Disease activity in and quality of life of patients with psoriatic arthritis mutilans: the Nordic PAM Study.

OBJECTIVE: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient's education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM. RESULTS: Sixty-seven patients were included. Patients with PAM had a protracted disease history (33 ± 14 years) and disease onset at a relatively early age (30 ± 12 years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60 years of age reported the most impaired quality of life in comparison to the control group. CONCLUSION: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.

Fatigue in psoriasis: a controlled study.

BACKGROUND: Fatigue is associated with various chronic inflammatory diseases, but few studies have focused on its occurrence in psoriasis. OBJECTIVES: To describe fatigue prevalence and degree among patients with chronic plaque psoriasis vs. age- and sex-matched healthy subjects, and to examine how fatigue is influenced by essential clinical and demographic factors. METHODS: In 84 patients and 84 healthy subjects, fatigue severity was assessed using three different generic fatigue instruments: the fatigue Visual Analogue Scale (fVAS), the Fatigue Severity Scale (FSS) and the Short Form 36 (SF-36) Vitality scale. Cut-off scores for clinically important fatigue were defined as ≥ 4 for FSS, ≥ 50 for fVAS and ≤ 35 for the SF-36 Vitality scale. Disease activity was evaluated using the Psoriasis Area and Severity Index (PASI), and the impact on quality of life with the Dermatology Life Quality Index (DLQI). RESULTS: Patients and healthy control subjects, respectively, showed median fVAS scores of 51 [interquartile range (IQR) 21-67] and 11 (IQR 3-20); FSS scores of 4 (IQR 2·5-5·3) and 1·6 (IQR 1·1-2·2); and SF-36 Vitality scores of 43 (IQR 25-85) and 73 (IQR 65-85). The rates of clinically important fatigue among patients vs. healthy controls, respectively, were 51% vs. 4% (fVAS); 52% vs. 4% (FSS); and 42% vs. 2% (SF-36 Vitality) (P < 0·001 for all differences). Fatigue was associated with DLQI scores, but not PASI scores, in univariate analysis but not in multivariate analysis. CONCLUSIONS: Nearly 50% of patients with psoriasis suffered from substantial fatigue. Fatigue severity was associated with smoking, pain and depression, but not with psoriasis severity.

Fatigue in psoriasis: a phenomenon to be explored.

Fatigue is a prevalent and substantial phenomenon in many patients with chronic inflammatory diseases, often rated by patients as the most troublesome symptom and aspect of their disease. It frequently interferes with physical and social functions and may lead to social withdrawal, long-standing sick leave and disability. Although psychological and somatic factors such as depression, sleep disorders, pain and anaemia influence fatigue, the underlying pathophysiological mechanisms by which fatigue is generated and regulated are largely unknown. Increasing evidence points towards a genetic and molecular basis for fatigue as part of the innate immune system and cellular stress responses. Few studies have focused on fatigue in dermatological diseases. Most of these studies describe fatigue as a phenomenon related to psoriatic arthritis and describe the beneficial effects of biological agents on fatigue observed in clinical studies. It is therefore possible that this problem has been underestimated and deserves more attention in the dermatological community. In this review, we provide a definition and explanation for chronic fatigue, describe some commonly used instruments for measuring fatigue, and present hypothetical biological mechanisms with an emphasis on activation of the innate immune system and oxidative stress. An overview of relevant clinical studies covering the theme 'psoriasis and fatigue' is given.

Psoriatic arthritis mutilans (PAM) in the Nordic countries: demographics and disease status. The Nordic PAM study.

