Cutaneous sarcoidosis due to immune-checkpoint inhibition and exacerbated by a novel BRAF dimerization inhibitor.

Sarcoidosis is a non-infective granulomatous disorder of unknown aetiology, with cutaneous involvement affecting up to 30% of patients. Drug-induced sarcoidosis has been reported secondary to modern melanoma therapies including immune-checkpoint inhibitors and first generation BRAF inhibitors such as vemurafenib and dabrafenib. Herein, we report a case of cutaneous micropapular sarcoidosis that first developed on immune-checkpoint inhibition with ipilimumab and nivolumab for metastatic melanoma, which was exacerbated and further complicated by pityriasis rubra pilaris-like palmar plaques upon transition to a next-generation BRAF-dimerisation inhibitor. Both the micropapular eruption and palmar plaques rapidly resolved after cessation of the novel BRAF-inhibitor and concurrent commencement of hydroxychloroquine. It is unclear how inhibition of BRAF-dimerisation results in granuloma formation, though upregulation of TH1/TH17 T-cells and impairment of T-reg cells may be responsible. Clinicians should be aware of the potential for exacerbation of sarcoidosis when transitioning from immune-checkpoint inhibitors to these novel BRAF-dimerisation inhibitors, particularly as their uptake in treating cancers increases beyond clinical trials. Further studies are required to assess whether these next-generation agents can trigger sarcoidosis de-novo, or simply exacerbate pre-existing sarcoidosis.

Nicotinamide reduces photodynamic therapy-induced immunosuppression in humans.

BACKGROUND: The immune suppressive effects of topical photodynamic therapy (PDT) are potential contributors to treatment failure after PDT for nonmelanoma skin cancer. Nicotinamide (vitamin B(3) ) prevents immune suppression by ultraviolet radiation, but its effects on PDT-induced immunosuppression are unknown. OBJECTIVES: To determine the effects of topical and oral nicotinamide on PDT-induced immunosuppression in humans. METHODS: Twenty healthy Mantoux-positive volunteers received 5% nicotinamide lotion or vehicle to either side of the back daily for 3 days. Another group of 30 volunteers received 500 mg oral nicotinamide or placebo twice daily for 1 week in a randomized, double-blinded, crossover design. In each study, methylaminolaevulinate cream was applied to discrete areas on the back, followed by narrowband red light irradiation (37 J cm(-2) ) delivered at high (75 mW cm(-2) ) or low (15 mW cm(-2) ) irradiance rates. Adjacent, nonirradiated sites served as controls. Delayed-type hypersensitivity (Mantoux) reactions were assessed at treatment and control sites to determine immunosuppression. RESULTS: High irradiance rate PDT with vehicle or with placebo caused significant immunosuppression (equivalent to 48% and 50% immunosuppression, respectively; both P < 0·0001); topical and oral nicotinamide reduced this immunosuppression by 59% and 66%, respectively (both P < 0·0001). Low irradiance rate PDT was not significantly immunosuppressive in the topical nicotinamide study (15% immunosuppression, not significant), but caused 22% immunosuppression in the oral study (placebo arm; P = 0·006); nicotinamide reduced this immunosuppression by 69% (P = 0·045). CONCLUSIONS: While the clinical relevance of these findings is currently unknown, nicotinamide may provide an inexpensive means of preventing PDT-induced immune suppression and enhancing PDT cure rates.

An action spectrum for ultraviolet radiation-induced immunosuppression in humans.

