CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

OBJECTIVES: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures. METHODS: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables. RESULTS: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020). CONCLUSIONS: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Enhancing rheumatology education during the COVID-19 pandemic.

During the COVID-19 pandemic, rheumatology educational programs around the world, face the daunting challenge of maintaining education for their trainees. Reduced in-person clinic exposures and social distancing requirements have significantly affected trainee education. Similar to programs around the USA, in early March 2020, our program was faced with an urgent need to pivot both our clinical and educational programs to virtual platforms. Within these limitations, we harnessed innovative educational models and restructured our curriculum to ensure adequate clinical and didactic exposure. We divided trainee's clinical rotations into four blocks, which include Inpatient consult service, Outpatient in-person and procedure clinics, Telehealth Clinics and Research/Elective week. By assigning specific rotations, we were able to ensure fellows were seeing adequate numbers of patients both through telemedicine and inperson while ensuring we complied with social distancing requirements. We further were able to ensure that trainee hands-on procedure training was not compromised. Acknowledging challenges presented by the COVID-19 pandemic and learner engagement in virtual environment, we designed an innovative educational portfolio. Utilizing synchronous and asynchronous learning methods, we have developed multiple complementary educational initiatives including: Rocket Rheumatology, Board Games, At the Elbow, Radiology Reading Rheum, Ultrasound Buddies, The History Rheum, and Rapid-Fire Journal Club. Virtual learning methods will become a cornerstone of medical education moving forwards. The GW Division of Rheumatology has rapidly incorporated innovative educational tools into our curriculum. Our approach will help Rheumatology training programs across the globe enhance rheumatology training.

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile.

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated. RESULTS: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression. CONCLUSIONS: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Co-occurrence of Anaerobes in Human Chronic Wounds.

Chronic wounds are wounds that have failed to heal after 3 months of appropriate wound care. Previous reports have identified a diverse collection of bacteria in chronic wounds, and it has been postulated that bacterial profile may contribute to delayed healing. The purpose of this study was to perform a microbiome assessment of the Wound Healing and Etiology (WE-HEAL) Study cohort, including underlying comorbidities less commonly studied in the context of chronic wounds, such as autoimmune diseases, and investigate possible relationships of the wound microbiota with clinical healing trends. We examined chronic wound specimens from 60 patients collected through the WE-HEAL Study using 16S ribosomal RNA gene sequencing. A group of co-occurring obligate anaerobes was identified from taxonomic analysis guided by Dirichlet multinomial mixtures (DMM) modeling. The group includes members of the Gram-positive anaerobic cocci (GPAC) of the Clostridia class (i.e., Anaerococcus, Finegoldia, and Peptoniphilus) and additional strict anaerobes (i.e., Porphyromonas and Prevotella). We showed that the co-occurring group of obligate anaerobes not only co-exists with commonly identified wound species (such as Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas, Corynebacterium, and Streptococcus), but importantly, they could also predominate the wound microbiota. Furthermore, examination of clinical comorbidities of the WE-HEAL specimens showed that specific obligate and facultative anaerobes were significantly reduced in wounds presented with autoimmune disease. With respect to future healing trends, no association with the wound microbiome community or the abundance of individual wound species could be established. In conclusion, we identified a co-occurring obligate anaerobic community type that predominated some human chronic wounds and underrepresentation of anaerobes in wounds associated with autoimmune diseases. Possible elucidation of host environments or key factors that influence anaerobe colonization warrants further investigation in a larger cohort.

