Cutaneous adverse events of biological therapy for psoriasis: review of the literature

The use of biological agents is expanding worldwide as a new treatment alternative for chronic inflammatory diseases including more recently skin diseases, especially psoriasis. Although frequently observed, the knowledge about acute and chronic dermatological adverse events is limited, and potential pathogenic mechanisms still have to be identified. Exact diagnosis is required considering that dermatological adverse events raise a decisional challenge about potential treatment discontinuation. The object of this publication is to present an overview of the dermatological adverse events of these new treatment alternatives.     

Serum soluble CD163 and proinflammatory chemokines may be biomarkers of the onset of adverse events in dabrafenib plus trametinib combination therapy for advanced melanoma

Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon‐inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune‐related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs.     

The rationale for combination therapy

Fungal infections of the nail are common in European populations. There are a number of clinical presentations usually resulting from an infection by one of the dermatophyte species, notably Trichophyton rubrum . A number of modern treatment strategies are available and are generally well tolerated and effective. However, a significant proportion of patients, 20–30%, can expect treatment failure and/or relapse following treatment. The search for new treatment modalities and drugs is hampered by our lack of understanding of the basic pathophysiological mechanisms that underlie these frequently encountered infections. A correct diagnosis is key to the implementation of successful treatment. Even then, some infections do appear to be more recalcitrant than others. This may be the result of a number of interacting factors: patient susceptibility, fungal growth patterns that resist treatment and the occurrence of dormant fungal spores (arthrospores) in the nail. Increasingly, research is turning towards the identification of clinical indicators of poor prognosis and the development of new treatment strategies to overcome them. The combination of drugs to produce synergistic activity is one possible advance towards achieving higher cure rates.     

No association found between late-onset inflammatory adverse events after soft tissue filler injections and the adaptive immune system

Background

To date, it is unknown why some individuals develop late-onset inflammatory adverse events after treatment with fillers. These events may result from various factors, including an immunological response of the adaptive immune system.

Objective

In a pilot study, we looked for evidence that is there a relation between late-onset inflammatory adverse events and the presence of immune cells surrounding the injected filler.

Methods and Materials

We included 47 patients, of whom 20 experienced late-onset inflammatory adverse events to different fillers (inflammatory group) and 27 who did not (reference group). A biopsy was taken from the area of the adverse event. Hematoxylin–eosin staining and immunohistochemistry analysis with CD3 (T-cells) and CD68 (macrophages) on paraffin tissue sections was used to assess the biopsies.

Results

Immune cells were found in biopsies obtained from 18 of 47 patients: Nine biopsies from the inflammation group and nine from the reference group. All these 18 cases showed CD68-positive immune cells. Virtually no CD3-positive immune cells were found.

Conclusion

Our results indicate that there is no T-cell activity in biopsies from areas with late-onset adverse events after filler injections. The macrophages found in the biopsies are probably not responsible for the inflammatory response.     

Rate of acute adverse events for narrow-band UVB and Psoralen-UVA phototherapy

BACKGROUND: Ultraviolet (UV) radiation therapies are commonly used to treat a wide range of dermatological conditions. However, no published data exist regarding the rate of acute adverse events occurring within the different UV therapy modalities. AIM: The aim of this study was to determine the rate of acute adverse events experienced by patients receiving narrow-band UVB or photochemotherapy in 3 neighboring dermatology units. METHOD: Standardized adverse event forms from all 3 units were retrospectively analysed over a 12-month period between October 2003 and September 2004. The treatments included were narrow-band UVB and systemic, bath and hand/foot PUVA. RESULTS: A total of 8784 treatments were given over the study period. The total number of acute adverse events recorded for all phototherapy treatments was 70 (0.8%). The rates of acute adverse events for each treatment modality were 0.6% for narrow-band UVB, 1.3% for systemic PUVA, 1.3% for bath PUVA and 0.8% for hand/foot PUVA. Adverse events were due to patient non-compliance with standard operating procedures in 15 cases (21%) and operator error in 2 (3%). Only 4 of the acute adverse events were considered to be severe, accounting for 0.05% of all treatments. CONCLUSIONS: The rates of acute adverse events with phototherapy in this analysis were low, in particular the rate of severe adverse events. The highest rate was seen with both systemic and bath PUVA. The number of adverse events resulting from operator error was low. These published rates for adverse events associated with narrow-band UVB and PUVA may help other units when analyzing their own rate of adverse events.     

Calcipotriene and corticosteroid combination therapy for vitiligo

Corticosteroids and photochemotherapy, using a combination of psoralen and ultraviolet A (PUVA) exposure, are the most widely prescribed therapies for vitiligo. These treatments are not uniformly effective and many patients have inadequate responses. Calcipotriene has been shown to be effective in adults and children with psoriasis when used as monotherapy and in combination with corticosteroids and phototherapy. We hypothesized that since the mechanisms of action for calcipotriene and corticosteroids are different, patients may develop more repigmentation with a combination of the two agents, while decreasing the side effects from both agents. Twelve patients with vitiligo (average age 13.1 years) were advised to use topical corticosteroids in the morning and topical calcipotriene in the evening. Of the 12 patients, 83% responded to therapy, with an average of 95% repigmentation by body surface area. Four of the patients who responded had previously failed trials of topical corticosteroids alone. All of the patients in this group had repigmentation. Eyelid and facial skin responded best to this therapy. None of the patients had adverse reactions to the treatment. Our results show that topical calcipotriene in combination with corticosteroids can repigment vitiligo, even in those patients who were previous topical corticosteroid failures.     

Hair and nail adverse events during treatment with targeted therapies for metastatic melanoma

Background

Targeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed.

Materials and methods

Patients treated with BRAF andMEKinhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute’s Common Terminology Criteria.

Results

Of the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1.

Conclusion

Hair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.

     

Newer approaches in topical combination therapy for acne

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Its pathophysiology is multifactorial and complex, including obstruction of the pilosebaceous unit due to increased sebum production, abnormal keratinization, proliferation of Propionibacterium acnes (P. acnes), and inflammation. Topical agents are the most commonly used therapy for acne. First generation topicals mainly consist of single agent retinoids, benzoyl peroxide (BPO) and antibacterials that target comedones, P. acnes, and inflammation. Novel topical therapies include combination products with advanced vehicle formulations that target multiple acne pathophysiologies and offer simplified treatment regimes. For example, the combination of clindamycin and tretinoin in a unique vehicle formulation allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BPO combinations target comedones, inflammation, and P. acnes synergistically. These newer combination products have the potential to increase both efficacy and patient adherence when compared with single agent treatment.     

Clindamycin and rifampicin combination therapy for hidradenitis suppurativa

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory condition affecting apocrine gland-bearing areas of the skin. There is currently no satisfactory treatment. OBJECTIVES: To assess the efficacy of a 10-week course of combination clindamycin 300 mg twice daily and rifampicin 300 mg twice daily in the treatment of HS. METHODS: Patients who had received combination therapy with clindamycin and rifampicin for HS at one U.K. Dermatology Centre between the years 1998 and 2003 were identified from pharmacy records. Their records were analysed retrospectively. RESULTS: Fourteen patients with HS had received treatment with combination therapy. Eight of these patients achieved remission and a further two achieved remission when minocycline was substituted for clindamycin. Four patients were unable to tolerate therapy. CONCLUSIONS: This small retrospective study indicates that combination therapy with clindamycin and rifampicin may be effective for HS. However, there is a need for a placebo-controlled trial.