Janus Kinase Inhibitors: A Review of Their Emerging Applications in Dermatology

The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.

Risk of prion disease transmission from ocular donor tissue transplantation.

PURPOSE: Recent new reports of possible iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) in Europe have prompted renewed scrutiny of current Eye Bank Association of America criteria for evaluation of potential corneal donors in this country. A prior study evaluated the risk of CJD occurring in U.S. corneal donors by using data to 1994. This report updates these data, analyses the risk by using data to 1997, and predicts potential risk into the next decade. METHODS: EBAA data inclusive through 1997 were reviewed and correlated with incidence figures for CJD in the United States as provided by the Communicable Disease Center in Atlanta. RESULTS: The annual incidence of CJD has remained stable at 1 case per million population. Thus approximately 270 new cases of CJD would be expected to occur each year in the United States. From this, the calculated risk of a prion-infected corneal donor appearing in the donor pool is 0.045 cases per year. If the data are corrected for age (90% of CJD patients are older than 60 years) and for possible infected but asymptomatic CJD patients (prevalence, 70 cases per million), at worst, 2.12 cases per year would appear for potential corneal donation (0.005% of all donors). Whereas donors completely without any neurologic symptoms cannot be screened by using any currently available laboratory method, those with a characteristic quadrate clinical prodrome including cognitive changes, speech abnormalities, cerebellar findings, and myoclonus could all be potentially excluded by using tightened medical record and historical screening criteria. Although no cases of bovine spongiform encephalopathy (mad-cow disease) or new variant CJD have been reported in the United States, if such should occur, only 4.2 cases of CJD would be expected in potential donors each year (0.009% of all donors). Tightening of exclusionary queries would significantly reduce the risk of even this number of patients appearing for corneal donation. CONCLUSIONS: Historical queries of potential corneal donors should be tightened to assure exclusion of donors with early neurologic alterations. Any patient undergoing autopsy for evaluation of possible central nervous system (CNS) disease should be absolutely excluded. With this approach, the risk of inclusion of CJD-infected transplant tissues derived from ocular sources is very small, and all previously reported cases would have been prospectively excluded from surgical use. Clearly, the benefits of corneal transplantation in the overall population continue significantly to outweigh the risks of transmission of prion disease.

Does consumption of beer, alcohol, and bitter substances affect bitterness perception?

The relation between consumption of beer, alcohol, and bitter substances was investigated by comparing 20 each of male adults, low users ( < 720 ml/week) and high users ( > 3.61/week) of beer for sensitivity to and like/dislike for the bitterness of isohumulones. Intake of beer, alcohol, and bitter substances was measured with a food frequency questionnaire and a 14-day recall journal. Intake of alcohol (including alcohol from sources other than beer) and bitter substances was higher for high users of beer than for low users. The average bitterness units (BUs) in the beers consumed by the two groups did not differ, indicating that high users do not consume more bitter beers than low users. Detection thresholds for isohumulones in water did not differ between the two groups, but high users had higher difference thresholds for isohumulones in beer (p < 0.10). In time-intensity measurements of bitterness in beer, low users of beer recorded significantly higher maximum intensities (p < 0.001) and shorter total durations (p < 0.001) than high users, with no difference between the two groups for time to maximum intensity and area under the TI curve. There was no significant difference between the two groups for BUs of beers produced by ad lib mixing of low- and high-bitterness beers, or for mean hedonic ratings of various concentrations of isohumulones in beer. These results suggest that intakes of beer, alcohol, and bitter substances are not major determinants of taste responses to the bitterness of isohumulones.

The impact on tissue utilization of screening donor corneas by specular microscopy at the University of Texas Southwestern Medical Center.

To determine how frequently specular microscopy results affect the outcome of eye-bank judgments on the transplantability of donor corneas, 1,011 consecutive donor records from a 3-year period at the Transplant Services Center of the University of Texas Southwestern Medical Center at Dallas were analyzed. Specular microscopy cell counts from each decade of donor age were determined, and it was found that there were no cell counts < 2,000 mm2 for any donor age < 40. Above age 40, the percentage of cell counts < 2,000 per mm2 rose from 3.9% for donors in their forties of 6% for donors in their seventies. For donors between 40 and 69 years, specular microscopy was used to rule out unacceptable tissue in an additional 3.3% of a prescreened pool of corneas evaluated by current Eye Bank Association of America standards. While corneas from donors over age 69 were initially presumed to be unacceptable for transplant at this eye bank, routine specular microscopic examination helped to clear for transplant of 31 corneas from donors of this age group.