BACKGROUND: The immune-suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear. OBJECTIVES: We previously determined wavelength dependencies for immunosuppression by UVB and UVA wavebands in humans. We now aimed to calculate relative and solar immune-suppressive effectiveness across the UVB and UVA spectra. METHODS: We used the nickel model of recall contact hypersensitivity to determine UV immunosuppression dose responses and minimum immune suppression doses (MISDs) at 11 narrowbands from 289 to 392 nm. The relative immune-suppressive effectiveness of each narrowband was then determined as 1/MISD vs. wavelength. This curve was multiplied by the solar spectrum to show the relative immune-suppressive effectiveness of each waveband in sunlight. RESULTS: We found peaks of immune-suppressive effectiveness in the UVB waveband at 300 nm and in the UVA at 370 nm. Because of the far greater amount of longwave UVA in sunlight, the relative solar immune-suppressive effectiveness of UVA was threefold higher than that of UVB at doses equivalent to sun exposure from normal daily activities. CONCLUSIONS: Longwave UVA, which abuts the visible light spectrum and is less effectively filtered by sunscreens than UVB, is likely to be the largest contributor to immunosuppression resulting from incidental daily sun exposure.

Topical photodynamic therapy is immunosuppressive in humans.

BACKGROUND: Visible light irradiation after application of a photosensitizer (topical photodynamic therapy; PDT) is increasingly used to treat nonmelanoma skin cancers and premalignant actinic keratoses. PDT can provide a cosmetically superior alternative to surgery, but carries failure rates of 10-40%. While some murine studies have suggested immune enhancement by PDT, others reported immunosuppressive effects, which may indicate impaired antitumour immunity and thus compromised tumour clearance. OBJECTIVES: This study aimed to determine the in vivo immune effects of PDT in humans. METHODS: Using healthy, Mantoux-positive volunteers, we irradiated discrete areas of the back with narrowband red light (630 nm; 37 J cm(-2)), with and without prior application of 5-aminolaevulinic acid (ALA) or methyl aminolaevulinate (MAL). Adjacent, untreated areas served as immunologically intact control sites. Delayed-type hypersensitivity responses to tuberculin purified protein derivative (Mantoux reactions) were then elicited in each of the irradiated, unirradiated and control sites, and the intensity of the reactions was quantitated with an erythema meter and by measurement of Mantoux diameter. By comparing Mantoux intensity at treated and control sites, immunosuppression was determined in each volunteer for each intervention. RESULTS: We found that both MAL-PDT and ALA-PDT significantly suppressed Mantoux erythema (by 30% and 50%, respectively) and diameter (41% and 38%). Red light alone significantly suppressed diameter (22%) but not erythema (13%). CONCLUSIONS: Topical PDT induced significant immune suppression, which could impair local antitumour immune responses and may thus contribute to treatment failure.

Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans.

BACKGROUND: Ultraviolet (UV) radiation can profoundly suppress the cutaneous immune system, thus enhancing carcinogenesis. Agents that prevent UV-induced immunosuppression may thus reduce skin cancer. Nicotinamide (vitamin B3) prevents UV-induced immunosuppression and carcinogenesis in mice, and solar-simulated (ss) UV-induced immunosuppression in humans. Its effectiveness against different UV wavebands and mechanism of action is as yet unknown. OBJECTIVES: To determine the effects and mechanisms of topical nicotinamide on UV-induced suppression of delayed type hypersensitivity (DTH) responses in humans. METHODS: Healthy Mantoux-positive volunteers in four randomised, double-blinded studies were irradiated with solar-simulated (ss)UV (UVB + UVA) or narrowband UVB (300 nm) or UVA (385 nm). Topical nicotinamide (0.2% or 5%) or its vehicle were applied immediately after each irradiation. Mantoux testing was performed at irradiated sites and adjacent unirradiated control sites 48 h after the first irradiation and measured 72 h later. Immunosuppression was calculated as the difference in Mantoux-induced erythema and induration at test sites compared to control sites. Human keratinocyte cell cultures, with and without ssUV and nicotinamide, were used for quantitative real-time reverse transcriptase-polymerase chain reaction assessment of TP53 and enzymes that regulate oxidative phosphorylation. RESULTS: Nicotinamide cooperated with ssUV to increase enzymes involved in cellular energy metabolism and p53, and significantly protected against immunosuppression caused by UVB, longwave UVA and single and repeated ssUV exposures. CONCLUSIONS: Longwave UVA, which is poorly filtered by most sunscreens, was highly immune suppressive even at doses equivalent to 20 min of sun exposure. Nicotinamide, which protected against both UVB and UVA, is a promising agent for skin cancer prevention.

