Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: open-label extension of the NOR-SWITCH trial.

BACKGROUND AND OBJECTIVES: The 52-week, randomized, double-blind, noninferiority, government-funded NOR-SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT-P13 was not inferior to continued treatment with infliximab originator. The NOR-SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT-P13 throughout the 78-week study period (maintenance group) versus patients switched to CT-P13 at week 52 (switch group). The primary outcome was disease worsening during follow-up based on disease-specific composite measures. METHODS: Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. RESULTS: Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per-protocol set). Adjusted risk difference was 5.9% (95% CI -1.1 to 12.9). Frequency of adverse events, anti-drug antibodies, changes in generic disease variables and disease-specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. CONCLUSION: The NOR-SWITCH extension showed no difference in safety and efficacy between patients who maintained CT-P13 and patients who switched from originator infliximab to CT-P13, supporting that switching from originator infliximab to CT-P13 is safe and efficacious.

Dysfunctional arteriovenous anastomoses in hands of systemic sclerosis patients with digital ulcers.

OBJECTIVES: Previous studies indicate that the arteriovenous anastomoses (AVAs) and the arterioles with the nutritive flow are involved in the pathophysiologic process disturbing hand blood flow in systemic sclerosis (SSc). However, impact of different part of the microvascular system involved in digital ulcers (DU) is not well known. Here, we aimed to assess the vasomotor activity of the AVAs in the hands of patients with and without DU in SSc. METHODS: Simultaneous recordings were made of laser Doppler flux in the finger pulp and thenar eminence, together with ipsilateral radial artery blood velocity and mean arterial blood pressure (MAP) in 22 non-smoking SSc patients and 13 aged-matched healthy controls. RESULTS: AVA responses in the finger pulp to spontaneous vasoconstrictor nerve impulses were abolished in 64% of the SSc patients. Correlation and cross-spectra analysis showed positive correlation between blood flow changes and MAP changes, indicating a passive vascular bed in the SSc finger pulp with blood flow variations depending on short-term variability in MAP. Dysfunctional AVAs were identified in all the patients with a history of DU (n=8), while none of the patients with normal AVA function had episodes of DU (n=8) (p= 0.017). CONCLUSIONS: We found that in SSc patients with DU there is a dysfunction of the AVAs of the finger pulp. This proof-of-concept study supports the notion that AVA dysfunction may play a critical role in SSc related DU. AVA dysfunction may be a part of autonomic dysfunction in SSc.

[Requirements for perioperative intensive care of geriatric patients]. / Besonderheiten der perioperativen Intensivmedizin beim geriatrischen Patienten.

BACKGROUND: Demographic change has also caused changes in perioperative intensive care because the proportion of geriatric patients who must undergo surgical procedures is increasing. With the current preoperative assessment instruments, it is still not possible to identify high-risk patients of this collective or to make a reliable prognosis concerning postoperative course. MATERIALS AND METHODS: In addition to pain control, important aspects to minimize complications in postoperative intensive care include adequate oxygenation, adequate fluid management, an adequate supply of energy and nutrients, good control of blood sugar levels, and early mobilization of patients. RESULTS: The perioperative intensive care treatment of geriatric patients requires the readiness to engage in interdisciplinary collaboration because only with this close dialog can the treatment results be sustained.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

High and sustained efficacy after two sessions of topical 5-aminolaevulinic acid photodynamic therapy for basal cell carcinoma: a prospective, clinical and histological 10-year follow-up study.

BACKGROUND: Prolonged follow-up data on topical photodynamic therapy (PDT) in basal cell carcinoma (BCC) are necessary for a full evaluation of its effect and for comparison with conventional treatment methods. OBJECTIVES: To assess 10-year long-term PDT efficacy in primary and recurrent BCC and to evaluate clinical and histopathological factors which may be associated with treatment failure. METHODS: We performed a longitudinal study on 60 histologically verified BCCs in 44 patients treated with curettage and one or two sessions of dimethylsulphoxide (DMSO)-supported topical 5-aminolaevulinic acid (ALA)-based PDT. Treated lesions were investigated by clinical and histopathological examination at regular intervals. The main outcomes were 10-year lesion complete response rate using a time-to-event analysis, histological treatment failure and cosmesis. RESULTS: Overall complete response rate for all lesions was 75% (95% confidence interval 64-87%); 60% after one and 87% after two treatment sessions. The response rate was 78% for primary lesions; 63% after one and 90% after two sessions. The cosmetic outcome was rated as good or excellent in 91-100% of evaluated cases. Treatment failure was documented in 15 (25%) of 60 lesions; clinical investigation identified 14 of them. All failures were noted within 3 years of treatment. Male gender, recurrent tumour and one treatment session were factors significantly associated with treatment failure. The only lesion larger than 2·0 cm relapsed. CONCLUSIONS: Two sessions of DMSO-supported topical ALA-PDT and curettage can provide long-term effective treatment results with favourable cosmetic outcome in primary, small BCC.

Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study.

BACKGROUND: Photodynamic therapy (PDT) is an attractive therapy for nonmelanoma skin cancers and actinic keratoses (AKs). Daylight-mediated PDT is a simple and tolerable treatment procedure for PDT. Methyl aminolaevulinate (MAL)-PDT is approved for the treatment of thin or nonhyperkeratotic AKs on the face and scalp. However, thick AK lesions are often treated as well when present in the field-cancerized treatment area. OBJECTIVES: In a randomized multicentre study to evaluate efficacy of daylight-mediated PDT for different severity grades of AKs. METHODS: One hundred and forty-five patients with a total of 2768 AKs (severity grades I-III) of the face and scalp were randomized to either 1½ or 2½ h exposure groups. After application of a sunscreen (sun protection factor 20) and gentle lesion preparation, MAL was applied to the entire treatment area. Patients left the clinic immediately after application and exposed themselves to daylight according to randomization. Daylight exposure was monitored with a wrist-borne dosimeter. RESULTS: No difference in lesion response was found between the 1½ and 2½ h exposure group. The mean lesion response rate was significantly higher in grade I lesions (75·9%) than in grade II (61·2%) and grade III (49·1%) lesions (P < 0·0001). Most grade II (86%) and III AKs (94%) were in complete response or reduced to a lower lesion grade at follow-up. Large variations in response rate of grade II and III AKs were found between centres. No association was found between response rate and light dose in patients who received an effective light dose of > 3·5 J cm(-2). CONCLUSIONS: Daylight-mediated PDT of moderate to thick AKs was less effective than daylight-mediated PDT of thin AKs especially in some centres. However, nearly all thicker lesions (grades II and III) were reduced to a lower lesion grade at 3 months after a single treatment of daylight-mediated PDT.

Skin pain and skin discomfort is associated with quality of life in patients with psoriasis.

BACKGROUND: Patients with psoriasis commonly report severe sensory skin symptoms, sleep disturbance, psychological distress and impaired health related quality of life (HRQoL). However, the complex associations among these factors are poorly investigated in this patient group. OBJECTIVES: The purpose of this study was to investigate the association between skin pain or skin discomfort and HRQoL, and explore whether sleep disturbance and psychological distress were mediators of these associations. METHODS: A total of 139 psoriasis patients from a university hospital setting participated in this exploratory, cross-sectional study. Data were obtained through interviews and questionnaires (Dermatology Life Quality Index, General Sleep Disturbance Scale, Illness Perception Questionnaire) and analysed using a series of multiple regression analyses. HRQoL was the dependent variable. Independent variables and assumed mediators were entered into the model in a predefined order. RESULTS: Skin pain, skin discomfort, sleep disturbance and psychological distress were significantly associated with HRQoL (all P < 0.05). Sleep disturbance was a partial mediator for the association between skin pain and HRQoL. No such mediation effect was found in terms of psychological distress. The total model explained 40% of the variance in HRQoL. CONCLUSION: In this study, skin pain and skin discomfort were significantly related to HRQoL when controlling for demographic and clinical characteristics. In addition, sleep disturbance mediated the association between skin pain and HRQoL. An understanding of the complex association among physiological and psychological factors, and HRQoL is clinically important in order to provide proper treatment and care of patients with psoriasis.

A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp.

