Clinical experience with biologic treatment in resistant eosinophilic fasciitis: Case reports and review of the literature.

RATIONALE: Eosinophilic fasciitis (EF) is an uncommon connective tissue disorder characterized by limb and trunk erythema, with symmetrical thickening of the skin. Its pathogenesis is poorly understood. Treatment consists mainly of glucocorticoids. Yet, no randomized trials have evaluated therapies for this rare disease and the optimal treatment modality remains unclear. Although most patients show partial or complete response to glucocorticoids, many relapse upon drug tapering, while others either do not respond at all or fail to sustain prolonged remission. Second-line therapy for this rare disorder includes mainly methotrexate (MTX), azathioprine, cyclosporine and hydroxychloroquine. Recently, several attempts using rituximab and intravenous immunoglobulins (IVIG) have shown good clinical results. PATIENT CONCERNS: The three patients had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. Adding methotrexate in all patients and azathioprine to patient 3 did not lead to remission. DIAGNOSES: EF was diagnosed in all patients based on clinical presentation accompanied by fascia biopsy that demonstrated eosinophilic fasciitis. INTERVENTIONS: The patients were successfully treated with rituximab or IVIG, achieving sustained remission. OUTCOMES: The three cases had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. The patients were then successfully treated with rituximab or IVIG, achieving sustained remission. LESSONS: This review of three cases of EF supports the results of previous reports, suggesting addition of rituximab and IVIG is an effective treatment for patients with refractory disease.

Observation using thermography of post-operative reaction after fascial manipulation®.

INTRODUCTION AND OBJECTIVE: Fascia Manipulation® is one of the methods focusing on the deep fascia. The assumption is that fascial manipulation is carried out on precisely determined points - coordination centres (cc), and on a limited area so as the friction occurring during manipulation would cause a local rise in temperature due to the inflammatory reaction. Rise in temperature influences modification in consistency of elementary matter in the manipulated area, and by the same token causing a decrease in the negative effects of fascia densification which stems from accumulation of hyaluronic acid. The purpose of the research is to prove the thesis that fascial manipulation causes local rise in temperature due to inflammatory reaction. MATERIAL AND METHODS: For the research, 25 individuals with densification in lower limb area were qualified. They were exposed to a single, 3-minute facial manipulation®. By means of a thermal-imaging camera, changes in the temperature of the body in the examined area were evaluated. The body's temperature evaluation was carried out 8 times: before the treatment, 5 minutes after the treatment, and, next, 6, 12, 18, 24, 36, 48 hours after the treatment. RESULTS: The average surface temperature of the treated area before mobilization was 33.4°C. A statistically relevant increase in temperature was already observed 5 minutes after the treatment (increase of 0.5°C; p<0.001). However, the highest temperature was observed 24 hours after mobilization (increase of 2.4°C). The difference between the first and 7 other measurements was statistically relevant (p<0.001). CONCLUSIONS: The statistically relevant increase in temperature under the influence of fascial manipulation® in the treatment area can confirm the occurrence of inflammatory reaction.

Group A Streptococcal DNase Sda1 Impairs Plasmacytoid Dendritic Cells' Type 1 Interferon Response.

Group A Streptococcus causes severe invasive infections, including necrotizing fasciitis. The expression of an array of virulence factors targeting specific host immune functions impedes successful bacterial clearance. The virulence factor streptococcal DNase Sda1 was previously shown to interfere with the entrapment of bacteria through neutrophil extracellular traps and TLR9 signaling. In this study, we showed that plasmacytoid dendritic cells are recruited to the infected tissue during group A streptococcal necrotizing fasciitis. We found that the streptococcal DNase Sda1 impairs plasmacytoid dendritic cell recruitment by reducing IFN-1 levels at the site of infection. We found that streptococcal DNase Sda1 interferes with stabilization of the DNA by the host molecule HMGB1 protein, which may account for decreased IFN-1 levels at the site of infection.

