N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation.

N-myristoyltransferase (NMT) attaches the fatty acid myristate to the N-terminal glycine of proteins to sort them into soluble and membrane-bound fractions. Function of the energy-sensing AMP-activated protein kinase, AMPK, is myristoylation dependent. In rheumatoid arthritis (RA), pathogenic T cells shift glucose away from adenosine tri-phosphate production toward synthetic and proliferative programs, promoting proliferation, cytokine production, and tissue invasion. We found that RA T cells had a defect in NMT1 function, which prevented AMPK activation and enabled unopposed mTORC1 signaling. Lack of the myristate lipid tail disrupted the lysosomal translocation and activation of AMPK. Instead, myristoylation-incompetent RA T cells hyperactivated the mTORC1 pathway and differentiated into pro-inflammatory TH1 and TH17 helper T cells. In vivo, NMT1 loss caused robust synovial tissue inflammation, whereas forced NMT1 overexpression rescued AMPK activation and suppressed synovitis. Thus, NMT1 has tissue-protective functions by facilitating lysosomal recruitment of AMPK and dampening mTORC1 signaling.

Reactivation of Chagas Disease in a Patient With an Autoimmune Rheumatic Disease: Case Report and Review of the Literature.

Reactivation of Chagas disease has been described in immunosuppressed patients, but there is a paucity of literature describing reactivation in patients on immunosuppressive therapies for the treatment of autoimmune rheumatic diseases. We describe a case of Chagas disease reactivation in a woman taking azathioprine and prednisone for limited cutaneous systemic sclerosis (lcSSc). Reactivation manifested as indurated and erythematous cutaneous nodules. Sequencing of a skin biopsy specimen confirmed the diagnosis of Chagas disease. She was treated with benznidazole with clinical improvement in the cutaneous lesions. However, her clinical course was complicated and included disseminated CMV disease and subsequent septic shock due to bacteremia. Our case and review of the literature highlight that screening for Chagas disease should be strongly considered for patients who will undergo immunosuppression for treatment of autoimmune disease if epidemiologically indicated.

Risk of Serious Infection Associated with Agents that Target T-Cell Activation and Interleukin-17 and Interleukin-23 Cytokines.

Co-stimulatory T-cell inhibitors are used in the treatment of rheumatoid arthritis and to prevent rejection of renal transplants. Inhibitors of the intereukin (IL-17) cytokine are indicated for psoriasis, psoriatic arthritis and ankylosing spondylitis and anti- IL-23 drugs for psoriasis. Serious infections occur in 4.2% to 25.0% of co-stimulatory inhibitors and 1.0% to 2.0% with IL-17 or IL-23 inhibitors. Underlying disease, steroid dose greater than 7.5 to 10.0 mg, and comorbidities influence risk in individual patients. Opportunistic infections or reactivation of tuberculosis are rare.

TNF-alpha inhibition for the treatment of cardiac sarcoidosis.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used for treating refractory cardiac sarcoidosis. There is a theoretical risk, however, that these therapies can worsen heart failure, and reports on efficacy and safety are lacking. METHODS: We conducted a retrospective review of all cardiac sarcoidosis patients seen at Stanford University from 2009 to 2018. Data were collected on patient demographics, diagnostic testing, and treatment outcomes. RESULTS: We identified 77 cardiac sarcoidosis patients, of which 20 (26%) received TNF-α inhibitor treatment. The majority were treated for progressive heart failure or tachyarrhythmia, along with worsening imaging findings. All TNF-α inhibitor treated patients demonstrated meaningful benefit, as assessed by changes in advanced imaging, echocardiographic measures of cardiac function, and prednisone use. CONCLUSIONS: A large cohort (n = 77) of cardiac sarcoidosis patients has been treated at Stanford University. Roughly one-fourth of these patients (n = 20) received TNF-α inhibitors. Of these patients, none had worsening heart failure and all saw clinical benefit. These results help support the use of TNF-α inhibitors for the treatment of cardiac sarcoidosis based on real-world evidence and highlight the need for future prospective studies.

Development and validation of a rheumatologist satisfaction with practice scale: The rheumatologist satisfaction scale.

There is a paucity of succinct measures of physician satisfaction. As part of a Performance Improvement Project, we developed and piloted a simple questionnaire to determine rheumatologists satisfaction.Thirty 5 rheumatologists in the academic or private setting were sent opened-ended questions to determine the factors that made them satisfied or dissatisfied with respect to their rheumatology practice. From the responses we formed 14 questions 1 to 10 scale centering on satisfaction and dissatisfaction that was piloted in 30 rheumatologists and subsequently validated in 173 rheumatologists within the US and Latin America.Our combined sample included 173 rheumatologists (55 English and 118 Spanish-speaking respondents). The mean satisfaction for the combined sample was 6.92 (standard deviation=1.1, range 4.08-9.62). The strongest contributors to physician satisfaction were "Seeing interesting and challenging cases" (8.6 ±â€Š1.5) and "The ability to make a difference in patient's life" as well as "Establishing long term relationship with patients" (8.39 ±â€Š1.5). The strongest contributors to physician dissatisfaction were "Getting inappropriate referrals not in the scope of practice" (4.3 ±â€Š2.13) and "Time spent on documentation" (4.5 ±â€Š2.59). The scale had good reliability, relatively normal distribution, and little or no redundancy among items.A simple and practical questionnaire to measure physician satisfaction, in particular rheumatologists satisfaction, was developed, piloted and successfully validated on a predominately academic sample of rheumatologists within the US and Latin America. This scale will serve as a means to identifying potential barriers to the implementation of performance improvement projects in the practice of Rheumatology.

Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study.

BACKGROUND: Controversy has surrounded the question about whether high-dose rofecoxib increases or naproxen decreases the risk of serious coronary heart disease. We sought to establish if risk was enhanced with rofecoxib at either high or standard doses compared with remote non-steroidal anti-inflammatory drug (NSAID) use or celecoxib use, because celecoxib was the most common alternative to rofecoxib. METHODS: We used data from Kaiser Permanente in California to assemble a cohort of all patients age 18-84 years treated with a NSAID between Jan 1, 1999, and Dec 31, 2001, within which we did a nested case-control study. Cases of serious coronary heart disease (acute myocardial infarction and sudden cardiac death) were risk-set matched with four controls for age, sex, and health plan region. Current exposure to cyclo-oxygenase 2 selective and non-selective NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib. FINDINGS: During 2302029 person-years of follow-up, 8143 cases of serious coronary heart disease occurred, of which 2210 (27.1%) were fatal. Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses), 1.59 (95% CI 1.10-2.32, p=0.015); for rofecoxib 25 mg/day or less, 1.47 (0.99-2.17, p=0.054); and for rofecoxib greater than 25 mg/day, 3.58 (1.27-10.11, p=0.016). For naproxen versus remote NSAID use the adjusted odds ratio was 1.14 (1.00-1.30, p=0.05). INTERPRETATION: Rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious coronary heart disease.

A cohort study of systemic and local complications of toe prostheses.

We investigated the role of toe implants in systemic disease and evaluated local complications after foot surgery. Information was obtained from the medical records of Kaiser Permanente (northern California) patients who had undergone toe surgery between 1979 and 1988. Computerized hospitalization records were used to identify patients with toe implants (N=814) and matched controls with foot surgery not involving implants (N=837). Brain cancer and alopecia areata occurred more among implant patients, whereas dysphagia occurred more among nonimplant patients. A larger proportion of implant patients were diagnosed with pain and swelling, tendonitis, and osteomyelitis or periostitis. Nonimplant patients were more often diagnosed with derangement of foot or ankle and delayed postoperative healing. We did not find a general association between implants and connective tissue diseases.

Incidence and prevalence of juvenile idiopathic arthritis among children in a managed care population, 1996-2009.

OBJECTIVE: Few studies based in well-defined North American populations have examined the occurrence of juvenile idiopathic arthritis (JIA), and none has been based in an ethnically diverse population. We used computerized healthcare information from the Kaiser Permanente Northern California membership to validate JIA diagnoses and estimate the incidence and prevalence of the disease in this well-characterized population. METHODS: We identified children aged ≤ 15 years with ≥ 1 relevant International Classification of Diseases, 9th edition, diagnosis code of 696.0, 714, or 720 in computerized clinical encounter data during 1996-2009. In a random sample, we then reviewed the medical records to confirm the diagnosis and diagnosis date and to identify the best-performing case-finding algorithms. Finally, we used the case-finding algorithms to estimate the incidence rate and point prevalence of JIA. RESULTS: A diagnosis of JIA was confirmed in 69% of individuals with at least 1 relevant code. Forty-five percent were newly diagnosed during the study period. The age- and sex-standardized incidence rate of JIA per 100,000 person-years was 11.9 (95% CI 10.9-12.9). It was 16.4 (95% CI 14.6-18.1) in girls and 7.7 (95% CI 6.5-8.9) in boys. The peak incidence rate occurred in children aged 11-15 years. The prevalence of JIA per 100,000 persons was 44.7 (95% CI 39.1-50.2) on December 31, 2009. CONCLUSION: The incidence rate of JIA observed in the Kaiser Permanente population, 1996-2009, was similar to that reported in Rochester, Minnesota, USA, but 2 to 3 times higher than Canadian estimates.

1st Proceedings of the European American Rheumatology Association Immunotherapy in Rheumatic Diseases--Science and Clinical Practice, February 25-28, 2009--Sonoma, CA, USA.

Evidence is often insufficient to answer questions in clinical practice. In an effort to fill these "gaps" between clinical investigation and daily conundrums, practicing rheumatologists use experience, logic, pathophysiology, individual patients and collegial consultation. In order to capture this science of clinical practice, a group of European and American clinicians and clinician investigators worked in investigative teams or Study Sections, each devoted to utilizing the science of clinical practice to address and critical clinical questions in Rheumatoid Arthritis, Imaging, Vasculitis and Gout that are inadequately answered by published evidence. Conclusions were summarized by a method of debate and discussion. It is anticipated that by defining uncertainty and using such an analytical and experiential method, rheumatologists can assist themselves in solving problems in their daily practice.