BACKGROUND: Actinic keratoses (AKs) are common dysplastic skin lesions that may differentiate into invasive squamous cell carcinomas. Although a superior cosmetic outcome of photodynamic therapy (PDT) is advantageous compared with equally effective treatments such as cryotherapy and curettage, the inconvenience of clinic attendance and discomfort during therapy are significant drawbacks. Daylight-mediated PDT could potentially reduce these and may serve as an alternative to conventional PDT. OBJECTIVES: To compare the efficacy of methyl aminolaevulinate (MAL)-PDT with 1½ vs. 2½ h of daylight exposure in a randomized multicentre study. METHODS: One hundred and twenty patients with a total of 1572 thin AKs of the face and scalp were randomized to either 1½- or 2½-h exposure groups. After gentle lesion preparation and application of a sunscreen of sun protection factor 20, MAL was applied to the entire treatment area. Immediately after, patients left the clinic and exposed themselves to daylight according to the randomization. Daylight exposure was monitored with a wristwatch dosimeter and patients scored their pain sensation during treatment. RESULTS: The mean lesion response rate at 3 months was 77% in the 1½-h group and 75% in the 2½-h group (P = 0·57). The mean duration of daylight exposure was 131 and 187 min in the two groups. The mean overall effective light dose was 9·4 J cm(-2) (range 0·2-28·3). Response rate was not associated with effective daylight dose, exposure duration, treatment centre, time of day or time of year during which the treatment was performed. Treatment was well tolerated, with a mean ± SD maximal pain score of 1·3 ± 1·5. CONCLUSIONS: Daylight-mediated MAL-PDT is an effective, convenient and nearly pain-free treatment for patients with multiple thin AKs. Daylight-mediated PDT procedures were easily performed and 2 h of daylight exposure resulted in uniformly high response rates when conducted in the period from June to October in Nordic countries.

Guidelines for practical use of MAL-PDT in non-melanoma skin cancer.

Methyl aminolaevulinate photodynamic therapy is increasingly practiced in the treatment of actinic keratoses, Bowen's disease and basal cell carcinomas. This method is particularly suitable for treating multiple lesions, field cancerization and lesions in areas where a good cosmetic outcome is of importance. Good treatment routines will contribute to a favourable result. The Norwegian photodynamic therapy (PDT) group consists of medical specialists with long and extensive PDT experience. With support in the literature, this group presents guidelines for the practical use of topical PDT in non-melanoma skin cancer.

Daily pattern of sweating and response to stress and exercise in patients with palmar hyperhidrosis.

BACKGROUND: Focal hyperhidrosis is an embarrassing condition that can have a significant negative impact on patient quality of life. It is characterized by excessive sweating affecting a variety of areas, including the palms. Little is known about the daily pattern of sweating in patients with palmar hyperhidrosis. OBJECTIVES: To compare the variation of sweating in patients with primary palmar hyperhidrosis with healthy individuals during daily activities. METHODS: Twenty patients with primary palmar hyperhidrosis and 20 healthy age- and sex-matched subjects were studied. Each participant self-assessed rates of sweating for 7 days on an hourly basis using a subjective evaluation scale (SES) ranging from 0 to 10. RESULTS: The 3763 assessments showed clear differences between patients and healthy controls (median SES score 5 and 0, respectively; P < 0.0001). Stress and exercise significantly increased SES by scores of 2-5 in both groups, with stress influencing patients more than controls. SES scores in patients varied significantly, from 0 to 2 during mornings and evenings, and between 5 and 6 at mid-day, while scores in control subjects remained consistently close to 0. The pattern of change depended weakly on sex and weekday/weekend distinction. Dynamic responses to stress and exercise in patients had the tendency to return to baseline more slowly than in controls. CONCLUSIONS: Hourly changes in sweating rates can be assessed successfully through self-assessment. Patients with primary palmar focal hyperhidrosis reported significantly increased palmar sweating and daily patterns of sweating showing considerable variation dependent on factors such as time of day and emotional stimuli.

Coping with exacerbation in psoriasis and eczema prior to admission in a dermatological ward.

Chronic dermatologic diseases, such as psoriasis and eczema, may cause significant psycho-social problems and stress. Our objectives were to characterize how hospitalised patients coped with psoriasis and eczema, and to investigate the relationship between coping and quality of life. Data are based on survey forms completed upon admission to the dermatology ward from 212 patients with chronic dermatological diseases, 146 with psoriasis and 66 with eczema. 108 were men, average age 48 years. The Norwegian versions of the standardized survey questionnaires, Jalowiec Coping Scale and Dermatological Life Quality Index, were used to evaluate coping and quality of life. We found that optimism, belief-in-oneself and confrontational coping strategies were most frequently used. Long duration of the disease was correlated to the belief-in-oneself strategy, while short duration was related to supportive strategies. More frequent use of confrontational and optimistic modes was significantly related to better quality of life. More frequent use of emotional and evasive modes was significantly related to poorer quality of life. There was no significant difference between the psoriasis and eczema groups in terms of use of coping strategies, with exception of emotional strategies. Knowledge of coping strategies and quality of life among patients with chronic dermatological diseases is important for improvement in health services for these patients.