Effects of low-dose ultraviolet radiation on in vivo human cutaneous recall responses.

Relatively few studies have examined the effects of low-dose ultraviolet (UV) radiation on in vivo human cutaneous immunity, or the ability of sunscreens to prevent UV-induced immunosuppression. We have studied the effects of solar-simulated UV radiation on nickel contact hypersensitivity (CHS) in nickel-allergic volunteers, and on delayed type hypersensitivity responses in Mantoux-positive volunteers. Nickel CHS and Mantoux responses were significantly suppressed by acute, suberythemal UV exposures equivalent to less than 8 min summer sunlight. Both UVA and UVB wavebands were immunosuppressive, but UVA-induced immunosuppression was transient, whereas UVB had a more sustained effect. Dose-responses for UV immunosuppression were determined using the nickel method, enabling calculation of in vivo sunscreen immune protection factors in a manner analogous with sun protection factor measurement. Sunscreens were found to confer significantly less protection against UV-induced immunosuppression than against UV-induced erythema.

Treatment of refractory hand warts by isolated limb infusion with melphalan and actinomycin D.

We present an immunocompetent man with extensive warts on the hands, refractory to a number of conventional treatment modalities and causing substantial morbidity and impairment of normal function. Isolated limb infusion (regional intra-arterial chemotherapy) with melphalan and actinomycin D was performed, with substantial clearing of the warts within 2 months. Treatment-induced morbidity was limited to mild local erythema and oedema which resolved within 3 weeks. After 9 months' follow up, the patient had only a few residual warts and was able to resume normal activities.

Sun protection factor measurement of sunscreens is dependent on minimal erythema dose.

This study investigates the influence of skin colour and minimal erythema dose (MED) on the in vivo determination of sunscreen sun protection factors (SPFs). The MEDs of groups of 10-20 subjects were measured on the lower back with a 1000-W solar-simulated xenon arc lamp. Five sunscreens, with commercially measured SPFs ranging from 4 to 30 + were then tested on the different groups, and their SPFs were correlated with volunteers' MEDs. We found that the sunscreens had higher SPF values when tested on subjects with lower MEDs and paler skin. The SPF values obtained with our ultraviolet (UV) source were lower than the SPF values reported with commercially used solar simulators. We conclude that while SPF tests with artificial UV sources and pale-skinned volunteers can and should be used to rank the efficacy of various sunscreens in preventing sunburn, they should not be interpreted as measures of a sunscreen's absolute level of sun protection. Factors such as the differences in skin colour and MED between subjects used for SPF testing and the general population, the spectral differences between sunlight and artificial UV, as well as the tendency of the public to apply only small amounts of sunscreen and to re-apply it infrequently, mean that laboratory and sunlight SPFs may be markedly different.

Low-dose UVA and UVB have different time courses for suppression of contact hypersensitivity to a recall antigen in humans.