Inherent differences in keratinocyte function in hidradenitis suppurativa: Evidence for the role of IL-22 in disease pathogenesis.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1-4% of the population. Defective keratinocyte function has been postulated to play a role in HS pathogenesis. Using an in vitro scratch assay, differences between normal, HS, and chronic wound (CW) keratinocytes were evaluated. Normal keratinocytes exhibited faster scratch closure than HS or CW, with normal samples showing 93.8% closure at 96 hours compared to 80.8% in HS (p = 0.016) and 71.5% in CW (p = 0.0012). The keratinocyte viability was similar in normal and HS (91.12 ± 6.03% and 86.55 ± 3.28%, respectively, p = 0.1583), but reduced in CW (72.34 ± 13.12%, p = 0.0138). Furthermore, apoptosis measured by annexin V/propidium iodide, was higher in CW keratinocytes (32.10 ± 7.29% double negative cells compared to 68.67 ± 10.37% in normal and 55.10 ± 9.46% in HS, p = 0.0075). Normal keratinocytes exhibited a significantly higher level of IL-1α (352.83 ± 42.79 pg/ml) compared to HS (169.96 ± 61.62 pg/ml) and CW (128.23 ± 96.61 pg/ml, p = 0.004). HS keratinocytes exhibited significantly lower amounts of IL-22 (8.01 pg/ml) compared to normal (30.24 ± 10.09 pg/ml) and CW (22.20 ± 4.33 pg/ml, p = 0.0008), suggesting that defects in IL-22 signaling may play a role in HS pathogenesis. These findings support intrinsic differences in keratinocyte function in HS which cannot be attributed to reduced keratinocyte viability or increased apoptosis.

Relationship between opioid treatment and rate of healing in chronic wounds.

Opioids are routinely used analgesics in patients with chronic wounds; however the impact of opioid exposure on wound healing is poorly understood. The purpose of this study was to investigate the association between opioid exposure and wound outcome in the Wound Etiology and Healing study. This longitudinal observational study was conducted on 450 subjects enrolled in the Wound Etiology and Healing biorepository. Data were collected prospectively including baseline characteristics, pain score, longitudinal opioid exposure, and total wound surface area (tWSA). Data were analyzed using static multivariate models, fixed-effects mixed models, and time to event analysis. Using fixed-effects models, opioid dose was significantly associated with tWSA after accounting for the effects of pain score and baseline co-variates (p < 0.0001). For each 1-unit increase in ln(opioid dose + 1) the ln(tWSA + 1) increased by 0.16 units (95% confidence interval 0.13-0.19, p < 0.0001). Visits where opioids were present had ln(tWSA + 1) 0.48 units larger (95% confidence interval 0.38-0.58, p < 0.0001) than visits with no opioid exposure. Using time-to-event analysis, patients who never received opioids healed faster than those who received opioids (log-rank chi-square 11.00, p  = 0.0009). Using Cox regression analysis, patients with mean opioid dose ≥10 mg were significantly less likely to heal than those with no opioid (HR 0.67 [0.49-0.91], p = 0.011) after adjusting for wound size. Patients with opioid dose >0 to <10 mg had a similar hazard of not healing as those with no opioid exposure (HR 0.88 [0.65-1.19], p = 0.40). In conclusion, opioid analgesics are commonly prescribed to patients with chronic wounds; however, the data presented suggest that opioid exposure is associated with reduced likelihood of healing in patients with chronic wounds. Whether this is a causal relationship will require further study.

Interferon-gamma (IFN-γ) is Elevated in Wound Exudate from Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic recurrent inflammatory disease of apocrine glands which affects 1-4% of young adults. The purpose of this study was to investigate inflammatory cytokines in effluent from HS lesions and to identify potential local drivers of inflammation in HS. Wound fluid specimens from HS patients (n = 8) and age-matched chronic wound patients (n = 8) were selected for analysis. The hidradenitis suppurativa score (HSS) was used to determine the extent of HS activity. Cytokine analysis was conducted using Meso Scale Discovery cytokine and proinflammatory panels. Interferon-gamma (IFN-γ) was significantly elevated in the HS effluent compared to chronic wounds (1418 ± 1501 pg/ml compared to 102.5 ± 138 pg/ml, p = 0.027). HS effluent also had significantly higher levels of tumor necrosis factor-ß (TNF-ß) (9.24 ± 7.22 pg/ml compared to 1.65 ± 2.14 pg/ml, p = 0.03). There was no significant difference in any other cytokines. There was no significant difference in demographics in the HS compared to chronic wound cohorts. Mean HSS in the HS cohort was 68.88 (SD ± 41.45). In this proof-of-concept pilot study, IFN-γ was significantly elevated in HS effluent. TNF-ß/LT-α levels were also elevated in HS, although the levels were more modest. Further studies should focus on molecular drivers of tissue injury in HS and the relationship between HS effluent cytokine profile and disease activity.

