Retinal vasculitis with Chronic Recurrent Multifocal Osteomyelitis: a case report and review of the literature.

BACKGROUND: Concurrent presentation of retinal vasculitis with mixed sclerotic and lytic bone lesions is rare. CASE PRESENTATION: We present the case of a 37-year old woman with a several year history of episodic sternoclavicular pain who presented for rheumatologic evaluation due to a recent diagnosis of retinal vasculitis. We review the differential diagnosis of retinal vasculitis, along with the differential diagnosis of mixed sclerotic and lytic bone lesions. Ultimately, bone marrow biopsy confirmed diagnosis of chronic recurrent multifocal osteomyelitis (CRMO). Concurrent presentation of CRMO with retinal vasculitis is extremely rare but important to recognize. The patient demonstrated clinical response to prednisone and tumor necrosis factor-alpha inhibition (TNF-i). CONCLUSION: This case reports and unusual presentation of CRMO spectrum disease involving the sternum and sternoclavicular joint with concurrent retinal vasculitis.

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.

Prevalence of antinuclear antibodies in hidradenitis suppurativa.

AIM: The purpose of this study was to investigate the prevalence of antinuclear antibody (ANA) positivity in a cohort of patients with hidradenitis suppurativa (HS), and to assess the frequency of seroconversion during treatment with tumor necrosis factor (TNF)-α inhibitor therapy. METHODS: This prospective study was conducted through the Wound Etiology and Healing (WE-HEAL) Study. Immunofluorescence ANA testing was performed at baseline, and repeated when clinically indicated. ANA titers of ≥1 : 160 were considered positive. Data were collected on demographics and disease activity scores including the Hurley stage, the HS Sartorius score (HSS) and the active nodule (AN) count. RESULTS: At the time of data lock, 73 patients with a confirmed diagnosis of HS were enrolled, and four (5.4%) had baseline positive ANA. None of the patients had clinical evidence of systemic lupus erythematosus or other autoimmune diseases. There were no significant differences in demographics, baseline HSS (43.25 ± 47.55 compared to 59.48 ± 56.67, P = 0.58) or AN count (3.25 ± 3.20 compared to 3.45 ± 2.36, P = 0.87) in the ANA positive group. Of the 69 patients who were ANA negative at enrollment, 31 (45%) received TNF-α inhibitor therapy. During follow up, one patient developed drug-induced lupus secondary to TNF-α inhibitor use. Additionally, one patient seroconverted to ANA positive without sequelae and one patient developed drug-induced hepatitis secondary to TNF-α inhibitor use. CONCLUSION: The prevalence of baseline ANA positivity in this HS population was similar to that seen in the general population (5.4%). The rate of seroconversion and drug-induced complications in this population were low.

Prevalence of positive QuantiFERON gold in-tube testing in hidradenitis suppurativa.

AIM: Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of the apocrine sweat glands. Tumor necrosis factor-alpha (TNF-α) inhibitors are commonly used to treat HS. However, prior to initiating therapy patients must be screened for mycobacterium tuberculosis (mTB) exposure. Several mTB screening tests based on interferon gamma release assays are commercially available, but the performance of these assays in the HS population is unknown. The purpose of this study was to investigate the performance of the QuantiFERON gold in-tube assay (QFT-GIT) in a cohort of patients with HS. METHODS: This prospective study was conducted through the Wound Etiology and Healing (WE-HEAL) study. QFTGIT testing was performed using a commercial laboratory. Patients with positive test results underwent follow-up testing to evaluate for latent tuberculosis infection (LTBI). Data were collected on demographics and disease activity scores including Hurley stage, HS Sartorius score (HSS) and active nodule (AN) count. RESULTS: Of the 69 patients with a confirmed diagnosis of HS, seven (10.1%) tested QFT-GIT positive and 5.8% were diagnosed with LTBI. CONCLUSIONS: QFT-GIT results did not correlate with demographic characteristics or HS disease activity.

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.

Longitudinal observational study of hidradenitis suppurativa: impact of surgical intervention with adjunctive biologic therapy.