This study investigates the relative effects of low-dose solar-simulated ultraviolet, ultraviolet A, and ultraviolet B radiation on the elicitation of contact hypersensitivity to nickel in nickel-allergic volunteers. A xenon arc lamp with changeable filters was used to irradiate groups of volunteers daily, on separate areas of their lower backs, with both solar-simulated ultraviolet (ultraviolet B, ultraviolet AII + ultraviolet AI) and ultraviolet A (same ultraviolet AII content but twice the ultraviolet AI as the solar-simulated ultraviolet spectrum) for 1 and 2 d; 3, 4, and 5 d; and from 1 to 4 wk. A fourth group was irradiated for 1-5 d with the ultraviolet B component of solar-simulated ultraviolet. Following the final irradiation in each group, nickel-containing patches were applied to both ultraviolet-treated sites and adjacent, unirradiated control sites. Erythema caused by nickel contact hypersensitivity at each site was quantitated 72 h later with a reflectance erythema meter. By comparing the nickel reactions of irradiated and unirradiated skin, ultraviolet immunosuppression was assessed with the different spectra and durations of ultraviolet exposure. We found significant immunosuppression with daily doses of ultraviolet B and ultraviolet A equivalent to approximately 6 min of summer sun exposure, and that ultraviolet A and ultraviolet B exerted their maximal immunosuppressive effects at different times. Solar-simulated ultraviolet-induced immunosuppression was significant after one exposure, near-maximal after two exposures and remained elevated thereafter. Ultraviolet B-induced immunosuppression was lower than that induced by solar-simulated ultraviolet, but followed a similar time-course. In contrast, ultraviolet A-induced immunosuppression was transient, peaking after three exposures. Immune responses returned towards normal with subsequent ultraviolet A exposure, suggesting that an adaptive mechanism may prevent immunosuppression by continued ultraviolet A irradiation.

Measurement of in vivo sunscreen immune protection factors in humans.

This study investigates the level of protection provided by sunscreens against solar-simulated UV radiation-induced immunosuppression in humans. The in vivo immune protection factors (IPF) of two broad-spectrum sunscreens were determined by assessing their ability to prevent UV-induced suppression of nickel contact hypersensitivity (CHS) in 15 nickel-allergic volunteers. Each volunteer was irradiated on unprotected skin of the back with different doses of UV daily for 4 days. Multiples of these UV doses were concurrently delivered to sunscreen-treated sites on the contralateral back. Nickel patches were then applied to both irradiated sites and adjacent, unirradiated control sites. Nickel-induced erythema at each site was measured 72 h later with a reflectance spectrometer. Comparison of the nickel reactions of irradiated and unirradiated skin revealed linear UV dose-responses for immunosuppression in both unprotected and sunscreen-treated skin. The minimum level of immunosuppression that can be reliably detected with this method is 20%. Therefore, the UV dose that reduces mean nickel CHS by 20% is the minimal immune suppression dose (MISD). Sunscreen IPF were determined by dividing the mean MISD of sunscreen-treated skin by that of unprotected skin. The sunscreens, with sun protection factors of 9 and 24, had IPF of 6.5 and > 25, respectively.

Ultraviolet radiation induced suppression of Mantoux reactions in humans.

The effects of low dose ultraviolet (UV) radiation on delayed type hypersensitivity responses to tuberculin purified protein derivative were investigated in 17 healthy, Mantoux-positive volunteers. Suberythemal and erythemal doses of solar simulated UV from a fluorescent lamp source were delivered to the subjects' lower backs daily for five consecutive days. Mantoux testing with intradermally injected purified protein derivative was then performed at both the irradiated sites and an adjacent, unirradiated site, and the Mantoux induced erythema was quantitated 72 h later with a reflectance erythema meter. In comparison with the unirradiated Mantoux sites, Mantoux induced erythema was significantly reduced at the irradiated test sites. In six subjects, we compared the effects of chronic versus short term UV irradiation on the Mantoux reaction. These volunteers were irradiated on one side of their lower backs with the 5 d UV protocol, and on the other side of their backs for 4 or 5 wk. In all but one subject, the short irradiation protocol induced greater suppression of Mantoux responses than prolonged UV exposure. We conclude that even suberythemal doses of UV significantly reduce delayed type hypersensitivity responses to purified protein derivative, and that an adaptive mechanism appears to counteract the immunosuppressive effects of chronic irradiation.

Broad-spectrum sunscreens provide greater protection against ultraviolet-radiation-induced suppression of contact hypersensitivity to a recall antigen in humans.