Electrochemical detection of Pseudomonas in wound exudate samples from patients with chronic wounds.

In clinical practice, point-of-care diagnostic testing has progressed rapidly in the last decade. For the field of wound care, there is a compelling need to develop rapid alternatives for bacterial identification in the clinical setting, where it generally takes over 24 hours to receive a positive identification. Even new molecular and biochemical identification methods require an initial incubation period of several hours to obtain a sufficient number of cells prior to performing the analysis. Here we report the use of an inexpensive, disposable electrochemical sensor to detect pyocyanin, a unique, redox-active quorum sensing molecule released by Pseudomonas aeruginosa, in wound fluid from patients with chronic wounds enrolled in the WE-HEAL Study. By measuring the metabolite excreted by the cells, this electrochemical detection strategy eliminates sample preparation, takes less than a minute to complete, and requires only 7.5 µL of sample to complete the analysis. The electrochemical results were compared against 16S rRNA profiling using 454 pyrosequencing. Blind identification yielded 9 correct matches, 2 false negatives, and 3 false positives giving a sensitivity of 71% and specificity of 57% for detection of Pseudomonas. Ongoing enhancement and development of this approach with a view to develop a rapid point-of-care diagnostic tool is planned.

Outcomes After Combined Radical Resection and Targeted Biologic Therapy for the Management of Recalcitrant Hidradenitis Suppurativa.

BACKGROUND: Trials demonstrating the efficacy of biologic therapy for moderate to severe hidradenitis suppurativa (HS) have inspired new multidisciplinary treatment strategies. We present our experience with combined biologic and surgical therapy for recalcitrant HS. METHODS: Between 2011 and 2014, 21 patients (57 cases) with Hurley Stage III HS underwent radical resection with delayed primary closure alone, or in combination with adjuvant biologic therapy. Demographic data, treatment regimen, outcomes, and complications were retrospectively reviewed for all cases. RESULTS: Eleven patients underwent combined surgical and biologic therapy, whereas radical resection alone was performed in 10 patients. The average soft tissue deficit, before closure, for the combined and surgery-only patients was 56 cm and 48.5 cm, respectively (P = 0.66). Biologic agents including infliximab (n = 8) and ustekinumab (n = 3) were initiated 2 to 3 weeks after closure and were continued for an average of 10.5 months. Recurrence was noted in 19% (4/29) and 38.5% (10/26) of previously treated sites for combined and surgery-only patients (P < 0.01). For the combined cohort, the disease-free interval was approximately 1 year longer on average (P < 0.001); however, this difference was reduced to 4.5 months when considering time to recurrence after cessation of biologic therapy (P = 0.09). New disease developed in 18% (2/11) and 50% (5/10) of combined and surgery-only patients, respectively (P < 001). No adverse events were noted among patients who received biologic therapy. CONCLUSIONS: Lower rates of recurrence and disease progression, as well as a longer disease-free interval may be achieved with the use of adjuvant biologic therapy after radical resection for recalcitrant HS.

Postoperative wound dehiscence: Predictors and associations.

