Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

Gastric motility: Measurement, symptoms and therapy

Gastric motility disorders, including delayed gastric emptying (gastroparesis), impaired postprandial fundic relaxation, and gastric myoelectrical disorders, can occur in type 1 diabetes, chronic renal failure, and functional dyspepsia (FD). Symptoms like upper abdominal pain, early satiation, bloating, nausea and vomiting may be related to gastroparesis. Diabetic gastroparesis is related to autonomic neuropathy. Scintigraphy is the gold standard in measuring gastric emptying, but it is expensive, requires specific equipment, and exposes patients to radiation. It also gives information about the intragastric distribution of the test meal. The 13C-octanoic acid breath test (OBT) is an alternative, indirect method of measuring gastric emptying with a stable isotope. Electrogastrography (EGG) registers the slow wave originating in the pacemaker area of the stomach and regulating the peristaltic contractions of the antrum. This study compares these three methods of measuring gastric motility in patients with type 1 diabetes, functional dyspepsia, and chronic renal failure. Currently no effective drugs for treating gastric motility disorders are available. We studied the effect of nizatidine on gastric emptying, because in preliminary studies this drug has proven to have a prokinetic effect due to its cholinergic properties. Of the type 1 patients, 26% had delayed gastric emptying of solids as measured by scintigraphy. Abnormal intragastric distribution of the test meal occurred in 37% of the patients, indicating impaired fundic relaxation. The autonomic neuropathy score correlated positively with the gastric emptying rate of solids (P = 0.006), but HbA1C, plasma glucose levels, or abdominal symptoms were unrelated to gastric emptying or intragastric distribution of the test meal. Gastric emptying of both solids and liquids was normal in all FD patients but abnormal intragastric distribution occurred in 38% of the patients. Nizatidine improved symptom scores and quality of life in FD patients, but not significantly. Instead of enhancing, nizatidine slowed gastric emptying in FD patients (P < 0.05). No significant difference appeared in the frequency of the gastric slow waves measured by EGG in the patients and controls. The correlation between gastric half-emptying times of solids measured by scintigraphy and OBT was poor both in type 1 diabetes and FD patients. According to this study, dynamic dual-tracer scintigraphy is more accurate than OBT or EGG in measuring gastric emptying of solids. Additionally it provides information about gastric emptying of liquids and the intragastric distribution of the ingested test meal.

Very Low Birth Weight Infants as Young Adults : Focus on aspects of cognition, behavior and sleep

Major advances in the treatment of preterm infants have occurred during the last three decades. Survival rates have increased, and the first generations of preterm infants born at very low birth weight (VLBW; less than 1500 g) who profited from modern neonatal intensive care are now in young adulthood. The literature shows that VLBW children achieve on average lower scores on cognitive tests, even after exclusion of individuals with obvious neurosensory deficits. Evidence also exists for an increased risk in VLBW children for various neuropsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and related behavioral symptoms. Up till now, studies extending into adulthood are sparse, and it remains to be seen whether these problems persist into adulthood. The aim of this thesis was to study ADHD-related symptoms and cognitive and executive functioning in young adults born at VLBW. In addition, we aimed to study sleep disturbances, known to adversely affect both cognition and attention. We hypothesized that preterm birth at VLBW interferes with early brain development in a way that alters the neuropsychological phenotype; this may manifest itself as ADHD symptoms and impaired cognitive abilities in young adulthood. In this cohort study from a geographically defined region, we studied 166 VLBW adults and 172 term-born controls born from 1978 through 1985. At ages 18 to 27 years, the study participants took part in a clinic study during which their physical and psychological health was assessed in detail. Three years later, 213 of these individuals participated in a follow-up. The current study is part of a larger research project (The Helsinki Study of Very Low Birth Weight Adults), and the measurements of interest for this particular study include the following: 1) The Adult Problem Questionnaire (APQ), a self-rating scale of ADHD-related symptoms in adults; 2) A computerized cognitive test battery designed for population studies (CogState®) which measures core cognitive abilities such as reaction time, working memory, and visual learning; 3) Sleep assessment by actigraphy, the Basic Nordic Sleep Questionnaire, and the Morningness-Eveningness Questionnaire. Actigraphs are wrist-worn accelerometers that separate sleep from wakefulness by registering body movements. Contrary to expectations, VLBW adults as a group reported no more ADHD-related behavioral symptoms than did controls. Further subdivision of the VLBW group into SGA (small for gestational age) and AGA (appropriate for gestational age) subgroups, however, revealed more symptoms on ADHD subscales pertaining to executive dysfunction and emotional instability among those born SGA. Thus, it seems that intrauterine growth retardation (for which SGA served as a proxy) is a more essential predictor for self-perceived ADHD symptoms in adulthood than is VLBW birth as such. In line with observations from other cohorts, the VLBW adults reported less risk-taking behavior in terms of substance use (alcohol, smoking, and recreational drugs), a finding reassuring for the VLBW individuals and their families. On the cognitive test, VLBW adults free from neurosensory deficits had longer reaction times than did term-born peers on all tasks included in the test battery, and lower accuracy on the learning task, with no discernible effect of SGA status over and above the effect of VLBW. Altogether, on a group level, even high-functioning VLBW adults show subtle deficits in psychomotor processing speed, visual working memory, and learning abilities. The sleep studies provided no evidence for differences in sleep quality or duration between the two groups. The VLBW adults were, however, at more than two-fold higher risk for sleep-disordered breathing (in terms of chronic snoring). Given the link between sleep-disordered breathing and health sequelae, these results suggest that VLBW individuals may benefit from an increased awareness among clinicians of this potential problem area. An unexpected finding from the sleep studies was the suggestion of an advanced sleep phase: The VLBW adults went to bed earlier according to the actigraphy registrations and also reported earlier wake-up times on the questionnaire. In further study of this issue in conjunction with the follow-up three years later, the VLBW group reported higher levels of morningness propensity, further corroborating the preliminary findings of an advanced sleep phase. Although the clinical implications are not entirely clear, the issue may be worth further study, since circadian rhythms are closely related to health and well-being. In sum, we believe that increased understanding of long-term outcomes after VLBW, and identification of areas and subgroups that are particularly vulnerable, will allow earlier recognition of potential problems and ultimately lead to improved prevention strategies.

