Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions.

Allergist-immunologists face significant challenges as experts in an ever-evolving field of neuroimmunology. Among these challenges is the increasingly frequent need to counsel patients with suspected mast cell activation disorders about perceived comorbidities, which may include hypermobile Ehlers-Danlos syndrome, amplified pain syndrome, fibromyalgia, burning sensation syndromes, migraines, irritable bowel syndrome, and postural orthostatic tachycardia syndrome. Patients may experience comorbid anxiety, panic disorder, and depression associated with disturbed sleep, fatigue, and cognitive impairment that often worsen when their physical symptoms increase in severity. These conditions may mimic mast cell activation disorders and are emotionally taxing for patients and clinicians because they are often accompanied by vague diagnostic courses, perceived unmanageability, social stigma, and significant impairment in quality of life. Combined with relatively poorly researched therapies, it is no surprise that clinicians may feel overwhelmed or find it difficult to provide consistently compassionate care for this population. In this article, we review available therapies for these conditions, which run the gamut from physical therapy to antidepressants to multimodal pain control. We highlight the benefit of multidisciplinary care within the primary care home, which includes an important role by the allergist-immunologist. By outlining simple approaches to initial treatment, we hope to empower clinicians with the tools needed to curb emotional burnout and embrace this patient population with compassion.

Nathan Zvaifler.

Nathan Zvaifler was one of the most original thinkers in the field of rheumatology contributing to modern understanding of the role of complement in mediating inflammation and the role of synoviocytes in the pathogenesis of the destructive changes of rheumatoid arthritis. His clinical acumen was unparalleled and his students are still in awe of the breadth of his knowledge.

Addressing Competency in Rheumatology Telehealth Care Delivery.

OBJECTIVE: Telehealth is an essential facet of care delivery for patients with rheumatic diseases. The Association of American Medical College's (AAMC) telehealth competencies (TCs) define the skills required for delivering general telehealth care across the range of clinician experience. In this study, the American College of Rheumatology's (ACR) TCs working group aimed to adapt the AAMC TCs to rheumatology, outlining the skills acquisition unique to rheumatology with a focus on knowledge, skills, and behaviors expected of recent rheumatology fellowship graduates. METHODS: Through a collaborative process, the working group adapted the AAMC TCs to the training structure and practice of rheumatology. The rheumatology TCs underwent peer review among recipients of the Clinician Scholar Educator Award and attendees at the ACR 2021 Convergence conference. RESULTS: The rheumatology TCs define 24 essential skills required for synchronous telehealth care of patients with rheumatic diseases. The working group adapted the AAMC's 20 TCs organized within 6 domains, added 2 skills to the AAMC's domains of patient safety and appropriate use, and data collection and assessment, and created a novel domain of systems-based requirements with 2 competencies. The rheumatology TCs define expected skill levels for recent rheumatology fellowship graduates and experienced rheumatology clinicians. CONCLUSION: The rheumatology TCs represent the first adaptation of the AAMC TCs to subspecialty care, expanding the scope to include rheumatology fellowship graduates and additional domains of rheumatology practice. These competencies can guide curricular innovations and measurements of proficiency in telehealth care delivery among rheumatology trainees and experienced clinicians, enhancing the care provided to patients with rheumatic diseases.

Pachydermodactyly associated with extensive computer gaming: A report of three cases.

Pachydermodactyly is an uncommon, progressive, nontender thickening of the fingers with prominent involvement of the proximal interphalangeal joints. Pachydermodactyly mimics inflammatory arthritis but plain film radiography is normal in this condition. Pachydermodactyly has been previously described in workers performing manual labor. Mechanical stimulation has been identified as a predisposing factor in the majority of cases. We present three cases in adolescent males arising in association with excessive computer gaming.

Novel presentations of periodic fever syndromes: Discrepancies between genetic and clinical diagnoses.