OBJECTIVE: To determine the prevalence and clinical characteristics of psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with putative PAM aged ≥ 18 years were recruited. Fifty-nine patients were included after clinical examination. RESULTS: The prevalence of PAM in the adult Nordic population was estimated to be 3.69 per million inhabitants [95% confidence interval (CI) 2.75-4.63]. The female to male ratio was close to 1:1. The mean age of skin disease onset was 25 years and the mean age of onset of joint disease was 30 years. The onset of skin disease was 2 years earlier among female patients. At inclusion, the mean duration of arthritis was 27 ± 11 years for male patients and 33 ± 11 years for female patients. PAM was most frequently seen in the distal interphalangeal (DIP) joints of the toes, followed by the IP joint of the thumb and the DIP joint of the little finger on the left hand. Female and male patients had similar numbers of painful and swollen joints. Enthesitis was found in 19 patients (32%), while 38 patients (64%) had a history of dactylitis. Twenty-three of these 38 patients (61%) had a history of dactylitis in the same finger/toe as they had PAM. At the time of inclusion, 45% of the patients were found to have clear or almost clear skin. CONCLUSIONS: PAM in the Nordic countries has a low prevalence, with only three to five cases per million inhabitants. The majority of the patients present with mild skin disease.

Treatment of head and neck dermatitis comparing itraconazole 200 mg and 400 mg daily for 1 week with placebo.

BACKGROUND: Head and neck dermatitis (HND) is a variant of atopic dermatitis often seen in young adults. A hypersensitivity to Malassezi antigens is considered to be of pathogenic importance. Previous mostly uncontrolled studies have shown that oral antimycotics might be of use in this condition. OBJECTIVE: To evaluate the efficacy of itraconazole in the treatment of HND in a randomized, double-blind, placebo-controlled trial. PATIENTS: Adult patients with HND were included. Systemic steroids and oral/topical antimycotics were avoided 1 and 2 months prior to the trial. Topical steroids were not allowed in the head and neck area within 2 weeks. Patients in generally good health were included and female patients had to have had a negative urine pregnancy test. The patients signed an informed consent. STUDY DESIGN: The study included a 7-day treatment period and a follow-up period of 105 days. Control visits were carried out on days 3, 7 and 14 and after 15 weeks. METHODS: The SCORAD index (one for the head and neck area and one for the remaining surface area) and global evaluations by patient and investigator were used for clinical evaluation at each visit. Prick tests with Malassezia antigens and Candida albicans antigen were carried out at the start of the trial and included positive and negative controls. The patients were randomized into three groups, which were treated with 400 mg itraconazole daily, 200 mg itraconazole daily or placebo, respectively, for 7 days. RESULTS: The number of patients included was 53: 18 had 200 mg itraconazole daily, 17 had 400 mg itraconazole daily and 18 placebo. At days 7 and 14, significant improvement was seen in the SCORAD of the head and neck area for the groups given 400 mg itraconazole daily (P = 0.0385 and P = 0.0134), and 200 mg daily (P = 0.0104 and P = 0.0006). Patients in the placebo group improved slightly (P = 0.0785). At day 14, comparison of improvement of SCORAD of the head and neck area between all three groups showed a significant difference in favour of the 200 mg itraconazole group compared to the placebo group (P = 0.0318). The prick test was positive for Pityrosporum ovale in 37% and negative for C. albicans in all patients. CONCLUSIONS: One week of treatment with 200 or 400 mg itraconazole as a single treatment has a significant effect on the head and neck area. Compared to placebo there was a significant improvement in SCORAD of the head and neck area in favour of the 200 mg itraconazole group after 14 days. The important observation seems to be that antifungal systemic treatment has a significant SCORAD reduction of atopic dermatitis, irrespective of the presence of allergy.

Characteristics of Staphylococcus aureus isolates from atopic dermatitis with reference to proteolytic activity.

