Virtual Learning and Assessment in Rheumatology Fellowship Training: Objective Structured Clinical Examination Revisited.

OBJECTIVE: With the onset of the COVID-19 pandemic, an annual multi-institutional face-to-face rheumatology objective structured clinical examination (ROSCE) was transformed into a virtual format. The educational goals of the virtual ROSCE (vROSCE) were to reproduce the educational value of the previous in-person ROSCE, providing a valuable formative assessment of rheumatology training activities encompassing the 6 Accreditation Council for Graduate Medical Education (ACGME) core competencies for fellows-in-training (FITs). This article describes the novel design, feasibility, and stakeholder value of a vROSCE. METHODS: Through an established collaboration of 5 rheumatology fellowship training programs, in February 2021, a vROSCE was created and conducted using a Zoom platform. Station development included learning objectives, FIT instructions, faculty proctor instructions, and a checklist by which to provide structured formative feedback. An anonymous, optional web-based survey was sent to FIT participants to evaluate the experience. RESULTS: Twenty-three rheumatology FITs from 5 institutions successfully rotated through 6 stations in the vROSCE. Immediate feedback was given to each FIT using standardized rubrics structured around ACGME core competencies. A total of 65% of FITs (15 of 23) responded to the survey, and 93% of survey respondents agreed or strongly agreed that the vROSCE was a helpful educational activity and identified individualized opportunities for improvement. CONCLUSION: A vROSCE is an innovative, feasible, valuable, and well-received educational technology tool. The vROSCE enriched rheumatology FITs' education and offered collaborative learning experiences across institutions.

Incorporating Telemedicine in Rheumatology Fellowship Training Programs: Needs Assessment, Curricular Intervention, and Evaluation.

OBJECTIVE: To increase the confidence of rheumatology fellows in training (FITs) in delivering virtual care (VC) and prepare them for independent practice, we developed educational materials addressing gaps in their skills. METHODS: We identified gaps in telemedicine skills based on FIT performance in a virtual rheumatology objective structured clinical examination (vROSCE) station on VC delivery using video teleconference technology and survey (survey 1) responses. We created educational materials including videos of "mediocre" and "excellent" VC examples, discussion/reflection questions, and a document summarizing key practices. We measured change in the confidence levels of FITs for delivering VC with a post-intervention survey (survey 2). RESULTS: Thirty-seven FITs (19 first-year, 18 second- plus third-year fellows) from 7 rheumatology fellowship training programs participated in a vROSCE and demonstrated gaps in skills mapping to several Rheumatology Telehealth Competency domains. Confidence levels of FITs improved significantly from survey 1 to survey 2 for 22 of 34 (65%) questions. All participating FITs found the educational materials helpful for learning and reflecting on their own VC practice; 18 FITs (64%) qualified usefulness as "moderately" or "a lot." Through surveying, 17 FITs (61%) reported implementing skills from the instructional videos into VC visits. CONCLUSION: Continually assessing our learners' needs and creating educational materials addressing gaps in training are requisite. Using a vROSCE station, needs assessments, and targeted learning with videos and discussion-guidance materials enhanced the confidence level of FITs in VC delivery. It is imperative to incorporate VC delivery into fellowship training program curricula to ensure breadth in skills, attitudes, and knowledge of new entrants into the rheumatology workforce.

Rheumatology Milestones 2.0: A Roadmap for Competency-Based Medical Training of Rheumatology Fellows in the 21st Century.