Evidence for the existence of nociceptors in rat thoracolumbar fascia.

Recently, the existence of nociceptive fibers in fascia tissue has attracted much interest. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, little is known about the properties of fascia nociceptors and possible changes of the fascia innervation by nociceptors under pathological circumstances. In this histologic study, the density of presumably nociceptive fibers and free nerve endings was determined in the three layers of the rat TLF: inner layer (IL, covering the multifidus muscle), middle layer (ML) and outer layer (OL). As markers for nociceptive fibers, antibodies to the neuropeptides CGRP and SP as well as to the transient receptor potential vanilloid 1 (TRPV1) were used. As a pathological state, inflammation of the TLF was induced with injection of complete Freund's adjuvant. The density of CGRP- and SP-positive fibers was significantly increased in the inner and outer layer of the inflamed fascia. In the thick middle layer, no inflammation-induced change occurred. In additional experiments, a neurogenic inflammation was induced in the fascia by electrical stimulation of dorsal roots. In these experiments, plasma extravasation was visible in the TLF, which is clear functional evidence for the existence of fascia nociceptors. The presence of nociceptors in the TLF and the increased density of presumably nociceptive fibers under chronic painful circumstances may explain the pain from a pathologically altered fascia. The fascia nociceptors probably contribute also to the pain in non-specific low back pain.

Innervation changes induced by inflammation of the rat thoracolumbar fascia.

Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors.

The adjuvant use of N-palmitoylethanolamine and transpolydatin in the treatment of endometriotic pain.

OBJECTIVE: To test the adjuvant use of the combination of N-palmitoylethanolamine and transpolydatin in the medical treatment of endometriotic pain. STUDY DESIGN: We enrolled 47 patients admitted to the Outpatient Endometriosis Care Unit of Ferrara University from January 2011 to December 2011. They were divided into two groups according to the endometriosis site (group A: recto-vaginal septum; group B: ovary). One tablet, containing 400 mg of micronized N-palmitoylethanolamine plus 40 mg transpolydatin, was administered twice daily on a full stomach for 90 days. Each patient was requested to grade the severity of dysmenorrhea, chronic pelvic pain, dyspareunia and dyschezia using a 0-10 cm visual analogic scale prior to beginning treatment (T0), after 30 days (T1), 60 days (T2) and 90 days (T3). The continuous and categorical variables were compared, respectively, using Student's t-test and the chi-square test. Analysis of variance for repeated measures was used to verify the reduction of endometriotic pain. RESULTS: The intensity of endometriotic pain decreased significantly for both groups (p<0.0001). The efficacy of drug treatment was significant after 30 days. Pain intensity decreased equally in the two groups except for dysmenorrhea, which was reduced more rapidly in group B. CONCLUSIONS: The combination of N-palmitoylethanolamine and transpolydatin reduced pain related to endometriosis irrespective of lesion site. It had a marked effect on chronic pelvic pain determined by deep endometriosis and on dysmenorrhea correlated to ovarian endometriosis.

Macrophagic myofascitis associated with rheumatoid arthritis.

Macrophagic myofascitis (MMF) is an unusual inflammatory myopathy characterized by muscle infiltration by macrophages and lymphocytes. Here, we describe a case of MMF which is associated with rheumatoid arthritis. A 53-year-old Japanese rheumatoid arthritis (RA) patient presented with focal tenderness of lower extremities. Magnetic resonance imaging showed evidence of myofascitis involving fascias of anterior tibialis muscle. Muscle biopsy showed a unique pathological pattern of MMF. MMF is known to be associated with vaccination containing aluminum. However, our case was not related to aluminum containing vaccinations and etiologies are unknown. The possible link needs to be discussed.

Evidence for superantigen involvement in severe group a streptococcal tissue infections.