OBJECTIVE: The Periodic fever syndromes (PFS) are a group of disorders of the innate immune system. We investigated patients diagnosed with PFS at the Dartmouth Hitchcock Pediatric Rheumatology Clinic. METHODS: Case acquisition was performed by reviewing ICD 9/10 coded records for familial Mediterranean fever (ICD 9 277.31), laboratory test records for PFS genetic screening, and clinic records between 1/1/2011 and 12/31/2017. RESULTS: Twenty-seven cases had clinical evaluations including PFS genetic screening. Clinical diagnoses included familial Mediterranean fever (FMF) (10 cases), Muckle-Wells (2 cases), tumor necrosis factor receptor associated periodic syndrome (TRAPS) (4 cases), hyper IgD syndrome (HIDS) (1 case), Crohn's Disease (1 case), systemic onset juvenile idiopathic arthritis (SoJIA) (1 case), fever of unknown origin (FUO) (1 case), periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) (6 cases), and cold-induced urticaria (1 case). Fifteen cases were associated with a genetic cause. Seven of the 10 FMF cases were confirmed genetically and were either heterozygous or compound heterozygotes. Both cases of Muckle-Wells had either a compound heterozygote for CIAS 1 or a NOD gene mutation. Both TRAPS cases presented atypically with patients developing systemic lupus erythematosus (SLE) or being asymptomatic. Two patients had novel syndromes. One FMF patient had a TRNT1 gene mutation who responded to intravenous immunoglobulin (IVIg) and colchicine after failing multiple treatments. The other had SoJIA with a LPIN 2 gene mutation but responded to colchicine. Only one of the 15 genetically proven cases had classical presentation and genetics (HIDS secondary to a mevalonate kinase (MVK) gene mutation). CONCLUSION: PFS screening was helpful in over half of the cases to develop therapeutic treatment plans. Given the atypical clinical presentations seen with genetically determined PFS, extensive genetic testing is indicated for all patients presenting with a PFS, excluding classical PFAPA syndrome.

Are All Biologics the Same? Optimal Treatment Strategies for Patients With Early Rheumatoid Arthritis: Systematic Review and Indirect Pairwise Meta-Analysis.

BACKGROUND: The use of biologic agents has revolutionized the treatment of rheumatoid arthritis (RA). However, there is much uncertainty about whether any agent may be preferable. PURPOSE: The aim of the study was to evaluate the comparative efficacy of biologic agents with a disease-modifying antirheumatic drug (DMARD) in RA patients without prior exposure to a DMARD, that is, DMARD naive. METHODS: MEDLINE, Cochrane, and Clinicaltrials.gov were searched from 1990 to August 2013 for randomized controlled trials comparing biologic agents in conjunction with a DMARD and DMARDs alone in DMARD (methotrexate [MTX])-naive RA patients. Information on patient characteristics, disease duration, and the American College of Rheumatology (ACR) 20/50/70/90 response rates after 52 weeks was extracted. RESULTS: Six randomized controlled trials totaling 9 study arms fulfilled the inclusion criteria. Data were analyzed by direct and indirect pairwise comparisons of 2 drugs against a common comparator. In the direct comparison, all 6 biologic therapies were associated with significantly higher likelihood of achieving an ACR20 compared with MTX alone (mean ORs, 1.43-2.99). For ACR50 and ACR70, all biologic agents except golimumab showed statistically significant mean ORs of 1.31 to 2.52 (ACR20) and 1.79 to 2.59 (ACR50). At ACR90, abatacept 10 mg/kg, adalimumab 40 mg, and rituximab 500 and 1000 mg were significantly better compared with MTX (mean ORs 1.92-2.89). The indirect comparison for ACR20 showed etanercept 50 mg significantly favored against adalimumab 40 mg (OR, 1.05-3.34), golimumab 50 mg (OR, 1.16-4.07), infliximab 3 mg/kg (OR, 1.21-3.61), and infliximab 6 mg/kg (OR, 1.02-3.06). At ACR50, etanercept 50 mg and rituximab 1000 mg showed significantly higher ORs compared with golimumab 100 mg at ORs 1.06 to 3.42 and ORs 1.07 to 3.42, respectively. No significant differences were observed in the biologic agents for indirect pairwise comparisons at ACR70 and ACR90.Lack of head-to-head clinical trial data directly comparing biologic agents makes indirect meta-analysis the only substitute. Safety and cost of these agents were not evaluated. Only a small number of trials could be evaluated because of the strict inclusion criteria required for an indirect meta-analysis. Unmeasured confounders could contribute to trial heterogeneity. The data on golimumab were difficult to reconcile with the other trials because of methodological differences. CONCLUSIONS: Overall, biological agents in conjunction with a DMARD performed similarly in the settings evaluated. However, there were some statistically significant differences. Etanercept 50 mg appears superior to adalimumab 40 mg, golimumab 50 mg, and infliximab 3 and 6 mg/kg at ACR20. Rituximab 1000 mg and etanercept 50 mg appeared superior to golimumab 100 mg at ACR50 in DMARD-naive patients. No agent was superior to all others at each ACR level.