OBJECTIVE: Since 2014, rheumatology fellows have been assessed not only based on their ability to provide patient care and possession of medical knowledge but also on their skill in serving as patient advocates, navigators of health systems, and members of a health care team. Such assessments have been carried out through the use of competency-based milestones from the Accreditation Council of Graduate Medical Education (ACGME). However, a needs assessment has demonstrated interest in more context validity and subspecialty relevance since the development of the ACGME internal medicine (IM) subspecialty reporting milestones. The ACGME thus created a milestones working group, and the present study was undertaken to develop Rheumatology Milestones 2.0 as well as a supplemental guide to assist with implementation. METHODS: The working group, consisting of 7 rheumatology program directors, 2 division directors, a community practice rheumatologist, a rheumatology fellow in training, and a public member who is a rheumatology patient, was overseen by the ACGME vice president for milestones development and met through three 12-hour, in-person meetings to compose the rheumatology specialty milestones and supplemental guide within the ACGME Milestones 2.0 project. RESULTS: Informed by the needs assessment data and stakeholders, the working group revised and adapted the ACGME IM subspecialty reporting milestones to create a rheumatology-specific set of milestones and a supplemental guide for their implementation. CONCLUSION: The Rheumatology Milestones 2.0 provides a specialty-specific, competency-based evaluation tool that can be used by program directors, clinical competency committees, and others to assess the competencies of rheumatology fellows during training and help measure readiness for independent practice.

New Roadmap for the Journey From Internist to Rheumatologist.

OBJECTIVE: Measurement is necessary to gauge improvement. US training programs have not previously used shared standards to assess trainees' mastery of the knowledge, skills, and attitudes necessary to practice rheumatology competently. In 2014, the Accreditation Council for Graduate Medical Education (ACGME) Next Accreditation System began requiring semiannual evaluation of all medicine subspecialty fellows on 23 internal medicine subspecialty reporting milestones. Since these reporting milestones are not subspecialty specific, rheumatology curricular milestones were needed to guide rheumatology fellowship training programs and fellows on the training journey from internist to rheumatologist. METHODS: Rheumatology curricular milestones were collaboratively composed by expanding the internal medicine reporting milestones to delineate the specific targets of rheumatology fellowship training within 6 ACGME core competencies. The 2006 American College of Rheumatology core curriculum for rheumatology training programs was updated. RESULTS: A total of 80 rheumatology curricular milestones were created, defining progressive learning through training; most focus on patient care and medical knowledge. The core curriculum update incorporates the new curricular milestones and rheumatology entrustable professional activities. CONCLUSION: Rheumatology curricular milestones are now available for implementation by rheumatology fellowship training programs, providing a clear roadmap for specific training goals and a guide to track each fellow's achievement over a 2-year training period. The comprehensive core curriculum delineates the essential breadth of knowledge, skills, and attitudes that define rheumatology, and provides a guide for educational activities during fellowship training. These guiding documents are now used to train and assess fellows as they prepare for independent rheumatology practice as the next generation of rheumatologists.

Rheumatology Research Foundation Clinician Scholar Educator Award: Fifteen Years Promoting Rheumatology Educators and Education.

OBJECTIVE: The Rheumatology Research Foundation's Clinician Scholar Educator (CSE) award is a 3-year career development award supporting medical education research while providing opportunities for mentorship and collaboration. Our objective was to document the individual and institutional impact of the award since its inception, as well as its promise to strengthen the subspecialty of rheumatology. METHODS: All 60 CSE Award recipients were surveyed periodically. Fifty-six of those 60 awardees (90%) responded to requests for survey information that included post-award activities, promotions, and further funding. Data were also collected from yearly written progress reports for each grant. RESULTS: Of the total CSE recipients to date, 48 of 60 (80%) are adult rheumatologists, 11 of 60 (18%) are pediatric rheumatologists, and 1 is an adult and pediatric rheumatologist. Two-thirds of survey respondents spend up to 30% of their total time in educational activities, and one-third spend greater than 30%. Thirty-one of the 60 CSE recipients (52%) have published a total of 86 medical education papers. Twenty-six of 52 (50%) had received an academic promotion following the award. Eleven awardees earned advanced degrees. CONCLUSION: We describe the creation and evolution of a grant program from a medical subspecialty society foundation and the impact on producing education research, individual identity formation, and ongoing support for educators. This community of rheumatology scholar educators now serves as an important resource at the national level for the American College of Rheumatology and its membership. We believe that this grant may serve as a model for other medical societies that want to promote education scholarship and leadership within their specialties.

Fellow As Teacher Curriculum: Improving Rheumatology Fellows' Teaching Skills During Inpatient Consultation.