Host-pathogen interactions were studied in tissue biopsy samples from patients with severe invasive group A streptococcus (GAS) infections. Skin, subcutaneous tissue, and fascia biopsy samples were divided into clinical grade 1 (no evidence of inflammation [n=7]) or clinical grade 2 (inflamed tissue--erythema and edema including cellulitis, fasciitis, and necrotizing fasciitis [n=24]). In situ imaging demonstrated significantly higher bacterial load in biopsy samples of higher clinical grade (P<.05), and the bacterial load correlated with the in vivo expression of the superantigen streptococcal pyrogenic exotoxin F (P<.02). Increased expression of the interleukin-1 cytokines and significantly higher expression of tumor necrosis factor-beta, interferon-gamma, and the homing receptors CC chemokine receptor 5, CD44, and cutaneous lymphocyte-associated antigen (P<.002-.05) were observed in biopsy samples of higher clinical grade. Thus, the cytokine profile at the local site of infection mimics that of a typical superantigen cytokine response. The findings of this study demonstrate a critical role for superantigens and Th1 cytokines in GAS tissue infections.

Imbrication versus excision for fascial healing.

BACKGROUND: The purpose of this study was to determine whether imbrication of native fascia versus excision and closure of new raw fascia forms a stronger union. METHODS: We utilized the anterior rectus sheath fascia of Sprague-Dawley rats as the model. Sixty rats underwent fascial tightening procedures. Each rat had the anterior rectus sheath shortened by 1 cm, 30 by imbrication and 30 by excision and closure. Ten of each group were harvested at 7 days' healing, 10 at 14 days, and 10 of each group at 28 days' healing. The anterior rectus sheath was removed, a "dumbbell" shape constructed, and the cross sectional area at the point of interest determined. The fascia was placed on an Instron tensiometer to determine the breaking strength. Tensile strength was calculated and the data analyzed by ANOVA and the Kruskall-Wallis test. Tissue samples of the closures were histologically analyzed for fibroblast counts, degree of inflammation, and presence of dense fibrous connective tissue. Tissue samples were also analyzed for enzymatic collagen crosslinking. RESULTS: There was a statistically significant difference in tensile strength between the two groups at 7, 14, and 28 days. Results show that at 7 days the mean tensile strength of excision was 0.133 kg/mm2 +/- 0.056 and the mean tensile strength of imbrication was 0.083 kg/mm2 +/- .048 (P < 0.05); at 14 days the mean tensile strength of excision was 0.105 kg/mm2 +/- 0.033 and the mean tensile strength of imbrication was 0.057 kg/mm2 +/- 0.014 (P < 0.002), and at 28 days the mean tensile strength of excision was 0.279 kg/mm2 +/- 0.143 and the mean tensile strength of imbrication was 0.145 kg/mm2 +/- 0.061 (P < 0.03). Histologic findings showed no statistical significance between the two closure methods when comparing degree of inflammation or the number of fibroblasts present. However, at 7 and 14 days there is a significantly greater presence of dense fibrous connective tissue in the excision group (P < 0.03 at 7 days and P < 0.044 at 14 days by ANOVA). Collagen crosslink analysis showed that by day 28 there is a significantly greater amount (P < 0.05 by ANOVA) of the difunctional crosslink dihydroxylysinonorleucine (DHLNL) and a greater ratio between DHLNL and the difunctional crosslink hydroxylysinonorleucine (HLNL) in the excision and closure group. CONCLUSION: We conclude that at 7, 14, and 28 days healing, excision provides a significantly stronger closure than imbrication. According to the crosslinking analysis, it is likely that this strength advantage may continue to increase over time. These findings suggest that excision and closure may be the preferred method for fascial tightening procedures.

Gentamicin distribution from a collagen carrier.

