Real-world data on the effectiveness of brodalumab in patients with moderate-to severe plaque psoriasis in the Greek clinical setting (the BrIDGE study).

BACKGROUND: Despite that brodalumab's efficacy and safety have been assessed in randomized clinical trials, real-life data remain scarce. BrIDGE was an observational, prospective, single-cohort, multicentre study that recruited patients with moderate-to severe plaque psoriasis in Greece. OBJECTIVES: The primary objective was to assess the proportion of patients who achieved Psoriasis Area and Severity Index (PASI)100 after 24 weeks. Other endpoints included: the maintenance of PASI90/100 through to 104 weeks, the short-term response [PASI75/90/100 and static Physician's Global Assessment (sPGA) 0/1] to brodalumab at 12-16 weeks and time to complete clearance. Moreover, we explored the change in quality of life [Dermatology Life Quality Index (DLQI) 0/1] and adherence to brodalumab. METHODS: Two hundred patients who were initiating treatment with or switching to brodalumab, were recruited. Analyses were conducted using the as observed data and three imputation approaches were also applied for the missing data (last observation carried forward, 'worst case' and 'best case' scenario). Continuous variables were reported using summary statistics, whereas categorical variables were reported in frequency tables. RESULTS: Based on the 'as observed data', 42.0% of patients achieved PASI100 at Week 24 after 25.9 ± 3.5 weeks and 65% of patients attained PASI100 at Week 104. In total, 70.2%, 47.5% and 32.0% achieved PASI75/90/100, respectively, whereas 72.6% of patients achieved sPGA 0/1, at Weeks 12-16. With respect to sPGA status 82.8%, 89.2% and 92.5% of patients achieved sPGA 0/1 at Weeks 24, 52 and 104, respectively. The time to achieve PASI100 at Weeks 12-16 was 13.7 ± 1.3, 52.1 ± 3.4 weeks at Week 52 and 105.5 ± 4.8 weeks at Week 104. Mean DLQI and Psoriasis Symptom Inventory (PSI) scores decreased by 11.4 ± 7.0 and 15.4 ± 6.5 points from baseline to Week 104, respectively. Adherence to treatment was equal to 98.9%. CONCLUSIONS: Brodalumab confers rapid and durable responses, as well as improvements in the quality of life of moderate-to-severe psoriasis patients.

Brodalumab Seems to Recover Its Therapeutic Efficacy After a Relatively Short "Washout" Period with Anti-TNF Agents: A Successful Pattern for Double-switch Therapy.

Psoriasis is a lifelong disease with a chronic relapsing course, and treatment agent switching is a common and accepted practice in cases of primary or secondary inadequate response. Patients with prior biologic treatment failure or loss of response are a subset of individuals who most likely have more severe disease with a greater impact on quality of life. Additionally, switching between multiple biologics is associated with clinical consequences (e.g. development of anti-drug antibodies), which may limit efficacy of subsequent biologic therapies (1,2). Adalimumab and brodalumab were both shown to be highly specific and efficient while sparing the cumulative toxicity observed in conventional anti-psoriatic drugs use. An observational study on 5 patients suffering from severe plaque psoriasis provided a successful pattern on double-switching of the aforementioned biologic agents. Therapy was initiated with brodalumab, and after secondary failure or occurrence of arthritic comorbidities, a short washout period with adalimumab followed without striking results. Re-administered brodalumab showed retrieval of initial therapeutic efficacy on both skin and joints. Patients provided written informed consent. Five Caucasian patients (mean age 53.2 years), with severe plaque psoriasis (mean baseline Psoriasis Area and Severity Index (PASI) score 18.58) and seriously affected Dermatology Life Quality Index (DLQI) (median score 19.3) underwent brodalumab treatment with excellent response. However, a secondary loss of efficacy occurred within an average period of 23 months, with intense arthritic implication in three patients. A switch to adalimumab followed, which lasted 4.2 months on average. Due to inadequate response, treatment with brodalumab was resumed (Figure 1). Resumption of treatment with brodalumab, after a rather short ''washout'' period with adalimumab, led to immediate remission of psoriasis, reducing median PASI and DLQI scores to 1.84 and 2.3 respectively, while still maintaining this effectiveness for an average of 8.8 months (follow-up timepoint). The clinical course over time for patient 2 is presented from the start of brodalumab treatment to the first and second relapse before completing and maintaining treatment with this biologic agent (Figure 2). Interestingly, at the same time, comorbidities in 3 of 5 patients with the axial psoriatic arthritis type that had arisen earlier subsided with remarkable clinical amelioration. Switch therapy in patients with severe psoriasis is a common clinical practice, due to the chronic and unpredictable course of the disease, both in nonresponsive or relapsing cases, and few studies have assessed the efficacy of a second line biologic treatment in this population. A real-life, multicenter, prospective study in Italy supported the switch from anti-IL 17 to adalimumab or ustekinumab as a safe and effective therapeutic strategy, but there was a gap for patients with loss of efficacy after failure of the second biologic treatment (3). The mechanism for secondary loss of efficacy of a biologic agent is still unclear, possibly due to altered immunogenicity closely connected to complex cytokine imbalance and activation of secondary pathways in disease induction and/or exacerbation. Brodalumab, having a unique mechanism of action inhibiting the receptor of the central cytokine implicated in the pathogenesis of psoriasis, not only has a broader effect on downstream inflammatory pathways but also overcomes the loss of response to anti-TNF inhibitors. The immunogenicity profile of brodalumab may supports its potential efficacy, which overlaps with the other biologic therapies (4-6). The present observational study described an unobserved successful management of severe psoriasis in which, for some reason, the initially administered brodalumab temporarily lost its effectiveness. It seems that the interference of adalimumab for a relatively short period enables the full healing capacity of brodalumab to be restored, with a positive rebound-like therapeutic outcome. The observed model may be worth studying in a larger number of patients in order to elucidate the underlying mechanisms and provide a pattern for a more efficient approach in cases of primary or secondary resistance.