OBJECTIVE: Enhancing rheumatology fellows' teaching skills in the setting of inpatient consultation may have a broad positive impact. Such efforts may improve fellows' clinical skills and overall patient care. Most importantly, effective resident-fellow teaching interactions may not only increase residents' knowledge of rheumatology but may influence their career choice. However, a number of barriers to the resident-fellow teaching interaction have been identified, including fellows' teaching skills. We developed the Fellow As Clinical Teacher (FACT) curriculum in order to enhance fellows' teaching skills during inpatient consultation. METHODS: The FACT curriculum was delivered in two 45-minute workshops during the 3-day Winter Symposium of the Carolinas Fellows Collaborative. We evaluated its effect with self-assessment surveys and fellow performance on the objective structured teaching exercise (OSTE) before and after participation in the curriculum. RESULTS: Nineteen fellows from 4 rheumatology training programs participated in the pre- and post-curriculum OSTEs and 18 fellows completed pre- and post-curriculum surveys. OSTE scores improved on 5 of the 8 items assessed, and the total OSTE score improved as well (34.7 versus 29.5; P < 0.01) after the FACT curriculum. Fellows' self-assessment of their teaching skills and intent to teach during consultation also increased after participation in the curriculum. CONCLUSION: The FACT curriculum, focused on teaching during consultation, improved fellows' teaching skills and attitudes toward teaching. Improving and increasing fellow teaching, particularly in the consultation setting, may impact patient care, resident and fellow learning, and teaching skills of future faculty, and could potentially influence residents' career choice.

What Is a Rheumatologist and How Do We Make One?

OBJECTIVE: Graduate medical education is a critical time in the training of a rheumatologist, and purposeful evaluation of abilities during this time is essential for long-term success as an independent practitioner. The internal medicine subspecialties collectively developed a uniform set of reporting milestones by which trainees can be assessed and receive formative feedback, providing clarity of accomplishment as well as areas for improvement in training. Furthermore, the reporting milestones provide a schema for assessment and evaluation of fellows by supervisors. The internal medicine subspecialties were also tasked with considering entrustable professional activities (EPAs), which define the abilities of a subspecialty physician who has attained sufficient mastery of the field to be accountable to stakeholders and participate in independent practice. Although EPAs have been established for a few specialties, they had not yet been described for rheumatology. EPAs have value as descriptors of the comprehensive abilities, knowledge, and skills of a practicing rheumatologist. The rheumatology EPAs have a role in defining a specialist in rheumatology upon completion of training, and also represent the ways our specialty defines our abilities that are enduring throughout practice. METHODS: We describe the collaborative process of the development of both the subspecialty reporting milestones and the rheumatology EPAs. The reporting milestones evolved through discussions and collaborations among representatives from the Association of Specialty Professors, the Alliance for Academic Internal Medicine, the American Board of Internal Medicine, and the Accreditation Council for Graduate Medical Education. The EPAs were a product of deliberations by the Next Accreditation System (NAS) working group of the American College of Rheumatology (ACR) Committee on Rheumatology Training and Workforce Issues. RESULTS: Twenty-three subspecialty reporting milestones and 14 rheumatology EPAs were advanced and refined over the course of 3 subspecialty reporting milestone development summits and 3 ACR NAS working group meetings, respectively. CONCLUSION: The subspecialty reporting milestones and rheumatology EPAs presented here stipulate reasonable and measurable expectations for rheumatologists-in-training. Together, these tools aim to promote enrichment and greater accountability in the training of fellows. Additionally, the EPAs define, for all stakeholders, the expertise of a rheumatologist in practice.

Expert panel consensus on assessment checklists for a rheumatology objective structured clinical examination.