Treatment of asymptomatic hyperuricemia and prevention of vascular disease: a decision analytic approach.

OBJECTIVE: Elevated serum urate may be associated with an increase in cardiovascular (CV) disease. Treating asymptomatic hyperuricemia with urate-lowering drugs such as allopurinol may reduce CV events. We designed a model to simulate the effect of allopurinol treatment on reducing frequency of CV events in individuals with elevated serum urate. METHODS: A Markov state-transition model was constructed to assess occurrence of vascular events (VE) for 2 treatment strategies: treat all asymptomatic individuals with allopurinol (Treat All) and treat only if symptomatic (Treat Symptomatic). The model simulated a hypothetical cohort of 50-year-old men with different serum urate concentrations (6-6.9 and 7-7.9 mg/dl) followed over 20 years. Age and sex subgroups were analyzed. Model inputs were derived from current literature. The main outcome measures were mean number of VE and mean number of deaths from VE. RESULTS: For 50-year-old men with serum urate 6.0-6.9 mg/dl, individuals in the Treat All strategy have a 30% reduction in the mean number of VE compared to those in the Treat Symptomatic strategy (mean VE: 0.078 vs 0.11), and a 39% reduction in mean number of deaths from VE. At higher serum urate concentrations, treatment is more effective in reducing the mean number of VE and mean number of deaths from VE (38% event, 54% death). Results for women show similar trends. As the cohort ages, treatment has less effect on reducing VE. The number needed to treat to prevent 1 event is 20 (men, 7.0-7.9 mg/dl). CONCLUSION: The model predicts that treating asymptomatic hyperuricemia with allopurinol is most effective in preventing VE at a serum urate above 7.0 mg/dl in men and 5.0 mg/dl in women.

The lupus family registry and repository.

The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR's effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.

Hyperuricemia and coronary heart disease: a systematic review and meta-analysis.

OBJECTIVE: The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension. METHODS: A systematic review and meta-analysis using a random-effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults. RESULTS: Twenty-six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19-1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03-1.16) for CHD incidence and 1.16 (95% CI 1.01-1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30-2.04). CONCLUSION: Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.

Hyperuricemia and risk of stroke: a systematic review and meta-analysis.

OBJECTIVE: To assess the association between hyperuricemia and risk of stroke incidence and mortality because hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but, to date, results from observational studies are conflicting. METHODS: A systematic review and meta-analysis were conducted. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Prospective cohort studies were included only if they contained data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated. RESULTS: A total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence (6 studies; RR 1.41, 95% confidence interval [95% CI] 1.05, 1.76) and mortality (6 studies; RR 1.36, 95% CI 1.03, 1.69) in our meta-analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence (4 studies; RR 1.47, 95% CI 1.19, 1.76) and mortality (6 studies; RR 1.26, 95% CI 1.12, 1.39). The pooled estimate of multivariate RRs did not differ significantly by sex. CONCLUSION: Hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.

Optimal treatment of knee monarthritis in juvenile idiopathic arthritis: a decision analysis.

OBJECTIVE: To identify the optimal initial treatment strategy for knee monarthritis in juvenile idiopathic arthritis (JIA) using a decision model and parents' preferences. METHODS: We utilized a decision analysis model with Markov states and a 6-month multi-attribute outcome with 7 dimensions pertinent to the treatment decision. The 3 most common treatment strategies for knee monarthritis were compared: nonsteroidal antiinflammatory drugs (NSAIDs) only, NSAID trial followed by intraarticular corticosteroid injection (IACI) if arthritis was not resolved after 2 months, and initial IACI. Probability estimates for the efficacy and adverse effects of NSAIDs and IACIs were derived from a systematic review of the literature. Parents' preferences for the 7 dimensions of the multi-attribute outcome were elicited by a unique hybrid of the time tradeoff and magnitude estimation techniques. These preferences were then combined with the outcomes of the decision analysis to determine an individual's preferred treatment. RESULTS: The NSAID trial strategy may avert IACIs in some patients, but at a cost of continued active arthritis. The number of patients that need to be treated with the NSAID trial strategy to avoid a single IACI compared with the initial IACI strategy is 3.8 with an expected additional cost of 6.7 months of active arthritis. Of the 12 parent subjects, 11 (92%) preferred the initial IACI strategy and 1 preferred the NSAID-only strategy. These preferences were not sensitive to model assumptions or probability estimates. CONCLUSION: Initial IACI appears to be the optimal treatment strategy for knee monarthritis in JIA.