Depression in caregivers of demented patients is associated with altered immunity: impaired proliferative capacity, increased CD8+, and a decline in lymphocytes with surface signal transduction molecules (CD38+) and a cytotoxicity marker (CD56+ CD8+).

Changes in relevant immune parameters, including function, were found to be associated with depression in elderly caregiver wives of demented patients. We studied the relationship between immune cell phenotype and T cell proliferative capacity of such caregivers to levels of stress and depression over the course of a support group intervention. The data indicate the strongest association between depression (of all stress parameters) and impaired T cell proliferative capacity. Depression was also most strongly (of stress parameters) associated with a shift in T cell populations with an increase in CD8+ T cells, and a reduced percentage of CD38+ cells in both CD8+ and CD4+ T cell populations. Since CD38 is a signal transduction factor, it was interesting that a decreased percentage of CD38+ cells correlated with impaired T cell function (proliferation). Another significant difference was the reduction in natural killer (NK) cells as well as the percentage of the CD56+ component of the CD8+ population. This latter subset is important in MHC-unrestricted cytotoxicity, and has been found expanded in healthy centenarians. This study shows that both chronic stress, and depression in particular, and age have deleterious effects on T cells, and together could significantly contribute to the higher risk of disease and mortality associated with being a caregiver of a demented individual.

Using the CAGE to screen for drinking-related problems in college students.

OBJECTIVE: As a brief alcohol screening instrument the CAGE has demonstrated a high degree of accuracy in identifying problem drinkers among adults. However, some studies have questioned its screening accuracy within a college population. The research presented in this article contains the results of two additional studies that examined the ability of the CAGE to identify problem drinkers within a college student population. METHOD: In both 1988 and 1992 a questionnaire of various drinking practices, including CAGE items, was mailed to a random sample of 1,000 students at a large midwestern university (response rate: 58.2%, 1988; 49.8%, 1992). Using identical problem-drinking criteria, sensitivity, specificity and positive predictive values at various cutoff scores of the CAGE were calculated for both sets of data and for gender. RESULTS: At the recommended CAGE cutoff score of > 2 for a positive test the sensitivity and positive predictive values (PPV) were slightly higher for the 1992 sample. The PPV values at that cutoff score were 46% (1988) and 49% (1992) and 48% for the combined data. In both samples the screening values were lower for women. CONCLUSIONS: These data from both surveys do not support the CAGE as a screening measure for problem drinking with this population. It appeared to be less accurate with women although that conclusion should be tempered by the fact that there was a relatively low percentage of problem drinkers found among women.

Criterion variability in problem-drinking research on college students.

A persistent issue confronting research on problem drinking (PD) and heavy drinking (HD) among college-age adults is the lack of a consistent, valid definition and criteria for either of the two conditions. This article presents a review and analysis of the criteria used in a selected group of studies on college students' PD and HD from 1974 to 1993. All studies within the time period that employed a random sample of students were analyzed for variations in criteria used to define either PD or HD. Sample characteristics, the specific criteria used, and data on prevalence rates found with those criteria are described. Areas of uniformity and inconsistency were identified and effects of criterion variations were described for the 23 studies reviewed. Of particular note was the lack of differential criteria for gender.

Guidelines for preventing "dilution false negatives" in in vitro laboratory testing of the donor population.

In this article we develop a calculation or formula for use in determining the potential dilution effect of fluids administered during patient treatment on serologic testing parameters. The formula uses basic principles of (a) fluid distribution over time from administration; (b) ratios of plasma and extravascular fluid volumes to body weight; and (c) common practices of fluid resuscitation. A dilution threshold of 50% was set using data from enzyme-linked immunosorbent assay human immunodeficiency virus antibody determinations performed on in vitro diluted seropositive serum samples. These data respond to issues raised by guidelines from the Centers for Disease Control and the U.S. Food and Drug Administration to achieve recipient safety without unnecessarily restricting the potential donor pool.

Developing a screening questionnaire for problem drinking in college students.