OBJECTIVE: While several regional fellowship groups conduct rheumatology objective structured clinical examinations (ROSCEs), none have been validated for use across programs. We aimed to establish agreement among subspecialty experts regarding checklist items for several ROSCE stations. METHODS: We administered a 1-round survey to assess the importance of 173 assessment checklist items for 11 possible ROSCE stations. We e-mailed the survey to 127 rheumatology educators from across the US. Participants rated each item's importance on a 5-point Likert scale (1 = not important to 5 = very important). Consensus for high importance was predefined as a lower bound of the 95% confidence interval ≥4.0. RESULTS: Twenty-five individuals (20%) completed the expert panel survey. A total of 133 of the 173 items (77%) met statistical cutoff for consensus to retain. Several items that had population means of ≥4.0 but did not meet the predetermined definition for consensus were rejected. The percentage of retained items for individual stations ranged from 24% to 100%; all items were retained for core elements of patient counseling and radiograph interpretation tasks. Only 24% of items were retained for a rehabilitation medicine station and 60% for a microscope use/synovial fluid analysis station. CONCLUSION: This single-round expert panel survey established consensus on 133 items to assess on 11 proposed ROSCE stations. The method used in this study, which can engage a diverse geographic representation and employs rigorous statistical methods to establish checklist content agreement, can be used in any medical field.

Trends in the outpatient medication management of lupus erythematosus in the United States.

BACKGROUND: Systemic lupus erythematosus (SLE) and chronic cutaneous lupus (CCLE) therapy has changed little over the past 50 years. In March 2011, the US Food and Drug Administration (FDA) approved belimumab, complementing the three preexisting approved therapies: low dose aspirin, prednisone, and hydroxychloroquine. OBJECTIVE: The objectives for this study were to evaluate trends in the medications prescribed for the management of lupus erythematosus (LE) and to assess how treatment varies among different specialists. METHODS: Outpatient visits for treatment of lupus and its comorbidities were identified in the National Ambulatory Medical Care Survey (NAMCS), a representative survey of visits to physician offices in the United States. Data was evaluated to determine patient demographics, treatments prescribed by each specialty, and comorbidities encountered during the study period of 1993-2010. RESULTS: From 1993-2004, prednisone was the most frequently prescribed medication; however, prednisone became the second most frequently prescribed medication in 2005-2010, as hydroxychloroquine became the leading medication prescribed for LE. In primary care physicians and other non-dermatology specialists, the most frequently prescribed medications for lupus were prednisone and hydroxychloroquine; whereas, hydroxychloroquine and triamcinolone were the top two medications preferred by dermatologists. LIMITATIONS: The NAMCS collects cross-sectional data, such that individual patients cannot be followed over time. Hence, it does not provide data regarding the incidence of disease, patient age at the time of diagnosis, change in individual patient's medication regimens over time, or prognosis related to patient demographics. In addition, it is possible that the physician did not always record nonprescription medication use, such as NSAIDS, since these are typically used first line. CONCLUSION: First-line treatment of LE changed minimally from 1993 to 2010, with prednisone and hydroxychloroquine serving as the primary medications utilized by most physicians for the management of LE.

Competency-based goals, objectives, and linked evaluations for rheumatology training programs: a standardized template of learning activities from the Carolinas Fellows Collaborative.

OBJECTIVE: American Council on Graduate Medical Education program requirements mandate that rheumatology training programs have written goals, objectives, and performance evaluations for each learning activity. Since learning activities are similar across rheumatology programs, we aimed to create competency-based goals and objectives (CBGO) and evaluations that would be generalizable nationally. METHODS: Through an established collaboration of the 4 training programs' directors in North Carolina and South Carolina, we collaboratively composed CBGO and evaluations for each learning activity for rheumatology training programs. CBGO and linked evaluations were written using appropriate verbs based on Bloom's taxonomy. Draft documents were peer reviewed by faculty at the 4 institutions and by members of the American College of Rheumatology (ACR) Clinician Scholar Educator Group. RESULTS: We completed templates of CBGO for core and elective rotations and conferences. Templates detail progressive fellow performance improvement appropriate to educational level. Specific CBGO are mirrored in learning activity evaluations. Templates are easily modified to fit individual program attributes, have been successfully implemented by our 4 programs, and have proven their value in 4 residency review committee reviews. CONCLUSION: We propose adoption of these template CBGO by the ACR, with access available to all rheumatology training programs. Evaluation forms that exactly reflect stated objectives ensure that trainees are assessed using standardized measures and that trainees are aware of the learning expectations. The objectives mirrored in the evaluations closely align with the proposed milestones for internal medicine training, and will therefore be a useful starting point for creating these milestones in rheumatology.