A mechanistic approach to anticancer therapy: targeting the cell cycle with histone deacetylase inhibitors.

The activity of genes encoded by the highly-condensed DNA in cellular nuclei must be precisely regulated. Regulation of the accessibility of gene promoters to transcription complexes is one level of gene regulation and is influenced by histone tail modifications such as acetylation, methylation, and phosphorylation. Acetylation is a reversible modification catalyzed by histone acetyl transferase (HAT) and histone deacetyltransferase (HDAC) enzymes. Histone deacetylation is associated with transcriptional repression of genes, as the removal of acetyl groups from lysine residues allows for tighter electrostatic interactions between DNA and histones, limiting accessibility of the DNA for transcription. Inhibition of HDAC activity permits histones to remain in an acetylated state, and through the resulting alterations in gene regulation, inhibits cell cycle progression, inhibits differentiation, and in some cases induces apoptosis. Inhibition of proliferation by HDAC inhibitors is characterized by arrest at the G1 or G2/M phases of the cell cycle. Many types of tumor cells then undergo programmed cell death. Exposure to HDAC inhibitors may also allow reactivation of tumor suppressor genes which had been silenced by hypoacetylation during tumorigenesis. HDAC inhibitors from a number of chemical classes have shown promise as anti-cancer agents in animal studies and early clinical trials. The development of HDAC inhibitors which specifically target HDAC isozymes, and more detailed understanding of their anti-neoplastic actions, heralds a new epigenetic antitumor therapeutic strategy.

Self-reported stress reactivity and psoriasis-related stress of Nordic psoriasis sufferers.

OBJECTIVES: The purpose of the study was to investigate the perceived influence of stress on psoriasis onset and disease severity in a large sample of psoriatics and to compare stress reactors and non-reactors with respect to psoriasis-related stress, disease severity, family history of psoriasis and sociodemographic factors. PATIENTS/METHODS: A total of 5795 members of the Nordic psoriasis associations and 702 patients recruited from Nordic dermatologists or university clinics were asked whether their first outbreak of psoriasis occurred during times of worry and stress. They were also asked to rate the degree to which their psoriasis was influenced by stress and to complete the Psoriasis Life Stress Index, the Psoriasis Disability Index and a number of additional questions concerning sociodemographic factors. RESULTS: Seventy-one per cent of the members and 66% of the patients reported that their psoriasis was exacerbated by stress, and 35% in both groups reported that the onset of their psoriasis occurred during a time of worry and stress. Stress reactors, scoring above the median on stress reactivity, reported greater disease severity, psoriasis-related stress and impairment of disease-related quality of life. They also reported more frequent use of tobacco, tranquillizers and antidepressants. More women than men were stress reactors, and stress reactors were more likely to have a family history of psoriasis. CONCLUSION: Our findings confirm and extend the results of previous studies and indicate that a subgroup of psoriatics may be more psychologically reactive to their disease and its influence on everyday life. Whether this group is also physiologically more reactive to psychosocial stress remains to be investigated.

Quality of life in 6497 Nordic patients with psoriasis.

BACKGROUND: Disease-specific psoriasis-related quality of life (QOL) measures have recently been developed and used in several hospital-based investigations. However, little is known about the impact of psoriasis on QOL in people with psoriasis who are not referred by dermatologists. OBJECTIVES: The purpose of the study was to investigate psoriasis-related QOL in a large sample of members of the psoriasis associations from the Nordic countries, and to compare the results with those from psoriasis patients recruited from Nordic dermatologists or Nordic University clinics. PATIENTS AND METHODS: A total of 5795 association members and 702 patients rated their psoriasis severity and completed the Psoriasis Disability Index and the Psoriasis Life Stress Index. RESULTS: Patients reported greater disease severity and greater impairment of QOL than members of associations, and Norwegian participants reported greater disease severity and greater impairment of QOL than participants from the remaining Nordic countries. Older and married participants reported less impairment of QOL than younger participants and those living alone. When controlling for the influence of these and other demographic and socio-economic factors, self-reported severity emerged as the most significant predictor of psoriasis-related QOL, explaining 32-26% of the variation in QOL scores, with the remaining factors only accounting for 4-5% of the variation. Although correlated with self-reported severity, Psoriasis Area and Severity Index scores were not a significant predictor of QOL in the patient sample. CONCLUSIONS: Though self-reported severity may be the most important predictor, further research is needed to determine factors explaining the remaining variance in psoriasis-related QOL.