Real world experience of brodalumab treatment in patients with moderate-to-severe plaque psoriasis in the Greek population: Results from an interim analysis of the BrIDGE study.

Brodalumab's clinical efficacy and favorable safety profile have been demonstrated during controlled clinical trials, but real-world data remain scarce. BrIDGE, an ongoing 104 week, observational, prospective, multicenter study conducted in Greece, enrolled moderate-to-severe plaque psoriasis patients, with body surface area (BSA) > 10 or psoriasis area severity index score (PASI) > 10 and dermatology life quality index (DLQI) > 10, based on European consensus, initiating brodalumab treatment as per routine clinical practice. This interim analysis includes evaluations 12-16 weeks following treatment initiation. Key efficacy endpoints included proportion of patients achieving static Physician's Global Assessment (sPGA) score of "clear/almost clear" (0/1) and a reduction ≥75%, 90%, 100% from baseline in PASI (PASI75, PASI90, and PASI100) at weeks 12-16. Other endpoints included time to achieve PASI100, changes in self-reported DLQI and psoriasis symptom inventory (PSI) at weeks 12-16. From 200 patients (mean age 51.4 years, 70% male, mean disease duration 13.8 years) enrolled, 72.8% achieved sPGA of 0/1, whereas 70.2%, 47.5%, and 32.0% achieved corresponding PASI75, PASI90, and PASI100 responses following 12-16 weeks of brodalumab treatment, according to the "as-observed" analysis. The mean time to achieve PASI100 was 13.7 ± 1.2 weeks for the 32% who achieved PASI100. Concurrent decreases in mean DLQI and PSI were observed. Furthermore, 90% adherence to brodalumab was noted and nine adverse events were reported. Brodalumab confers substantial clinical improvements short-term as reflected by high levels of skin clearance in moderate-to-severe plaque psoriasis patients within 12-16 weeks of treatment under everyday clinical conditions, followed by improvements in symptoms and quality of life and a favorable safety profile.

Clinical evidence on the use of brodalumab for the treatment of psoriasis in Greece: Experience from clinical practice of four tertiary hospitals.

Despite brodalumad demonstrated efficacy in clinical trials, real-world data reflecting clinical benefits in unselected patient populations treated in routine clinical practice are limited. Thus, we performed a longitudinal, retrospective, real-world analysis assessing the long-term clinical benefits of patients with moderate-to-severe psoriasis treated with brodalumab in Greece in the long term (up to 24 months). Main efficacy assessments included changes from baseline in the psoriasis area and severity index (PASI) and proportions of patients achieving at least 50%, 75%, 90% and 100% reduction from baseline in PASI scores (PASI50, PASI75, PASI90 and PASI100) at different timepoints up to 24 months. Other endpoints included changes in the dermatology life quality index (DLQI) and body surface area (BSA) involvement. Data from medical records of 180 patients with moderate-to-severe psoriasis treated with brodalumab for up to 24 months were assessed. Following treatment, mean [standard deviation (SD)] PASI scores were decreased across all visits compared to baseline (p < 0.001). The proportion of patients achieving PASI50, PASI75, PASI90 or PASI100 were high as early as at month 1 and consistently tended to increase over time, mainly during the first 6 months. Improvements on disease severity were further reflected by reductions from baseline on BSA scores across all visits (p < 0.001). Concurrent improvements on DLQI scores were observed across all visits (p < 0.001). This retrospective analysis provides real-world evidence supporting the long-term efficacy profile of brodalumab in Greek patients with moderate-to-severe psoriasis treated in standard clinical practice, which is characterized by a rapid onset of action generally sustained over time.