T-cell specific defect in expression of the NTPDase CD39 as a biomarker for lupus.

Regulatory T cells (T(regs)) are critical for maintenance of peripheral tolerance via suppression of T-cell responses, and absence of T(regs) results in autoimmunity. The role of aberrations in the T(reg) pool for the development of systemic lupus erythematosus (SLE, lupus) remains uncertain. T(reg)-mediated generation of adenosine, dependent on the ectonucleotidase CD39, is an important mechanism for suppression of T-cell responses. We tested whether decreases in numbers of T(regs), and specifically CD39-expressing T(regs), are associated with human lupus. We studied 15 SLE patients, six patients with rheumatoid arthritis (RA) and 24 healthy controls. T(reg) phenotypic markers, including CD39 expression, were studied by flow cytometry. Varying numbers of sorted T(regs) cells were co-cultured with responder T (T(resp)) cells, with proliferation assessed by (3)H-thymidine incorporation. The proportion of T(regs) as defined by Foxp3(+) CD25(+high) CD127(-/low) was similar in lupus and control populations. CD39-expressing T(regs) comprised 37±13% of the T(reg) population in healthy controls and 36±21% in lupus subjects using nonsteroidal immunosuppressants to control active disease, but was nearly absent in five of six lupus subjects with minimally active disease. In contrast to healthy controls and lupus subjects without the CD39 defect, in SLE subjects with the CD39 defect, adenosine-dependent T(reg)-mediated suppression was nearly absent. These results suggest that functional defects in T(regs), rather than reduced T(reg) numbers, are important for the loss of peripheral tolerance in lupus. Presentation of this defect may serve as a biomarker for untreated disease.

Rheumatologists' recommendations on what to do in the dermatology office to evaluate and manage psoriasis patients' joint symptoms.

BACKGROUND: Psoriasis patients presenting to the dermatologist for skin disease management may have joint symptoms related to psoriatic arthritis. Dermatologists should ask psoriasis patients about these, yet may not be sure about how to best collaborate with rheumatologists in the management of these patients. OBJECTIVE: To describe how rheumatologists view the role of dermatologists in addressing and identifying signs and symptoms of psoriatic arthritis in psoriasis patients. METHODS: A questionnaire was developed concerning the evaluation and management of joint complaints in a dermatology setting. The survey was sent to rheumatologists interested in psoriatic arthritis. RESULTS: Rheumatologists recommended dermatologists ask psoriasis patients about joint pain, stiffness, swelling, and fatigue to evaluate for psoriatic arthritis. Rheumatology referral was recommended if patients had signs of inflammatory joint disease that were unrelieved by non-prescription non-steroidal anti-inflammatory drugs (NSAIDs). Patients with disabling joint symptoms, no improvement on (disease-modifying antirheumatic drug; DMARD) therapy, or with other causes of joint pain should be referred to rheumatology. Rheumatologists recommended that dermatologists only provide DMARD therapy for joint symptoms if concomitant skin disease warrants such treatment. CONCLUSIONS: Dermatologists play a pivotal role in preventing joint destruction in psoriasis patients by screening for signs of psoriatic arthritis, initiating treatment, and referring patients to a rheumatologist when appropriate.

Pilot study of the effect of ultraviolet light on pain and mood in fibromyalgia syndrome.