Staphylococcus aureus strains from atopic dermatitis (AD) patients were investigated. Diversities of biological properties, strain relationships and/or group tendencies between strains were analysed. Fifty four S. aureus strains were divided into seven biotypes using a standard biochemical API Staph system. The largest population (twenty two isolates, 40.7%) belonged to biotype A No. 6716153. Using a standard phage set S. aureus isolates were typed into three groups: I, II and III. However, twenty seven (50.0%) isolates belonged to group No. III. Production of proteolytic enzymes was expressed by all isolates, and 87.0% showed high or moderate proteolytic activity. Also alpha or beta haemolysins production by 83.0% of the strains was demonstrated. Antimicrobial susceptibility for each strain was analysed using fifteen antibiotics. Most isolates were sensitive to chloramphenicol (98.0%), neomycin (98.0%) and fucidin (88.0%) and were resistant to ampicillin, oxacillin and rondomycin (< 20.0%). No isolate was sensitive to all antibiotics of our study. Obvious correlations were not observed between biochemical types, phage types, haeomolysin production and antibiotic resistance pattern but proteolytic activity was demonstrated by most strains in each test.

Knemometry in children with atopic dermatitis treated with topical glucocorticoids.

Recently the knemometer, a lower leg length measuring device, has been introduced for sensitive assessment of systemic activity of exogeneous glucocorticoids in children. The aim of this study was to assess by means of knemometry whether the topical glucocorticoid budesonide affects short-term growth in children with atopic dermatitis. Fourteen children 5 to 12 years old were studied in an open longitudinal trial with three periods of 2 weeks duration. In periods 1 (run-in) and 3 (run-out), the children were treated with emollient. In period 2, budesonide cream 0.025% was followed by emollient twice daily to all of the body except the face. Eczema was evaluated according to a score based on extent and activity. Knemometry was performed twice weekly. Compared to the run-in and run-out periods the mean growth rate during budesonide treatment was reduced by 0.11 mm/wk (p > .05) and 0.40 mm/wk (p < .05), respectively. The mean growth rate during run-out was increased by 0.29 mm/wk as compared to run-in (p < .05). Compared to run-in the mean severity indices during budesonide treatment and run-out were reduced by 1.55 (p < .05) and 1.55 points (p <.05), respectively. The concomitant variations in lower leg growth rate and disease activity suggest that short-term treatment with topical glucocorticoids may provide a better growth potential during the weeks after withdrawal of the treatment. Whether this is due to improved disease control needs further study. Being a noninvasive method, knemometry may be useful for comparing different topical glucocorticoids and administration regimens in children in whom vasoconstrictor assays are difficult.

Insulin-like growth factor axis, bone and collagen turnover in children with atopic dermatitis treated with topical glucocorticosteroids.

BACKGROUND: Topical glucocorticosteroids are widely used in the treatment of children with atopic dermatitis. Due to percutaneous absorption, these agents may become systemically available and cause inhibition of growth in children. However, the mechanisms responsible for the growth-suppressive effective are not fully understood. OBJECTIVE: To evaluate whether treatment with topical budesonide has any adverse effects on growth-hormone-dependent serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), and on the serum markers of bone and collagen turnover osteocalcin, the carboxy-terminal propeptide of type I collagen (PICP), the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) and the amino-terminal propeptide of type III procollagen (PIIINP). METHODS: 13 children (mean age 9.5 years) with atopic dermatitis were studied in an open longitudinal trial with run-in and budesonide treatment periods of 2 weeks' duration. During the run-in, only emollient was used. During the treatment period, budesonide cream 0.025% followed by emollient were applied twice daily all over the body except on the face. At day 14 of each period, blood samples were taken and eczema was scored according to a severity index based on extent and activity of the disease. RESULTS: Compared to the run-in, budesonide treatment was associated with a statistically significant reduction in mean severity index (p = 0.002). No statistically significant effects on serum levels of IGF-I, IGFBP-3, osteocalcin or ICTP were observed. The serum concentrations of PICP and PIIINP were reduced with (mean +/- 1 SD) 43 +/- 64 milligrams (95% confidence interval 3.5-80 milligrams, p = 0.03, t = 2.4, d.f. = 12) and 1.2 +/- 1.5 milligrams (95% confidence interval 0.3-2.1 milligrams, p = 0.01, t = 3.0, d.f. = 12), respectively. CONCLUSION: Type I and III collagen turnover may be suppressed during short-term treatment with topical budesonide in children with atopic eczema. clinical implications need further study.