Local delivery of antibiotics by a degradable carrier has the potential for high local antibiotic levels and avoids systemic toxicity. Intravenous access, renal function monitoring, and subsequent surgical removal may not be required when degradable local delivery modalities are used. This study examined the in vivo elution of gentamicin from processed bovine collagen (type I) in 66 adult White rabbits. Collagen impregnated with gentamicin (3 mg/kg) was implanted into the vastus lateralis, and data were collected from 15 minutes to 28 days after implantation. Local tissue biopsies were taken a minimum of 2 mm from the implantation site. The gentamicin was released into the local tissue and averaged more than 3,800 micrograms/ml during the initial 4 hours after implantation. Local levels fell to 6.90 +/- 5.22 micrograms/ml at 24 hours and subsequently were 2.70 +/- 1.75 micrograms/ml or more through day 28. Serum levels reached an average peak of 4.04 +/- 1.75 micrograms/ml at 5 hours after implantation, decreased after the initial 24 hours, and subsequently were less than 0.41 +/- 0.20 microgram/ml through day 28. Collagen impregnated with gentamicin proved to be an effective degradable carrier of gentamicin in the healthy rabbit; it provided local tissue concentrations above the minimum inhibitory concentration and serum concentrations below levels associated with systemic toxicity for 28 days after implantation.

T-cell-mediated response in Dupuytren's disease.

The cause of Dupuytren's disease is unknown, but inflammatory cells might have a role. Enzymatic digestion of diseased tissue permits identification and immunofluorescent labelling of a cell subset displaying inflammatory cell morphology. Cytofluorimetry of this cell population demonstrated the presence of CD3-positive lymphocytes and expression of major histocompatibility complex (MHC) class II proteins. These results raise the possibility that Dupuytren's disease is a T-cell-mediated autoimmune disorder. The development of medical treatment on this basis may reduce the need for surgery, with its associated morbidity and high recurrence rates.

Electron microscopical and immunohistochemical studies on the induction of "Qi" employing needling manipulation.

During a sparrow-pecking and twisting-needle manipulation to the acupoints BL 23, 24 and 25 for an induction of "Qi", it was found that some transparent materials were binding to the needles after removed from the volunteer's skin. Electron-microscopical analysis of the transparent materials revealed that they corresponded to the injured fascia made up of collagen fibers, elastic fibers, fibroblasts, adipocytes and mast cells. Rarely were nerve fiber-like structures observed in the materials. Immunohistochemically, calcitonin gene-related peptide-positive nerve fibers could be demonstrated in the acupoint BL 24 associated fascia. A possible functional relationship between the needle manipulation and the induction of Qi-sensation is discussed along with the acupoint tissue constitution.

Diffuse fasciitis and eosinophilia with symmetric polyarthritis.

Articular involvement has been infrequently reported in diffuse fasciitis with eosinophilia. We report a patient with diffuse fasciitis with eosinophilia, concurrent symmetrical polyarthritis, and bilateral carpal tunnel syndrome. Light microscopy and immunofluorescence studies of synovium and full-thickness calf biopsy were done. Synovial fluid analyses showed mildly inflammatory fluid. Response to prednisone, clinically and by laboratory indicators, was prompt and dramatic.

Investigations on immunogenicity of bovine fibrous connective tissue.

The immunogenicity of fibrous connective bovine tissue preserved by different methods was tested by a regional lymph node blastic cell reaction. The results were presented after transplantation of 10 experimental groups of grafts.

Necrotizing fasciitis.

Two cases of necrotizing fasciitis, a disease poorly documented in the gynecologic literature because of its extreme rarity, are described. These are the only cases of this entity seen in our department during the last 24 years. Both patients underwent major surgical procedures for uterine stromal sarcoma and mixed mesodermal tumor. In both, the pathognomonic signs, undermining of the skin, and extensive necrosis of the subcutaneous tissue and the underlying fascia, were present. Later gangrene occurred, and both patients died. The literature is briefly reviewed, which emphasizes the importance of immediate surgery when the disease is recognized. The possibility is suggested that the development of such local processes in cases of mixed mesodermal tumor may be an immunologic reaction and the cultured organisms contaminants.