Safety of selective IL-23p19 inhibitors for the treatment of psoriasis.

Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. This article reviews published data on the safety of these IL-23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo- and active-controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk-benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL-23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL-23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long-term extension studies and patient registries will further establish the safety profile of IL-23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.

Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis.

BACKGROUND: Genital psoriasis (GenPs) is a common, debilitating and difficult-to-treat manifestation of plaque psoriasis. However, few controlled, interventional studies of GenPs exist. OBJECTIVES: To determine the efficacy of ixekizumab vs. placebo in patients with moderate-to-severe GenPs with ≥ 1% involved body surface area (BSA). METHODS: Patients with moderate-to-severe GenPs, defined as a baseline static Physician's Global Assessment of Genitalia (sPGA-G) score of ≥ 3, with BSA ≥ 1% were randomized 1 : 1 to receive placebo (n = 74) or the recommended dosing of ixekizumab (n = 75). Major outcomes included the percentage of patients achieving 0 or 1 scores on the sPGA-G (primary end point), overall sPGA, GenPs Sexual Frequency Questionnaire (GenPs-SFQ) item 2, and ≥ 3-point improvement from baseline on the GenPs itch numerical rating scale. RESULTS: At week 12, ixekizumab was superior to placebo for sPGA-G 0/1 (73% vs. 8%, P < 0·001), overall sPGA 0/1 (73% vs. 3%, P < 0·001), GenPs-SFQ item 2 score of 0 or 1 (78% vs. 21%, P < 0·001) and genital itch (60% vs. 8%, P < 0·001). No candidiasis was reported, no deaths occurred and one (1%) serious adverse event was reported in a patient receiving placebo. CONCLUSIONS: Ixekizumab was superior to placebo for the treatment of moderate-to-severe GenPs with BSA ≥ 1%. The safety profile of ixekizumab was consistent with previous studies in moderate-to-severe plaque psoriasis.

Impact of ixekizumab treatment on skin-related personal relationship difficulties in moderate-to-severe psoriasis patients: 12-week results from two Phase 3 trials.

BACKGROUND: Psoriasis symptoms may decrease quality of life for patients. Skin-related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood. OBJECTIVE: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis. METHODS: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately. RESULTS: PRD scores (mean ± standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 ± 1.9; ETN: 1.7 ± 1.8; IXEQ4W: 1.6 ± 1.8; IXEQ2W: 1.7 ± 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001). CONCLUSION: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to-severe psoriasis.

Cyclosporine and tacrolimus in dermatology.

Immune modulators are being used with increasing frequency in dermatology. This article reviews two such agents, cyclosporine and tacrolimus. Discussion emphasizes the pharmacology, side effects, and uses of these two drugs in dermatologic disorders.

Emerging new therapies for cutaneous T-cell lymphoma.

Improved therapy for CTCL will depend on a better understanding of the pathogenesis of this disease at a molecular level. It is clear that the T cells in MF and CTCL do not undergo normal programmed cell death and have prolonged lifespans. Skin flora or other antigens may stimulate the initial proliferation, offering another approach to change the course of the disease. There has been tremendous interest in biological response modifiers, and the first targeted fusion toxin to activated T cells has been approved for CTCL. New retinoids with increased selectivity and decreased side effects are being tested for this disease. In summary, the treatment of CTCL should continue to improve and should be focused on strategies that preserve the immune function in these patients.

Enterococcal eschars in cutaneous T-cell lymphoma tumors: a distinct clinical entity.

Cutaneous T-cell lymphomas (CTCL) are extranodal non-Hodgkin's T-cell lymphomas that present in the skin, the most common form being mycosis fungoides. The progression of disease is associated with acquired immunodeficiency and increased susceptibility to infections. Ten CTCL patients presented with dark brown to black eschars overlying ulcerated tumors that cultured positive for Enterococcus and healed with appropriate antibiotic therapy. Enterococcal infections in CTCL tumors may be recognized as a distinct clinical entity requiring specific intervention.

Ocular melanoma.

The eye is the second most common site for primary melanoma after the skin. An ophthalmologic evaluation should be an integral aspect of melanoma screening that is often not even considered by nonophthalmologists. Delays or failures to make an accurate and early diagnosis can have grave consequences. Early recognition and diagnosis, before the tumor has progressed into an advanced process with a poor prognosis, can often result in complete cures through early interventional treatments. It is imperative that physicians adequately understand and appropriately examine or refer patients for appropriate screening for ocular melanoma as a routine practice in screening for melanoma. This article is intended to raise the clinical awareness of the practicing physician regarding this disease.

Ichthyosiform sarcoidosis.

Ichthyosiform sarcoidosis is a rare specific cutaneous manifestation of sarcoidosis; it clinically and microscopically appears as acquired ichthyosis. We report a 68-year-old black man with a 10-year history of chronic obstructive pulmonary disease who presented with a 2-month history of acquired ichthyosis. His skin biopsy specimen showed both noncaseating granulomas in the dermis, consistent with sarcoidosis, and ichthyosis vulgaris. Ichthyosiform sarcoidosis is an uncommon presentation of cutaneous sarcoidosis that has been previously described in 19 nonwhite patients whose lesions were located on the legs. The skin lesions appeared either concurrently with or preceded the diagnosis of systemic sarcoidosis in 76% of patients; 95% of the patients eventually developed systemic involvement of their sarcoidosis. The onset of acquired ichthyosis should prompt evaluation for an associated malignancy, connective tissue disease, endocrine abnormality, nutritional deficiency, drug reaction, or sarcoidosis. A skin biopsy specimen consistent with acquired ichthyosis may point to the presence of cutaneous sarcoidosis.

Unusual presentation of mycosis fungoides as pigmented purpura with malignant thymoma.

Thymoma is known to be associated with many lymphoreticular and nonlymphoreticular tumors. A woman who presented with patch stage mycosis fungoides with skin lesions resembling a pigmented purpura was found to have an anterior mediastinal mass on routine staging evaluation. A core needle biopsy of the mass revealed a lymphocyte predominant malignant thymoma. Review of the literature reveals many diseases with dermatologic manifestations associated with thymoma; however, malignant thymoma coexisting with mycosis fungoides has not previously been reported.

Mycosis fungoides with focal segmental glomerular sclerosis and nephrotic syndrome.

Cutaneous T-cell lymphoma includes mycosis fungoides and the leukemic variant, Sézary syndrome. We report the first two cases of focal segmental glomerulosclerosis in patients with cutaneous T-cell lymphoma, with nephrotic range proteinuria and review the literature on renal disease coexisting with cutaneous T-cell lymphoma. We hypothesize that glomerular injury in cutaneous T-cell lymphoma may be related to interleukin-2.

Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.

Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection. Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor V beta repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific V beta gene, whereas 10 had oligoclonal or polyclonal expansion of several V beta families. All patients with TSST-1+ S aureus had overexpansion of V beta Z in blood and/or skin lesions. These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.