Health-related quality of life, symptoms and comorbidity in inflammatory bowel disease

Health-related quality of life (HRQoL) measurement has become an important outcome in treatment trials and in health policy decisions. HRQoL can be measured by using generic or disease-specific tools. Generic instruments can be used for comparing health status among patients in different health states and conditions but they do not focus specifically on the issues relevant in a particular disease. Disease-specific tools may be more responsive to changes within a specific condition. In earlier studies, impairment of HRQoL has been evident in patients with inflammatory bowel disease (IBD), especially when the disease is active. Data about the impact of comorbidity or demographic characteristics of the patients on HRQoL are partly controversial. This study, which comprised 2913 adult IBD patients, examined HRQoL using the disease-specific IBDQ and the general 15D instruments. The 15D scores of IBD patients were compared with scores of a gender and age matched general population sample. Frequency of IBD symptoms and arrangement of therapy were studied and compared with those of IBD patients in an earlier European study. Furthermore, data of other chronic diseases of the patients were obtained from the Social Insurance Institution s reimbursement register and comorbidity of IBD patients was compared with that of age and gender matched controls. --- Of the respondents, 37% reported that they suffered from disturbing IBD symptoms weekly. In 17% of the patients, the symptoms greatly affected the ability to enjoy leisure activities, and 14% stated that these symptoms greatly affected their capacity to work. Despite that, the great majority (93%) of patients expressed satisfaction with their current treatment, which exceeded the rate observed in the other European patients. The mean IBDQ score was 163, as the possible range is 32-224, and disease activity was strongly correlated with HRQoL. Older age, comorbid diseases, and female gender were also related to impairment of HRQoL. Lower HRQoL scores were seen also in newly-diagnosed patients and in those with a history of surgery, especially after stoma or ileal pouch-anal anastomosis (IPAA) operation. The range of 15D scores was 0.30-1.00, with mean of 0.87. As with the IBDQ, disease activity, older age and history of surgery were correlated with the score. Both the newly-diagnosed patients and patients with a long-lasting disease had lower scores than average even after adjusting for age. The 15D scores of IBD patients were significantly lower than those of the control group. A strong correlation was seen between the 15D and the IBDQ scores. Comorbidity with other chronic diseases was observed in 29% of IBD patients. Connective tissue diseases, chronic obstructive pulmonary diseases, pernicious anaemia, and coronary heart disease (CHD) were significantly increased in patients with IBD. Especially female IBD patients appeared to be at increased risk for CHD, and patients who reported weekly IBD symptoms had a higher risk for having other chronic diseases in addition to IBD. Comorbidity impaired HRQoL, as measured with both generic and disease-specific tools. In conclusion, HRQoL is impaired in IBD patients. An understanding of predictors of HRQoL will help to recognise patients who will need special support.