The CAGE questionnaire is one of several brief screening instruments that has been successful in detecting alcoholism in a general population. There is evidence, however, indicating that none of these instruments has sufficient validity for detecting the less severe pattern of problem drinking that is more typical of college students. This study analyzed survey data, including CAGE questions, to identify items that would have sufficient test operating characteristics more valid for screening problem drinkers. Problem and normal drinking patterns were defined by combining certain categories of quantity-frequency data with categories of alcohol-related problems. Problem and normal drinkers were identified as those students at the ends of the quantity-frequency/alcohol-problems continuum. Differences between the two groups in response frequencies to a 17-item alcohol-use survey were examined using chi-square analyses. Five items showing highly significant differences were identified, and sensitivity, specificity, and positive predictive values were calculated at possible cutoff points. These items were (1) a positive response to any 2 of the 4 CAGE items, (2) reporting rarely or never choosing nonalcoholic beverages at social events, (3) driving under the influence at least 6 to 10 times or more in the last year, and (4) having started regular use of alcohol before the college years. At the recommended cutoff score for a positive test, the items have a sensitivity of 88%, specificity of 87%, and positive predictive value of 52%. When used for screening in a population similar to this, it will fail to identify 12% of the problem drinkers and will falsely classify 13% of all normal drinkers as problem drinkers.(ABSTRACT TRUNCATED AT 250 WORDS)

ELISA HIV testing and viral culture in the screening of corneal tissue for transplant from medical examiner cases.

The spread of AIDS and its association with a retrovirus, commonly called T-lymphotropic virus type III (HIV) has produced great concern among those involved in transplantation about the possibility for transmission of this disease through tissue and organ transplant. Isolation of the virus from conjunctiva and tears further heightened this concern for corneal transplants. This review of medical examiner (ME) cases, a population in which high numbers of transplant corneas are retrieved, has revealed positive serologic tests for HIV in serum from 5 cases in 205 screens. These represent potential donors based on other standard medical criteria available at the time of collection. This tissue was also submitted for viral culture, and virus was recovered from the corneal tissue in McCarey-Kaufman (MK) media. These findings and case reviews are discussed.

Superior sorting and categorizing ability in a case of bilateral frontal atrophy: an exception to the rule.

This report presents the case of a patient with a naturally occurring, nonsurgical, frontal lesion who exhibited superior performances on the Wisconsin Card Sorting Test (WCST) and Halstead's Category Test (HCT) as an exception to the widely accepted clinical rule that patients with dorsolateral frontal damage are necessarily impaired with respect to maintaining cognitive set, shifting set, and sorting objects on the basis of different categories. The normal performance of this patient with unquestionable orbitofrontal and dorsolateral atrophy probably reflects a limitation of the WCST and HCT rather than true capacity on her part to perform the cognitive operations of set formation, maintenance, and categorization.

Isolation of the human T-cell leukemia/lymphotropic virus type III from the cornea.

Corneoscleral donor tissue from a donor with a positive serum antibody to HTLV-III but without the overt clinical signs of the acquired immune deficiency syndrome (AIDS) was cultured for the presence of the human T-cell leukemia/lymphotropic virus type III (HTLV-III). The virus was isolated from the two corneal specimens in this patient after the tissue had been stored for four days in McCarey-Kaufman medium. The presence of HTLV-III was confirmed by the detection of viral core proteins (approximately 24,000 protein, termed P24 gag), by immunofluorescence of a touch preparation of the corneal epithelium as well as in cells cultured in vitro. The percentage of immunofluorescent cells detected by HTLV-III anti-P24 antibody ranged between 2% and 3%. These findings emphasize the possibility of transmission of this virus via corneal transplantation surgery. Although no documented cases of AIDS have occurred in corneal transplant recipients, serologic screening of donors before the use of the tissue for transplantation is advisable.

Neuromuscular problems in the burn patient: cause and prevention.

Neuromuscular complications of the burn patient that occur during hospitalization frequently are overlooked. Eighty-eight patients with signs of weakness or complaints of easy fatigability were examined clinically and electrodiagnostically. The most frequently diagnosed neuromuscular abnormality in this study was generalized peripheral neuropathy. Other specific neuromuscular problems, in order of frequency of occurrence, were found to involve the deltoid muscle, peroneal nerve, ulnar nerve, median nerve, and brachial plexus. These lesions are found to be commonly due to (1) poor positioning, both in bed and in the operating room, and (2) heavy bulky dressings over superficial nerves. Thus, it is concluded that many of these injuries offer a significant potential for prevention through attention to physiologic positioning and meticulous patient care.