The Agency for Healthcare Research and Quality patient safety indicators (PSI) were developed as a metric of hospital complication rates. PSI-14 measures postoperative wound dehiscence and specifically how often a surgical wound in the abdominal or pelvic area fails to heal after abdominopelvic surgery. Wound dehiscence is estimated to occur in 0.5-3.4% of abdominopelvic surgeries, and carries a mortality of up to 40%. Postoperative wound dehiscence has been adopted as a surrogate safety outcome measure as it impacts morbidity, length of stay, healthcare costs and readmission rates. Postoperative wound dehiscence cases from the Nationwide Inpatient Sample demonstrate 9.6% excess mortality, 9.4 days of excess hospitalization and $40,323 in excess hospital charges relative to matched controls. The purpose of the current study was to investigate the associations between PSI-14 and measurable medical and surgical comorbidities using the Explorys technology platform to query electronic health record data from a large hospital system serving a diverse patient population in the Washington, DC and Baltimore, MD metropolitan areas. The study population included 25,636 eligible patients who had undergone abdominopelvic surgery between January 1, 2008 and December 31, 2012. Of these cases, 786 (2.97%) had postoperative wound dehiscence. Patient-associated comorbidities were strongly associated with PSI-14, suggesting that this indicator may not solely be an indicator of hospital safety. There was a strong association between PSI-14 and opioid use after surgery and this finding merits further investigation.

Late failure of a split-thickness skin graft in the setting of homozygous factor V Leiden mutation: a case report and correlative animal model from the Wound Etiology and Healing (WE-HEAL) study.

We present the case of a 53-year-old Caucasian male smoker with remote history of left lower extremity deep venous thrombosis (DVT) and a strong family history of thrombosis, who presented to the Center for Wound Healing at MedStar Georgetown University Hospital with spontaneous left leg ulceration. Prothrombotic evaluation showed homozygosity for the factor V Leiden (FVL) mutation. Therapeutic anticoagulation was commenced with warfarin (Coumadin®) and the patient underwent successful debridement and Apligraf® followed by split-thickness skin graft (STSG) of two wounds. He had an uneventful postoperative course and on the 27th postoperative day the grafts were 95% intact. However, by postoperative day 41 there was 10% graft loss, and over the subsequent 2 weeks both grafts necrosed. On further questioning, it transpired that the patient had discontinued his warfarin on postoperative day 37 because he thought that it was no longer necessary. The patient is enrolled in the Wound Etiology and Healing (WE-HEAL) study, and at the time of the original graft, residual skin fragments from the STSG were transplanted onto a nude mouse for development of an animal model of wound healing. The mouse graft was successful and was harvested at postoperative day 87 for pathological examination. We review the mechanisms by which prothrombotic states, particularly FVL mutation, can contribute to skin graft failure and delayed wound healing. This case highlights the importance of considering prothrombotic conditions in patients with spontaneous leg ulcerations and the impact of therapeutic anticoagulation on healing. It further allows us to demonstrate the efficacy of the animal model in which residual fragments of STSG tissue are utilised for transplant onto nude mice for manipulation in the laboratory.

Utility of a human-mouse xenograft model and in vivo near-infrared fluorescent imaging for studying wound healing.

To study the complex cellular interactions involved in wound healing, it is essential to have an animal model that adequately mimics the human wound microenvironment. Currently available murine models are limited because wound contraction introduces bias into wound surface area measurements. The purpose of this study was to demonstrate utility of a human-mouse xenograft model for studying human wound healing. Normal human skin was harvested from elective abdominoplasty surgery, xenografted onto athymic nude (nu/nu) mice, and allowed to engraft for 3 months. The graft was then wounded using a 2-mm punch biopsy. Wounds were harvested on sequential days to allow tissue-based markers of wound healing to be followed sequentially. On the day of wound harvest, mice were injected with XenoLight RediJect cyclooxygenase-2 (COX-2) probe and imaged according to package instructions. Immunohistochemistry confirms that this human-mouse xenograft model is effective for studying human wound healing in vivo. Additionally, in vivo fluorescent imaging for inducible COX-2 demonstrated upregulation from baseline to day 4 (P = 0·03) with return to baseline levels by day 10, paralleling the reepithelialisation of the wound. This human-mouse xenograft model, combined with in vivo fluorescent imaging provides a useful mechanism for studying molecular pathways of human wound healing.