BACKGROUND: There is a lack of effective systemic or adequate symptomatic treatment for pain associated with fibromyalgia syndrome (FMS). Anecdotes suggest ultraviolet (UV) light may be of some benefit. PURPOSE: The purpose of the present study was to determine if UV is effective in ameliorating chronic pain in persons with FMS. METHODS: Nineteen subjects with FMS were enrolled in a controlled trial of UV and non-UV (control) tanning beds for 2 weeks, followed by randomization to receive UV or non-UV (control) exposure for 6 additional weeks. A follow-up interview was conducted 4 weeks after the last treatment. Pain was assessed with an 11-point numerical pain rating (Likert scale), a visual analogue pain scale (VAS), and the McGill Pain Questionnaire. Mood variables were also assessed. RESULTS: During the initial 2 weeks when subjects received both UV and non-UV (control) exposures, the 11-point Likert scale pain score decreased 0.44 points after exposure to UV from pre-exposure levels (S.E. = .095). Additionally, UV exposure resulted in greater positive affect, well-being, relaxation, and reduced pain levels when compared to non-UV (control) exposure (Odds Ratio [OR] = 2.80, p = 0.0059). Following the randomized treatment period, there was slight improvement in pain as measured by the McGill Pain Questionnaire in the UV group compared to the non-UV (control) group (12.2 versus 14.1; p = 0.049); the other pain scales yielded nonsignificant results. Assessment 4 weeks after the last treatment showed no significant differences in scores in the adjusted means for outcomes. CONCLUSIONS: Results from this pilot study suggest that tanning beds may have some potential in reducing pain in persons with FMS.

Relationship of physical function to vastus lateralis capillary density and metabolic enzyme activity in elderly men and women.

BACKGROUND AND AIMS: There are no data showing whether or not age-related declines in physical function are related to in vitro properties of human skeletal muscle. The purpose of this study was to determine whether physical function is independently associated with histologic and metabolic properties of skeletal muscle in elderly adults. METHODS: The study was a cross-sectional observational study of 39 sedentary, older (60-85 yrs) men and women. A needle biopsy of the vastus lateralis for assessment of muscle fiber type, fiber area, capillary density and citrate synthase and aldolase activities was performed. Physical function tests included the Short Physical Performance Battery (balance, walking speed, and chair rise time), as well as self-reported disability. RESULTS: Total fiber area (R=-0.41, p=0.02), number of Type II fibers (R=-0.33, p=0.05), and aldolase activity (R=-0.54, p=0.01) were inversely related to age. Persons who reported greater difficulty with daily activities had lower capillary density (R=-0.51, p=0.03) and lower citrate synthase activity (R=-0.66, p=0.03). Walking speed was directly related to fiber area (R=0.40, p=0.02), capillary density (R=0.39, p=0.03), citrate synthase (R=0.45, p=0.03) and aldolase (R=0.55, p<0.01) activities, even after adjustment for age, BMI and disease status. CONCLUSIONS: In older adults, skeletal muscle capillary density and metabolic enzymatic activity are independent predictors of lower extremity physical function.

Altered editing in cyclic nucleotide phosphodiesterase 8A1 gene transcripts of systemic lupus erythematosus T lymphocytes.

The aetiopathogenesis of the abnormal immune response in systemic lupus erythematosus (SLE) remains incompletely understood. We and other investigators demonstrated altered expression of adenosine deaminase that act on RNA (ADAR) genes in SLE patients. Based on this information, we hypothesize that the altered expression and function of ADAR enzymes is a mechanism for the immunopathogenesis of SLE. ADARs edit gene transcripts through site-specific conversion of adenosine to inosine by hydrolytic deamination at C6 of the adenosine. Thirteen SLE subjects and eight healthy controls were studied. We assessed the role of ADAR enzymes in editing of PDE8A1 gene transcripts of normal and SLE T cells. These studies demonstrated the occurrence of ADAR-catalysed altered and site-selective editing profile of specific sites in the PDE8A1 gene transcripts of normal and SLE T cells. Two hot spots for A to I editing were observed in the PDE8A1 transcripts of normal and SLE T cells. A fundamental finding of this study is A to I hypo-editing followed by up-regulation of PDE8A1 transcripts in SLE T cells. These results are confirmed by analysing PDE8A1 transcripts of normal T cells activated with type I interferon-alpha. It is proposed that, the altered expression of ADAR enzymes tilt the balance of editing machinery and alter editing in SLE transcriptome. Such altered editing may contribute to the modulation of gene regulation and ultimately, immune functions in SLE and play an important role in the initiation and propagation of SLE pathogenesis.