Variation in the initial treatment of knee monoarthritis in juvenile idiopathic arthritis: a survey of pediatric rheumatologists in the United States and Canada.

OBJECTIVE: To characterize variations in initial treatment for knee monoarthritis in the oligoarthritis subtype of juvenile idiopathic arthritis (OJIA) by pediatric rheumatologists and to identify patient, physician, and practice-specific characteristics that are associated with treatment decisions. METHODS: We mailed a 32-item questionnaire to pediatric rheumatologists in the United States and Canada (n = 201). This questionnaire contained clinical vignettes describing recent-onset chronic monoarthritis of the knee and assessed physicians' treatment preferences, perceptions of the effectiveness and disadvantages of nonsteroidal antiinflammatory drugs (NSAID) and intraarticular corticosteroid injections (IACI), proficiency with IACI, and demographic and office characteristics. RESULTS: One hundred twenty-nine (64%) questionnaires were completed and returned. Eighty-three percent of respondents were board certified pediatric rheumatologists. Respondents' treatment strategies for uncomplicated knee monoarthritis were broadly categorized: initial IACI at presentation (27%), initial NSAID with contingent IACI (63%), and initial NSAID with contingent methotrexate or sulfasalazine (without IACI) (10%). Significant independent predictors for initial IACI were believing that IACI is more effective than NSAID, having performed > 10 IACI in a single patient at one time, and initiating methotrexate via the subcutaneous route for OJIA. Predictors for not recommending initial or contingent IACI were believing that the infection risk of IACI is significant and lacking comfort with performing IACI. CONCLUSION: There is considerable variation in pediatric rheumatologists' initial treatment strategies for knee monoarthritis in OJIA. This variation is primarily associated with perceptions of medication effectiveness and proficiency with IACI. Further studies are warranted to clarify the optimal treatment of OJIA.

Medicare coverage of tumor necrosis factor alpha inhibitors as an influence on physicians' prescribing behavior.

BACKGROUND: Rheumatoid arthritis is a chronic debilitating disease that affects 1% of the population. Tumor necrosis factor alpha inhibitors, such as etanercept and infliximab, have revolutionized the treatment of rheumatoid arthritis by averting disability but at great financial expense, generally borne by third-party payors. Prior to implementation of the Medicare Modernization Act, Medicare reimbursed for the infusion drug infliximab but not for the self-injectable drug etanercept. To determine the impact of this differential Medicare drug coverage on physicians' prescribing behavior in clinical practice, we analyzed patterns of prescribing etanercept and infliximab for patients with rheumatoid arthritis who had public insurance compared with those who had private insurance. METHODS: We conducted an observational cohort study of 1663 patients with rheumatoid arthritis newly prescribed etanercept or infliximab after enrollment in the National Databank for Rheumatic Diseases. Univariate and multivariable analyses of patient demographic and disease characteristics were conducted to characterize predictors of the biologic drug prescribed. RESULTS: Treatment groups who received etanercept and infliximab differed in 6 of 8 demographic variables and in 8 of 10 disease variables. However, stratification by type of insurance reduced many of these differences. In multivariable analyses, type of insurance plan and demographic factors were strong predictors of differential prescribing of etanercept compared with prescribing of infliximab, whereas disease characteristics generally were not. Patients with public insurance were 30% more likely to receive infliximab than those who were privately insured (P<.001). CONCLUSIONS: Public insurance predicted prescription of infliximab, reflecting preferential Medicare reimbursement for infusion drugs. Financial considerations are influential in physicians' prescription decisions. Differential drug coverage has an impact on patient care and health care costs because it influences physicians' prescribing behavior.