BACKGROUND: Hidradenitis supppurativa (HS) is a chronic inflammatory disease of the apocrine sweat glands affecting 1-4% of the population. While surgical excision is a mainstay of therapy, lesions often recur. Biologic therapies, including tumor necrosis factor-α and IL-12/23 inhibitors, are effective for mild to moderate HS. However, longitudinal studies investigating biologic therapy in conjunction with surgery are limited. The purpose of this analysis was to investigate impact of surgery and biologic therapy on HS disease activity. METHODS: Data from 68 HS patients were analyzed. Outcome measures included hidradenitis suppurativa Sartorius Score (HSS), active nodule (AN) count, Hurley stage, and probability of achieving 75% reduction in active nodule count (AN75). RESULTS: Mean age was 40 ± 14 years; 66% were female and 72% were African American. Mean disease duration was 10 years, and Hurley stage III disease was seen in 63% of patients. Patients who received biologics had a larger drop in HSS and AN count than those who never received biologics (P = 0.002). Biologic treatment was associated with average reduction in 22 (15-29) HSS points (P < 0.0001). The effect of biologics was greater in patients who also underwent surgery (P = 0.013). Timing of biologics relative to surgery did not impact efficacy. Patients who received HS surgery with biologic therapy were most likely to achieve the AN75 (P = 0.017). CONCLUSIONS: In this diverse cohort of patients with severe HS, biologic therapy was associated with a more rapid decline in disease activity, with the greatest effect in patients who also underwent HS surgery.

Review of Current Immunologic Therapies for Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1-4% of the population. The disease is more common in women and patients of African American descent and approximately one-third of patients report a family history. Obesity and smoking are known risk factors, but associations with other immune disorders, especially inflammatory bowel disease, are also recognized. The pathogenesis of HS is poorly understood and host innate or adaptive immune response, defective keratinocyte function, and the microbial environment in the hair follicle and apocrine gland have all been postulated to play a role in disease activity. While surgical interventions can be helpful to reduce disease burden, there is a high recurrence rate. Increasingly, data supports targeted immune therapy for HS, and longitudinal studies suggest benefit from these agents, both when used alone and as an adjunct to surgical treatments. The purpose of this review is to outline the current data supporting use of targeted immune therapy in HS management.

Vasculitic and autoimmune wounds.

OBJECTIVE: Chronic wounds are a major cause of morbidity and mortality. Approximately 20% to 23% of nonhealing wounds that are refractory to vascular intervention have other causes, including vasculitis, pyoderma gangrenosum, and other autoimmune diseases. The purpose of this article was to review the literature across medical and surgical specialties with regard to refractory chronic wounds associated with vasculitis and autoimmune diseases and to delineate clinical outcomes of these wounds in response to vascular and other interventions. METHODS: An electronic search encompassing MEDLINE, PubMed, Cochrane Library, and Scopus was completed using the following search terms: rheumatoid arthritis; systemic sclerosis; systemic lupus erythematosus; antineutrophil cytoplasmic antibody-associated vasculitis; mixed connective tissue disease; antiphospholipid syndrome; pyoderma gangrenosum; thromboangiitis obliterans; cryoglobulinemia; hydroxyurea; sickle cell; atrophie blanche; livedoid vasculitis; cholesterol emboli; calciphylaxis; antiphospholipid antibodies; prothrombotic; combined with the terms: chronic wound and leg ulcer. Full-text articles published in English up to March 1, 2016, that investigated the clinical outcomes of chronic wounds associated with autoimmune diseases were included. Review articles and evaluations of management of chronic wounds were also reviewed. Primary outcomes included in the review were amputation, ulcer healing, reduction in wound size, overall survival, and freedom from reintervention. Owing to the heterogeneity of data reporting among articles, qualitative analysis is also reported. RESULTS: Vasculitis and autoimmune diseases play a role in 20% to 23% of patients with chronic lower extremity ulcers. Furthermore, patients with autoimmune disease have a significantly high rate of split thickness skin graft failure (50% compared to 97% in patients without autoimmune disease; P = .0002). The management of leg ulcers associated with autoimmune diseases is discussed. CONCLUSIONS: Autoimmune and vasculitic causes should be considered in patients with chronic wounds who do not respond to appropriate vascular intervention and standard local wound care. A multidisciplinary approach with the involvement of rheumatologists allows investigation for underlying systemic disease and improves clinical outcomes for many of these challenging patients.

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.

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.

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.

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.