Induction of 150-kDa adenosine deaminase that acts on RNA (ADAR)-1 gene expression in normal T lymphocytes by anti-CD3-epsilon and anti-CD28.

We and other investigators have demonstrated up-regulation of the expression of the RNA-editing gene 150-kDa adenosine deaminase that acts on RNA (ADAR1) in systemic lupus erythematosus (SLE) T cells and B cells, peripheral blood mononuclear cells (PBMC), natural killer (NK) cells. The presence of a small proportion of activated T cells is the hallmark of SLE. Therefore, it was hypothesized that 150-kDa ADAR1 gene expression is induced by the physiological activation of T cells. To examine this hypothesis, normal T cells were activated by anti-CD3-epsilon plus anti-CD28 for various time periods from 0 to 48 hr. The expression of 110-kDa and 150-kDa ADAR1, and interleukin (IL)-2 and beta-actin gene transcripts was analysed. An approximately fourfold increase in 150-kDa ADAR1 gene expression was observed in activated T cells. ADAR2 gene transcripts are substrates for ADAR1 and ADAR2 enzymes. Therefore, we assessed the role of the 150-kDa ADAR enzyme in editing of ADAR2 gene transcripts. In activated T cells, site-selective editing of the -2 site was observed. Previous studies indicate that this site is predominantly edited by ADAR1. In addition to this, novel editing sites at base positions -56, -48, -45, -28, -19, -15, +46 and +69 were identified in activated T cells. On the basis of these results, it is proposed that 150-kDa ADAR1 gene expression is selectively induced in T cells by anti-CD3-epsilon and anti-CD28 stimulation and that it may play a role in site-selective editing of gene transcripts and in altering the functions of several gene products of T cells during activation and proliferation.

Altered editing in RNA editing adenosine deaminase ADAR2 gene transcripts of systemic lupus erythematosus T lymphocytes.

Adenosine Deaminases that act on RNA (ADARs) edit gene transcripts through site-specific conversion of adenosine to inosine by hydrolytic deamination at C6 of the adenosine. ADAR2 gene transcripts are substrates for the ADAR1 and ADAR2 enzymes and their expression is regulated by editing at the - 1 and - 2 sites. Our previous experiments demonstrated up-regulation of type I interferon (IFN) inducible 150 kDa ADAR1 in systemic lupus erythematosus (SLE) T cells. In this study we investigate the role of ADAR1 and ADAR2 in editing of ADAR2 gene transcripts of healthy controls and SLE patients. The ADAR2 gene transcripts were cloned into pCR2.1-TOPO vectors. A total of 150 clones from SLE and 150 clones from controls were sequenced. Sequence analysis demonstrated A to I editing at - 1, + 10, + 23 and + 24 in normal T cells. In SLE clones site-selective editing of the - 2 site was observed as a result of type I IFN-inducible 150 kDa ADAR1 expression. These results are confirmed by analysing ADAR2 transcripts of normal T cells activated with type I IFN-alpha. Editing of the + 23 and + 24 sites was decreased in SLE T cells compared to normal controls. In addition to A to G changes, U to C discrepancies were observed in normal and SLE T cells. In SLE cells, positions - 6 and + 30 were frequently edited from U to C compared to normal controls. Taken together, these results demonstrate altered and site-selective editing in ADAR2 transcripts of SLE patients. Based on these results, it is proposed that altered transcript editing contributes to the modulation of gene expression and immune functions in SLE patients.

Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil.

Systemic sclerosis (scleroderma) is a multisystem fibrotic disease that commonly manifests with severe Raynaud's phenomenon and slow-healing cutaneous ulcerations. Reduced nitric oxide levels have been proposed to play a role in the pathogenesis of vascular disease in scleroderma, and therefore sildenafil (which increases nitric oxide levels) is an attractive therapeutic prospect. We describe a patient with limited cutaneous systemic sclerosis who presented with severe nonhealing finger ulcerations despite conventional management, who showed marked improvement with oral sildenafil.