Maculopapular Cutaneous Mastocytosis Successfully Treated with Omalizumab.

Dear Editor, Maculopapular cutaneous mastocytosis (MPCM), formerly telangiectasia macularis eruptiva perstans (TMEP), is an uncommon form of cutaneous mastocytosis first described on 1930 (1). It is more frequent in adults, and early diagnosis is crucial since it has been reported to be associated with serious underlying systemic disorders, such as myeloproliferative diseases and severe manifestations like anaphylaxis (2,3). Treatment of MPCM depends on the presence of systemic involvement and/or the clinical symptoms of the disease itself. A 52-year-old woman was referred to us with pruritic brown red telangiectatic macules located on her arms, chest, and back (Figure 1, a, b, c) that had appeared over a period of 5 years. The patient also reported photosensitivity and facial flushing. Physical examination revealed a positive Darier sign (Figure 1, d) without other clinical signs suggestive of systemic involvement (e.g. lymphadenopathy, hepatosplenomegaly, malabsorption syndrome). Skin biopsy demonstrated abundant mast cells infiltration with granulomatic metachromasia (Giemsa stain; Figure 2, a) while immunohistochemistry demonstrated mast cells positivity in CD117/c-KIT (Figure 2, b). A detailed laboratory investigation was carried out, including complete blood count (IgE:1800 IU/mL), peripheral blood film examination, bone marrow biopsy, liver function tests, and serum tryptase levels (7 ng/mL). All performed tests were normal, thus excluding systemic disease. H1 receptor antagonists are considered the first-choice therapeutic option for control of symptoms among patients with skin mastocytosis (4,5). In our case, despite the standard application of an increased dose of different H1-receptor antagonists combined with topical steroid preparations, the patient showed no response to treatment and suffered a significant adverse influence on her quality of life and daily activities. Recent studies in single cases or small case-series have shown promising results for omalizumab in mastocytosis (6-8). Accordingly, our patient was switched to omalizumab 300 mg every 4 weeks for a one-year period. Both pruritus and flushing significantly improved after 2 months of treatment with only anti-IgE, and fully resolved during the fifth month of treatment. Almost 18 months, later the patient remains fully controlled with apparent significant improvement of her quality of life. The mechanisms of action for omalizumab in patients with mastocytosis are not well known. Omalizumab inhibits binding of IgE to the surface of mast cells and basophils by forming complexes with free IgE in serum, and this represents a possible explanation of the reduction of mast cell and basophil activation (9). In the future, omalizumab may be considered as a good alternative therapeutic option in cases where antihistamines have failed, though more research is necessary.

Case report: Treating a co-existence of hidradenitis suppurativa and psoriasis with different therapeutic approaches.

Hidradenitis suppurativa and psoriasis are considered chronic inflammatory diseases suggesting the existence of common pathogenetic pathways. We present two cases of comorbid psoriasis and hidradenitis suppurativa, treated with certolizumab pegol and brodalumab due to failure of response to other conventional therapies. Monoclonal antibody therapies have revolutionized the treatment of chronic inflammatory disorders such as psoriasis and hidradenitis suppurativa. Given the good clinical response to anti-IL-17 and anti-tumor necrosis factor agents in patients undergoing psoriasis and hidradenitis treatment, investigations on this direction could represent the starting point in new therapeutic approach for revolutionary treatment in these difficult-to-treat diseases.

Systemic sclerosis associated with generalized vasculitis and hypopituitarism.

Systemic sclerosis (SSc) is a progressively evolving multisystemic disorder of unknown etiology. Beyond skin, several other organs can also be affected with a severity of involvement that is often heterogeneous. We describe a 53-year-old female patient who was admitted urgently to the hospital almost collapsed, because of numerous bleeding deep skin ulcers, located all over the body. Clinical findings and autoantibody screening were typical of SSc. Moreover, both histopathology and immunofluorescence findings were compatible with scleroderma and vasculitis as well. In addition, pituitary hormone investigation revealed severely damaged function of the gland. We assume that severe skin ulceration and serious hypopituitarism were both implications of underlying SSc-associated vasculitis. To the best of our knowledge, these peculiar clinical manifestations have not been described in the international literature to date.

Isolated primary cardiac amyloidosis associated with porokeratosis of Mibelli.

In this report we briefly describe a 54-year-old woman who was referred to our institution for evaluation and management of newly diagnosed congestive heart failure associated with a skin rash. Detailed investigations revealed the presence of restrictive cardiomyopathy due to isolated primary cardiac amyloidosis as well as the presence of a skin disease named 'porokeratosis of Mibellli'. Interestingly, porokeratotic lesions rarely have been associated with localized cutaneous amyloidosis. Presumably, porokeratosis induces secondary dermal amyloid deposition by a yet unknown mechanism. This is the first case of primary amyloidosis associated with porokeratosis reported in the literature.