Treatment of early diffuse systemic sclerosis skin disease.

Diffuse systemic sclerosis carries a high morbidity and mortality. The Prospective Registry of Early Systemic Sclerosis (PRESS), a multicentre incident cohort study of patients with early diffuse cutaneous systemic sclerosis, has the goal of advancing the understanding of disease pathogenesis and identifying novel biomarkers. In this review, PRESS investigators discuss the evidence pertaining to the more commonly used treatments for early diffuse SSc skin disease including methotrexate, mycophenolate, cyclophosphamide, azathioprine, and intravenous immunoglobulin. This review highlights the unmet need for effective treatment in early diffuse SSc as well as its more rigorous study. Nonetheless, the PRESS investigators aim to decrease intra- and inter-institutional variability in prescribing in order to improve the understanding of the clinical course of early diffuse SSc skin disease.

Chronic leg ulceration associated with polycythemia vera responding to ruxolitinib (Jakafi(®)).

We present the case of a 63-year-old white male with bilateral chronic leg ulcers due to polycythemia vera and hydroxyurea therapy who demonstrated dramatic healing of his wounds in response to ruxolitinib (Jakafi(®), Novartis), a novel Janus kinase-1 and -2 inhibitor. This patient's wound had previously been refractory to multiple surgical interventions and immunosuppression. After the initiation of ruxolitinib, the patient underwent successful split-thickness skin grafting, with resultant healing of his wounds. He was stable without prednisone and other immunosuppressant therapy and had healed at 6 months. Ruxolitinib therapy could represent a novel option for patients who develop persistent inflammatory wounds in the setting of polycythemia vera and hydroxyurea therapy.

Levamisole-induced occlusive necrotising vasculitis in cocaine abusers: an unusual cause of skin necrosis and neutropenia.

We present three cases describing the various skin manifestations of presumed levamisole-contaminated cocaine use. Antibody-mediated vasculitis and neutropenia were consistent findings in these cases and repeat exposure resulted in distinct dermatologic complications. This phenomenon of levamisole-induced vasculitis and neutropenia is being increasingly described and has characteristic wound manifestations that must be recognised and treated early.

Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management.

PURPOSE OF REVIEW: Renal disease remains an important cause of morbidity and mortality in scleroderma. The spectrum of renal complications in systemic sclerosis includes scleroderma renal crisis (SRC), normotensive renal crisis, antineutrophil cytoplasmic antibodies-associated glomerulonephritis, penacillamine-associated renal disease, and reduced renal functional reserves manifested by proteinuria, microalbuminuria, or isolated reduction in glomerular filtration rate. The purpose of this review is to provide a concise and up-to-date review of the evaluation, risk stratification, pathogenesis, and management of scleroderma-associated renal disease. RECENT FINDINGS: Although SRC survival has significantly improved, mortality of this complication remains high outside of specialized centers. Recent data demonstrate strong associations between anti-RNA polymerase III antibodies and SRC. Subclinical renal impairment affects approximately 50% of scleroderma patients and may be associated with other vascular manifestations. Subclinical renal involvement rarely progresses to end-stage renal failure; however, recent studies suggest it may predict mortality in patients with other vasculopathic manifestations. SUMMARY: Testing for anti-RNA polymerase III antibodies should be incorporated into clinical care to identify patients at high risk for SRC. Recommendations from European League Against Rheumatism (EULAR), EULAR Scleroderma Trials and Research, and the Scleroderma Clinical Trials Consortium confirm angiotensin-converting enzyme inhibitors as first-line therapy for SRC, and give recommendations for second-line agents.

The CIRAS study: a case control study to define the clinical, immunologic, and radiographic features of aromatase inhibitor-induced musculoskeletal symptoms.