Selective inactivation of human neutrophil elastase by synthetic tannin.

Tannins of natural or synthetic origin are well-known adjuvants in topical anti-inflammatory therapy of skin diseases. In this study, the influence of synthetic tannin on neutrophil accumulation, enzyme release, and on the proinflammatory activity of neutrophil-derived enzymes was investigated. The results show that synthetic tannin (Tamol) specifically inhibits the neutrophil serine protease human leukocyte elastase (HLE) in an irreversible manner with a half-maximal inhibitory concentration (IC50) of 0.3 microgram/ml. Exogenous protein partially abolished the tannin-dependent HLE inhibition (IC50 of Tamol at 1% protein-concentration:1.0 microgram/ml). Synthetic tannin did not influence the activities of other neutrophil enzymes like Cathepsin G, beta-glucuronidase, and myeloperoxidase. The specificity of Tamol for HLE was further substantiated by the lack of inhibition of other serine proteases. Additionally, Tamol had no effect on f-met-leu-phe-induced neutrophil chemotaxis and did not alter enzyme degranulation of neutrophils in response to f-met-leu-phe and opsonized zymosan. We conclude from our results that the anti-inflammatory properties of synthetic tannin may at least in part be due to inactivation of the proinflammatory protease HLE.

Recombinant human tumour necrosis factor beta (lymphotoxin) lacks chemotactic activity for human peripheral blood neutrophils, monocytes, and T cells.

Human recombinant tumour necrosis factor beta (rhuTNF beta)/lymphotoxin was tested for human neutrophil granulocyte (PMN), monocytes (MO), and T-cell chemotactic activity by means of a modified Boyden chamber system. Over a wide range of concentrations (10(-7)-10(-14)M)rhuTNF beta showed no chemotactic activity for PMN, MO, or T cells. In contrast, strong chemotactic migration was elicited in PMN and MO with the tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and in T cells when complement split product C5a and leukotriene B4 (LTB4) were used as chemotaxins. The results of this study indicate that rhuTNF beta/lymphotoxin is not a chemotaxin for human PMN, MO, or T lymphocytes in vitro.

ETAF/interleukin-1 and epidermal lymphocyte chemotactic factor in epidermis overlying an irritant patch test.

We have previously demonstrated that the epidermal content of the lymphocyte activating peptide ETAF/IL-1 and lymphocyte chemotactic factor (ELCF) increases during the development of a cell-mediated immune reaction, represented either by the tuberculin skin reaction or by a positive patch test in patients with contact allergy. The present study describes the epidermal content of these mediators during an irritant patch test reaction. The results show that ELCF, but not ETAF/IL-1, is significantly increased in the epidermis of an irritant patch test with 3% SLS or 5% croton oil, irrespective of the intensity of the clinical patch test reaction. We observed that simple occlusion of epidermis did not induce ELCF activity in healthy persons, whereas patients with previous or current eczema had a significant release of ELCF following such occlusion. These results seem to indicate that there exist important functional differences between allergic and irritant patch test reactions with respect to the presence of lymphocyte activating signals in epidermis.

15-hydroxyeicosatetraenoic acid (15-HETE) specifically inhibits the LTB4-induced skin response.

15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase product of arachidonic acid, inhibits leukotriene B4 (LTB4)-induced chemotaxis of polymorphonuclear leukocytes (PMNs) in vitro. In this study the effects of intradermal injections of LTB4 were determined in the absence or presence of 15-HETE. For comparison intradermal injections of purified human complement split product C5a were performed in the absence or presence of 15-HETE. The skin response was evaluated by measuring the diameter of the wheal, the area of the flare and by intensity of the erythema (erythema index). LTB4 and C5a were injected at the concentration of 200 ng/ml. At this concentration the maximal skin response of LTB4 and C5a were equivalent. In contrast to C5a reaction, which resolved within 1 h, LTB4-induced skin response lasted up to 18 h. In all subjects the skin response was significantly decreased when LTB4 was injected together with 300 ng of 15-HETE. The decrease of wheal, flare, and erythema index averaged 81.9%, 56.6%, 53.6%, respectively, when all parameters were obtained at the maximal skin response. In contrast, the C5a-induced skin response was not affected by addition of 15-HETE, even when the final dose of 15-HETE was increased 10 times to 3 micrograms. The LTB4-induced reaction could last up to 18 h after injection. After the addition of 300 ng of 15-HETE the skin response resolved after 1 h. The present results demonstrate that 15-HETE is a specific inhibitor of the LTB4-induced skin response and brings additional evidence in support of the ability of 15-HETE to regulate the proinflammatory effects of LTB4 in vivo.