Treatment of psoriasis in the Nordic countries: a questionnaire survey from 5739 members of the psoriasis associations data from the Nordic Quality of Life Study.

The data from a questionnaire-based study of 5,739 members of the psoriasis associations of Denmark, Finland, Iceland, Norway, Sweden and the Faeroe Islands showed that the two most commonly used active agents were topical steroids (89.7% total use and 49.4% present use) and calcipotriol (73.1% total use and 35.8% present use), with only small variations between the countries. Marked differences between the countries were, however, found within all other types of psoriasis therapy, including the so-called alternative treatments. Significant priorities varied between the different countries. The use of dithranol in Finland was almost twice the average. While 14.2% of Danish members had received grenz-rays within the last week only 0.1% of the Finns had been given the same treatment. Psoralen plus ultraviolet A (PUVA) was being used by 13.1% of the Finnish psoriatics compared with 3.8% of Danes, while PUVA was almost non-existent on the Faeroe Islands. The use of non-PUVA phototherapy was highest in Norway and Sweden. Almost 10% of the Danes were presently on methotrexate, which was used far more than etretinate/acitretin or cyclosporine. In contrast, Finnish patients more often received etretinate than other systemic agents, and in Iceland there was a higher present use of cyclosporine than of etretinate. The popularity of alternative therapies was highest in Iceland, where 26.6% had taken such medication during the last week. The results of the study suggest that different treatment patterns should be taken into consideration when discussing the prognosis of psoriasis in different countries.

Microvascular arteriovenous shunting is a probable pathogenetic mechanism in erythromelalgia.

Erythromelalgia is a condition consisting of red, warm, and burning painful extremities. Symptoms are relieved by cold and aggravated by heat. A wide variety of etiologic conditions can cause erythromelalgia, but one common pathogenetic mechanism, microvascular arteriovenous shunting, has been hypothesized. The aim of this study was to test this hypothesis. Quantification of skin microvascular perfusion using laser Doppler perfusion imaging and skin temperature at rest and after central body heating was performed in 14 patients with erythromelalgia and 11 controls. Attacks of erythromelalgia were induced in eight patients after heat provocation. In the plantar region of the foot, the location of numerous anatomical arteriovenous shunts, these patients significantly increased the skin perfusion as compared with asymptomatic patients with erythromelalgia and controls. In the dorsal region with few arteriovenous shunts no significant differences between the groups were demonstrated. The results show a relation between clinical symptoms and increased perfusion in the region of numerous anatomical arteriovenous shunts, and support the hypothesis of increased thermoregulatory arteriovenous shunt flow during attacks in primary erythromelalgia.

Erythromelalgia in a patient with AIDS.

Erythromelalgia is a clinical syndrome characterized by burning pain in the extremities together with erythema and increased skin temperature. Typically, the patients experience relief from cold, and aggravation from warmth. Symptoms are hypothesized to be caused by arteriovenous shunting and reduced nutritive skin capillary perfusion with corresponding tissue hypoxia. Erythromelalgia is most often primary, but may be secondary to a wide variety of diseases. We report erythromelalgia in a patient with acquired immune deficiency syndrome (AIDS). At peak pain intensity he actively cooled hands and feet for more than 12 h/day. Many doctors handling human immunodeficiency virus/AIDS patients are unfamiliar with erythromelalgia, and the condition can easily be overlooked, especially the more common milder cases.

X linked mental retardation and infantile spasms in a family: new clinical data and linkage to Xp11.4-Xp22.11.

In order to describe the neurological abnormalities and to identify the gene localisation, we re-evaluated a previously reported family with X linked mental retardation (XLMR). Reliable data were obtained for six of the seven affected males, of whom two had had infantile spasms. Profound MR (IQ<20) was found in one and mild MR (IQ 50-70) in five males. No dysmorphic features, except for macrocephaly in one male, were found. Neurological abnormalities included varying degrees of spinocerebellar involvement. Neuroimaging studies showed abnormalities, such as cerebellar atrophy or corpus callosum hypoplasia or both, in three of the six males. Several affected and unaffected subjects suffered from hyperhidrosis, which appeared to segregate independently as an autosomal dominant trait. Genetic linkage analysis localised the XLMR disease gene to Xp11.4-Xp22.11 with a maximum multipoint lod score of 3.57, overlapping the candidate region recently found in two Belgian XLMR-infantile spasm families. Compared to the Belgian patients, the majority of the affected males in this report had a considerably milder phenotype.