Short-term and long-term success of electrical cardioversion in atrial fibrillation in managed care system.

BACKGROUND: Initial success of electrical cardioversion (ECV) of atrial fibrillation (AF) has been reported in several studies as 50%-90%, of which only 50% patients remain in sinus rhythm (SR) at the end of one year. We conducted this study to see if outcomes of other trials are applicable in managed care setting. METHODS: We conducted a retrospective study in 370 consecutive patients who underwent ECV for AF. They were reviewed for initial outcome of ECV and recurrence of AF after a successful ECV, with and without prophylactic antiarrhythmic drugs. RESULTS: Initial success of ECV for AF was 65.7%. At one year, 47% remained in SR. AF for

Myocardial Infarction and Its Association with the Use of Nonselective NSAIDs: A Nested Case-Control and Time-to-Event Analysis.

OBJECTIVE: In April 2005, the US Food and Drug Administration issued a public health advisory warning to health care clinicians about the cardiovascular (CV) safety of nonsteroidal anti-inflammatory drugs (NSAIDs). Although the warning about cyclooxygenase-2 selective NSAIDs was anticipated, little data exists about the CV safety of nonselective NSAIDs. We analyzed data from a group of NSAID users to determine if specific nonselective agents were associated with an increased risk of myocardial infarctions (MIs) and sudden cardiac death (SCD). DESIGN: A nested case-control design was used to study NSAID users ages 18 to 84 years. Cases were defined by a hospital admission for MI or an out-of-hospital SCD. Study control subjects were matched for age, sex, current Kaiser Permanente membership, and geographic location (Northern or Southern California). Odds ratios (OR) were estimated using conditional logistic regression. RESULTS: Our base population included 1,394,764 NSAID users. From this population we identified 8143 cases and 31,496 matched study control subjects. The median time to event was <100 days for all NSAIDs. Two nonselective NSAIDs were associated with increased odds of adverse CV outcomes: indomethacin (OR, 1.27; 95% confidence interval, 1.04-1.56) and naproxen (OR, 1.14; 95% confidence interval, 1.00-1.30). CONCLUSION: Our results suggest that some nonselective NSAIDs are associated with an increased risk of MI and SCD. We found the increased risk to be small compared with the risk associated with rofecoxib. Cardiovascular events occurred early in therapy. Caution is warranted with some nonselective NSAIDs, especially those for which other studies have found evidence of risk.

Athletes, nonsteroidal anti-inflammatory drugs, coxibs, and the gastrointestinal tract.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common self-administered and prescribed drugs taken in the United States. From 30% to 50% of those using these medications experience some degree of gastrointestinal (GI) side effect. Independent of NSAID use, a majority of athletes suffer GI symptoms, most of which has been documented in endurance athletes. Studies of NSAID use in patients with chronic osteo- and rheumatoid arthritis have defined a set of factors that can identify those who are at higher risk of serious GI events. Using such a model, clinicians can choose either to discontinue NSAID use, or prescribe a lower-risk NSAID or coxib (rofecoxib, celecoxib), prophylaxis with misoprostol, or proton pump inhibitor. Coxibs have been designed to decrease GI ulceration and bleeding by selective inhibition of cyclooxygenase-2, and offer an option for patients at high risk of GI hemorrhage. There are data suggesting that rofecoxib may be associated with an increased risk of myocardial infarction, and until further data are available, caution should be used when considering its prescription to patients at high risk of cardiovascular events.

Self-care and the doctor-patient relationship.

OBJECTIVES: An important factor contributing to the steep rise in health care costs in the late 1960s was a reversal from the predominance of acute illness to that of chronic disease. Beginning with the philosophy of Illich and Levin, and the practical instruments of Fries, Sehnert, Vickery, and Ferguson, a new movement in patient self-care emerged. However, such programs were not integrated into organized medical care plans and though theoretically attractive had not yet proven to improve health or decrease costs. METHODS: The contributions to the self-care movement made under the intellectual guidance of Halsted Holman and the relevant literature produced are reviewed. RESULTS: While caring for chronic rheumatic diseases, Halsted Holman discovered that patient self-report was a more powerful predictor of outcome than were traditional biologic measures such as anti-DNA antibodies. Realizing the role that patient knowledge of their own disease course might play, he developed the Arthritis Self-Management course, a lay-led self-care program emphasizing patient participation. Holman and colleagues next elucidated the pivotal importance of Bandura's theory of self-efficacy in the improved patient outcomes initially observed. These self-care techniques were woven into the structure of the Midpeninsula Health Service, showing for the first time reductions in subsequent office visits and enhanced quality. In partnership with Kaiser Health Plan, these techniques showed improvements in self-efficacy health behaviors, status, and use in a randomized trial of more than 1,000 patients. CONCLUSION: Halsted Holman and colleagues have played a seminal role in the translation of academic self-care theory into community practice.