Frequency of skeletal disease, arthro-osteitis, in patients with pustulosis palmoplantaris.

Fourteen randomly selected patients with pustulosis palmoplantaris were examined to determine the frequency of skeletal involvement. Symptoms and both clinical and radiographic signs of skeletal disease occurred in five patients (36%). Four patients had erosive and/or sclerotic changes in the region of the sternoclavicular, the first sternocostal, and/or the manubriosternal joint, in two with additional ossification of the costoclavicular ligament. Two patients had spinal involvement, one paravertebral ossifications, and the other sequelae of anterior spondylodiskitis. Peripheral joint complaints without radiographically detectable erosions, but with periarticular new bone formation, occurred in three patients. The skeletal changes are probably not incidental and seems to constitute a seronegative spondyloarthropathy associated with pustulosis palmoplantaris.

Epidermis and lymphocyte interactions during an allergic patch test reaction. Increased activity of ETAF/IL-1, epidermal derived lymphocyte chemotactic factor and mixed skin lymphocyte reactivity in persons with type IV allergy.

Recently, we have found an increased activity of epidermal-derived thymocyte-activating factor (ETAF/IL-1) and epidermal lymphocyte chemotactic factor (ELCF) in epidermis overlying a positive tuberculin skin reaction. In the present study, we investigated 20 patients with confirmed or suspected allergic contact dermatitis by using the suction blister technique before and during patch testing. The ETAF/IL-1 was found in epidermis before patch testing. Its presence increased 2.8-fold in epidermis overlying a positive patch test compared with pretesting values. This increase was statistically significant. Interestingly, nontested skin also showed a significant increase of ETAF/IL-1, which was 1.9-fold higher than pretest values. The ETAF/IL-1 activity in patch test areas was significantly correlated with the clinical response. ELCF is not present in epidermis from noneczematous persons. We observed a significant content of ELCF in three of seven patients with eczema prior to patch testing. After patch testing, all patients showed ELCF in epidermis. Nontested skin showed a 1.5-fold higher content of ELCF compared with pretest values, and in the test area ELCF was 1.8-fold higher. The increases were statistically significant. We performed mixed skin lymphocyte reactions in seven patients using epidermal cells from the patch test area. All patients with a positive patch test had an increased mixed skin lymphocyte reactivity compared with epidermis coming from a negative reaction.

Epidermal lymphocyte chemotactic factor specifically attracts OKT4-positive lymphocytes.

Epidermal lymphocyte chemotactic factor (ELCF) from skin overlying a positive tuberculin reaction was compared with the chemoattractants leukotriene B4 (LTB4), N-formyl-methionyl-leukyl-phenylalanine (FMLP), and complement split product C5a (C5a). The chemotactic assay used is a modified Boyden chamber technique. The lymphocytes were subsets of T lymphocytes from healthy young individuals first separated by flotation of E rosettes on Isopaque Ficoll followed by incubation of T cells with anti-CD4 and anti-CD8 monoclonal antibodies and further separation using fluorescence-activated cell sorting. ELCF specifically attracted OKT4+ lymphocytes, while LTB4, FMLP, and C5a induced significant migration in both OKT4+ and OKT8+ lymphocytes without any clear difference between the various chemoattractants or cell populations. We found no blocking of the chemotactic capacity of ELCF when we added antibodies towards IL-1 alpha and IL-1 beta to the chemotactic assay. Further recombinant IL-1 alpha and Il-1 beta did not induce any chemotactic response. Our observation may be of significance in explaining the predominance of OKT4+ cells in allergic contact dermatitis and certain other skin diseases.

