II or III. Ten (10/24, 41.6%) had received anti‐TNF drugs including infliximab, adalimumab and etanercept prior to UST treatment for HS. Although the initial doses varied from 45 mg s.c. to 390 mg i.v., all cases were treated with 45 or 90 mg s.c. every 8 or 12 weeks at the regular dose, by following the regimen for psoriasis or CD. HS in most of the cases started to improve after 3–5 months of UST initiation, and some achieved complete remission. To our knowledge, our case is the first Asian HS patient improved by UST. Overall, UST is useful for HS and could be an alternative treatment if HS patients do not respond to other medications including anti‐TNF drugs.     

Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized,double‐blind,phase III NAVIGATE trial

Psoriasis is a chronic disease causing red and scaling skin lesions. Current treatments, especially biologics, which are either given by injection or intravenous infusion (IV), are very effective in the treatment of moderate to severe plaque psoriasis. However, most patients look to achieve clear skin, so there is room for improvement. One approved biologic, ustekinumab, blocks two of the body's internal proteins, interleukin (IL)‐12 and IL‐23. Blocking these proteins prevents signals that cause inflammation in psoriasis. While ustekinumab is effective in many patients, most will not achieve complete skin clearance. Because recent scientific evidence shows that IL‐23 may be more important than IL‐12 in causing psoriasis, guselkumab, a new treatment that specifically targets IL‐23, but not IL‐12, has been developed and was recently approved in the U.S. to treat moderate to severe psoriasis. In the NAVIGATE trial, 871 patients with moderate‐to‐severe plaque psoriasis received ustekinumab and if, after 16 weeks, patients were not clear or almost clear, they were randomly assigned to either continue ustekinumab or start treatment with guselkumab until week 44. From week 16 until week 40, the average number of visits (maximum = 4) at which patients were clear or almost clear was significantly greater in patients treated with guselkumab (1.5) than with ustekinumab (0.7). In addition, at week 28, twice the proportion of patients on guselkumab (31.1%) were clear or almost clear than on ustekinumab (14.3%). Infections were the most commonly reported adverse event among patients on either guselkumab or ustekinumab. The authors conclude that for patients who do not achieve clear or almost clear skin after ustekinumab treatment, switching to guselkumab could be an effective treatment strategy and did not raise safety concerns.     

Long‐term safety of ustekinumab in patients with moderate‐to‐severe psoriasis: final results from 5 years of follow‐up

Summary Background Long‐term safety evaluations of biologics are needed to inform patient management decisions. Objectives To evaluate the safety of ustekinumab in patients with moderate‐to‐severe psoriasis treated for up to 5 years. Methods Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest [infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE)] per 100 patient‐years (PY) of follow‐up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow‐up (years 1–5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population. Results Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥ 4 years (including 838 patients ≥ 5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year‐to‐year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population. Conclusions No dose‐related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate‐to‐severe psoriasis.     

Biological therapies for psoriasis: Adherence and outcome analysis from a clinical perspective

We evaluated and compared patients' long‐term adherence to biological therapies in a real‐life clinical setting. Secondary aims included weight changes on biological therapy and reporting adverse effects. This prospective case‐note review included 58 patients, undergoing 84 treatment series including etanercept (21), adalimumab (24), infliximab (14) and ustekinumab (25). Patients' adherence was greatest with ustekinumab (being 6.7‐fold less likely to withdraw from treatment than etanercept, P = 0.014), while the difference in treatment adherence of adalimumab and infliximab compared to etanercept was not statistically significant. Adalimumab and infliximab were associated with an increase in weight, while ustekinumab was associated with weight loss compared with etanercept (not statistically significant). Long‐term patient adherence to biologic therapy in patients with psoriasis is greatest with ustekinumab.     

Sequential Stevens-Johnson syndrome and photo-recall phenomenon

Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)‐12/23 p40 to treat psoriasis. The IL‐12 pathway is also important in regulating immunity to Mycobacterium tuberculosis. Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in ustekinumab‐treated patients with psoriasis. Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON^®‐TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis. Results At baseline, 101/2898 (3·5%) non‐Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and ustekinumab‐treated patients, as well as between ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and ustekinumab‐treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and ustekinumab groups through week 12. The rate of INH‐related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline. Conclusions Across five trials of ustekinumab‐treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.     