Aromatase inhibitors (AIs) are widely prescribed for post-menopausal hormone receptor-positive breast cancer; however, musculoskeletal symptoms limit their tolerability. The purpose of this study was to determine whether joint pain in women receiving AIs is associated with inflammatory arthritis as measured by the disease activity score-28 (DAS-28), and to evaluate association with tenosynovitis on ultrasound. A total of 48 postmenopausal women with stage I-III breast cancer and hand pain were recruited from the Lombardi Comprehensive Cancer Center. Those receiving AIs were cases (n = 25), and those not receiving AIs were controls (n = 23). During a single study visit, subjects underwent blinded rheumatologic evaluation, DAS-28, health assessment questionnaires, autoantibodies, inflammatory markers, hand X-ray, and hand Duplex ultrasound. There were no significant differences between cases and controls in DAS-28, or inflammatory markers. A positive ANA (titer > 1:160) was found in ten patients, four of whom met criteria for autoimmune disease (two with rheumatoid arthritis and two with Sjogren's syndrome, equally distributed among cases and controls). This highlights the importance of considering underlying autoimmune disease in subjects with musculoskeletal complaints. Morning stiffness was more prolonged in women receiving AIs, but this did not reach statistical significance (P = 0.07). Ultrasound evidence of flexor tenosynovitis was common in both groups. Although tenosynovitis was not correlated with AI use (P = 0.26), there was a trend toward an association between tenosynovitis and morning stiffness (P = 0.089). While aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) were more common in subjects receiving AIs, they were not unique to AI users. There was no association between presence of AIMSS features and other chemotherapy or medication exposures. Although the majority of subjects had been using AIs for more than 6 months, this study did not find evidence for inflammatory arthritis in women with hand pain receiving AIs. Further studies are needed to develop a case definition of AIMSS, and to confirm whether these symptoms are attributable to AI use.

Impact of subspecialty elective exposures on outcomes on the American board of internal medicine certification examination.

BACKGROUND: The American Board of Internal Medicine Certification Examination (ABIM-CE) is one of several methods used to assess medical knowledge, an Accreditation Council for Graduate Medical Education (ACGME) core competency for graduating internal medicine residents. With recent changes in graduate medical education program directors and internal medicine residents are seeking evidence to guide decisions regarding residency elective choices. Prior studies have shown that formalized elective curricula improve subspecialty ABIM-CE scores. The primary aim of this study was to evaluate whether the number of subspecialty elective exposures or the specific subspecialties which residents complete electives in impact ABIM-CE scores. METHODS: ABIM-CE scores, elective exposures and demographic characteristics were collected for MedStar Georgetown University Hospital internal medicine residents who were first-time takers of the ABIM-CE in 2006-2010 (n=152). Elective exposures were defined as a two-week period assigned to the respective subspecialty. ABIM-CE score was analyzed using the difference between the ABIM-CE score and the standardized passing score (delta-SPS). Subspecialty scores were analyzed using percentage of correct responses. Data was analyzed using GraphPad Prism version 5.00 for Windows. RESULTS: Paired elective exposure and ABIM-CE scores were available in 131 residents. There was no linear correlation between ABIM-CE mean delta-SPS and the total number of electives or the number of unique elective exposures. Residents with ≤14 elective exposures had higher ABIM-CE mean delta-SPS than those with ≥15 elective exposures (143.4 compared to 129.7, p=0.051). Repeated electives in individual subspecialties were not associated with significant difference in mean ABIM-CE delta-SPS. CONCLUSIONS: This study did not demonstrate significant positive associations between individual subspecialty elective exposures and ABIM-CE mean delta-SPS score. Residents with ≤14 elective exposures had higher ABIM-CE mean delta-SPS than those with ≥15 elective exposures suggesting there may be an "ideal" number of elective exposures that supports improved ABIM-CE performance. Repeated elective exposures in an individual specialty did not correlate with overall or subspecialty ABIM-CE performance.