Epidermis and lymphocyte interactions during a tuberculin skin reaction. I. Increased ETAF/IL-1 like activity, expression of tissue antigens and mixed skin lymphocyte reactivity.

Forty-one persons were tested for tuberculin skin reactivity. Epidermal cells (ECs) were isolated from the tuberculin reaction and from a contra lateral, non injected skin area. We found a significant increase of epidermal thymocyte activating factor (ETAF) in epidermis overlying a positive tuberculin reaction together with an increase of OKT6 and class II (HLA-DR) positive cells. Allogeneic lymphocytes proliferated significantly more when mixed with ECs from a positive tuberculin skin test. Injection of tuberculin per se or a negative reaction did not induce similar changes. The described model seems useful for functional studies of ECs and lymphocytes in patients with contact dermatitis.

Chronic recurrent multifocal osteomyelitis: a follow-up study.

Thirteen children/adolescents and two young adults with unifocal or multifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were most often located at the metaphyseal region of tubular bones and the clavicle, but also at the spine, ischiopubic bone, and the sacroiliac joint. Progressive sclerosis and hyperostosis occurred mostly in the clavicle and occasionally in the tibia, femur, metatarsal, and ischiopubic bone, linking the changes to those described under the name Garré osteomyelitis. Seven patients had pustulosis palmoplantaris, and the skeletal disorder may be regarded a form of pustulotic arthroosteitis.

Neutrophil chemotaxis in patients with pustulotic arthro-osteitis.

The chemotactic response of peripheral blood polymorphonuclear leukocytes (PMNs) to N-formyl-methionyl-leucyl-phenylalanine was determined in four groups of persons (I) 19 patients with pustulosis palmoplantaris (PPP) and skeletal disorder (pustulotic arthro-osteitis); (II) 15 patients with a similar anterior chest wall involvement, but no PPP; (III) 9 patients with PPP, but without skeletal involvement, and (IV) 69 healthy adults (controls). The chemotactic activity of PMNs was found to be significantly increased in groups I-III, and patients with a similar osteoarthropathy, but no PPP compared with the controls. Furthermore the patients with pustulotic arthrosteitis had enhanced chemotactic activity compared with the patients with PPP only. This indicates that both skeletal involvement and PPP are somehow related to the function of PMNs. Colchicine was found of benefit in 2 of 3 group I, and in 6 group II patients, and it normalized their PMN chemotaxis.

15-Hydroxyeicosatetraenoic acid (15-HETE) specifically inhibits LTB4-induced chemotaxis of human neutrophils.

15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase (15-LO) product of arachidonic acid has the potential to inhibit leukotriene formation. In the present study the effect of 15-HETE on leukotriene B4 (LTB4)-induced polymorphonuclear leukocytes (PMN) and monocyte chemotaxis was investigated. LTB4-induced chemotaxis of PMNs was inhibited in a dose-dependent manner by 15-HETE. Maximum inhibition (68%) occurred at a 15-HETE concentration of 10(-4) M. The 15-LO product of eicosapentaenoic acid (15-HEPE) was approximately 10 times less potent in inhibiting LTB4-induced PMN chemotaxis. LTB4-induced chemotaxis of monocytes was unaffected by both 15-HETE and 15-HEPE. Using N-formyl-methionyl-leucyl-phenylalanine (FMLP) and complement split product C5a as chemoattractants, 15-HETE did not decrease PMN chemotaxis. Furthermore, 15-HETE itself did not affect random migration of leukocytes. The present results demonstrate that 15-HETE inhibits LTB4-induced chemotaxis of PMNs in vitro in a specific and selective way. Because 15-HETE not only inhibits formation, but also the effect of LTB4, it may be important in regulating LTB4-induced inflammation.