A systematic review of the literature on the treatment of pityriasis rubra pilaris type 1 with TNF‐antagonists

Background Adult pityriasis rubra pilaris (PRP) type 1 is a rare chronic papulosquamous disorder with clinical and histological parallels with psoriasis. Treatment is challenging and recent case reports suggest a potential role for tumour necrosis factor (TNF) antagonists. Objectives Our objective was to systematically review the literature for evidence of efficacy of TNF antagonists in the treatment of adult PRP. Methods We performed a systematic search of the Cochrane library, EMBASE, Pubmed and MEDLINE databases. We defined diagnosis of PRP, classified clinical response and whether this was clearly attributed to TNF‐antagonists. We also reviewed disease, treatment duration and follow up. Results Sixteen articles were selected for detailed review. From these, 12 articles (13 cases) met our predefined criteria and were included in the systematic review. The authors identified two more cases from their personal archive. A total of 15 evaluable cases were included for analysis. Twelve showed complete response (CR) (80%) to TNF‐antagonists with a mean time to maximal response of 5 months. In 10 of the CR cases (83%) this was clearly attributable to TNF antagonist therapy. Conclusion These data indicate that TNF‐antagonists may be of value in treating adult type 1 PRP refractory to other systemic agents but selective reporting bias, together with the lack of standard diagnostic criteria and established spontaneous resolution in PRP, prevent any firm recommendations on their place in management.     

How effective is ustekinumab in controlling psoriatic arthritis?

Recently ustekinumab has been approved for the therapy of psoriatic arthritis (PsA). Some case series have been published reporting new onset of inflammatory arthritis in psoriasis patients treated with ustekinumab. In addition, flare of joint inflammation in PsA patients has also been reported. We describe a case series of seven patients affected by PsA who experienced either a worsening or a flare of inflammatory arthritis during treatment with ustekinumab.     

Combination hyperbaric oxygen therapy and ustekinumab for severe hidradenitis suppurativa

Hidradenitis suppurativa is a painful chronic inflammatory skin condition characterized by inflammatory nodules that can lead to sinus tracts and scarring. Numerous treatments have been reported, though none have reliable efficacy. Antiinflammatory agents, such as tumor necrosis factor‐alpha inhibitors and interleukin inhibitors, have been used as medical therapy for refractory cases. We describe here a case of severe hidradenitis suppurativa in a pediatric patient successfully treated with a combination of high‐dose ustekinumab and hyperbaric oxygen therapy.     

Safety,efficacy and drug survival of biologics and biosimilars for moderate‐to‐severe plaque psoriasis

Psoriasis, a common disease affecting 2‐3% of the world's population, may in moderate‐to‐severe cases require systemic treatment with biological drugs (biologics). Treatment is usually permanent, but these drugs may loose their effect over time. When the patent for the original (originator) drug expires, other companies can produce a biosimilar, i.e. a drug that is very similar (but not completely identical, since biologics are derived from living human genes) to the originator. This Danish study compared safety, efficacy, and drug survival (i.e. how long patients stay on therapy) for five biologics: adalimumab, etanercept, infliximab, secukinumab, and ustekinumab. The study also compared the originator versions of etanercept and infliximab to their biosimilar versions. Data was examined from 3495 treatment series in 2161 patients. Drug survival was significantly higher for ustekinumab than for the other drugs. Secukinumab had the shortest survival and thereby also the highest risk of discontinuation of therapy. Adverse events also occurred the most frequently with secukinumab. Switching from an originator to a biosimilar version did not significantly affect drug survival. Among patients that obtained complete skin clearance, this occurred more rapidly for those treated with secukinumab as their first‐ever biologic. Over a 10‐year period, discontinuation of therapy occurred in 45·7% (adalimumab), 64·9% (etanercept), and 54·4% (infliximab) of patients. Ustekinumab and secukinumab have only been available for 8 and 2 years, respectively, during which time 30·3% and 28·8% of patients discontinued these therapies, respectively. Over time, response to therapy was generally highest for ustekinumab, followed by adalimumab.