This study investigates the extent to which sunscreens protect humans from ultraviolet (UV)-radiation-induced immunosuppression. In the presence of solar-simulated UV, three sunscreens with differing UVA transmission were assessed for their ability to protect the contact hypersensitivity (CHS) response to nickel of 16 nickel-allergic subjects. The sunscreens contained 2-ethylhexyl para-methoxycinnamate (cinnamate), cinnamate with oxybenzone, or cinnamate with zinc oxide, respectively. All had sun protection factors of 10 and hence inhibited UV erythema to similar extents. Volunteers were irradiated on their backs with suberythemal UV daily for 5 d after application of the sunscreens and their base lotion to different sites. Nickel-containing patches were then applied to both UV-treated sites and adjacent, unirradiated control sites. Erythema caused by nickel CHS at each site was quantitated 72 h later with a reflectance erythema meter. In comparison of the nickel reactions of irradiated and unirradiated skin, there was 35% mean immunosuppression in unprotected UV-treated skin. Significant immunosuppression also occurred at sites irradiated through the narrow-spectrum cinnamate-only sunscreen but was prevented by the two broad-spectrum sunscreens. To determine whether UV-induced suppression of the nickel response is specific for cell-mediated immunity or reflects suppression of nonspecific inflammation, a further 16 subjects were patch-tested with a skin irritant, sodium lauryl sulfate (SLS), following a sunscreen and irradiation protocol identical to that of the nickel volunteers. UV had no significant effect on SLS responses. We conclude that nickel patch testing is a valid means of assessing UV-induced immunosuppression in humans and that even with suberythemal UV, immune protection was provided only by sunscreens filtering both UVA and UVB.

Prediction of minimal erythema dose with a reflectance melanin meter.

The relationship between skin pigmentation and sensitivity to ultraviolet (UV) radiation-induced erythema was investigated in 60 healthy subjects of sun-reactive skin types I-V. Using a portable reflectance spectrometer, skin pigmentation was measured as the 'melanin index' (MI) in all subjects. A solar-simulated array of filtered UVA and UVB-emitting fluorescent lamps was then used to determine the UVB minimal erythema dose (MED) of each subject. MI readings and MED testing were both performed on the subjects' mid to upper backs. Using this technique, we found a close correlation between MI and MED. Comparison of the mean MI or MED of subjects with different skin types revealed progressive differences in MI and MED between all five skin types. Erythema dose-response curves, which provide further information about UV sensitivity, were also calculated for 43 subjects. A significant negative correlation was found between the gradients of these curves and both MI and MED, indicating that paler subjects respond more strongly to increments of UV above the MED than subjects with greater pigmentation. Our results indicate that although traditional, subjective means of predicting UV sensitivity to erythema are not without some value, MED correlates particularly strongly with objective measures of skin pigmentation. We therefore conclude that the reflectance spectrometer can rapidly and accurately predict UVB sensitivity, and should prove clinically useful for planning and optimizing UVB phototherapy.

Positron emission tomography in the detection and management of metastatic melanoma.

Initial reports suggest that positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) may offer greater diagnostic accuracy and versatility than conventional radiology in staging patients with metastatic melanoma. We reviewed the first 100 melanoma patients to have PET imaging at our institution. PET findings were correlated with all other available results, including plain X-ray, computed tomography (CT), magnetic resonance (MR) imaging, bone scintigraphy, clinical findings and histopathology. A total of 415 metastatic lesions were evaluated, 388 (93%) of which were detected by PET. In 20 patients, PET detected 24 metastases up to 6 months earlier than conventional imaging or physical examination. Selection of surgical or medical management was specifically influenced by PET findings in 22 patients, and PET was used to clarify another 12 cases where CT was inconclusive. In nine patients undergoing chemotherapy, PET was used to assess response to treatment. We conclude that FDG-PET can accurately detect metastatic melanoma with a single non-invasive scan, and can demonstrate some metastases months before conventional imaging techniques. PET can improve the selection of patients for surgery, has potential for monitoring response to treatment and may prove a cost-effective means of staging melanoma patients.