Randomized Controlled Trials for the Treatment of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease. Several treatment modalities are available, but most of them lack high-quality evidence. A systematic search was performed to identify all randomized controlled trials for the treatment of HS in order to review and evaluate the evidence. Recommendations for future randomized controlled trials include using validated scores, inclusion of patient rated outcomes, and thorough report of side effects. Evidence for long-term treatment and benefit/risk ratio of available treatment modalities is needed in order to enhance evidence-based treatment in daily clinical practice. Combining surgery with antiinflammatory treatment warrants further investigation.

[Treatment of patients with venous leg ulcers: what if compression therapy alone is no longer beneficial?]. / Behandeling van patiënten met een veneus ulcus cruris: wat als compressietherapie alleen niet meer helpt?

Non-healing venous leg ulcers are a cumbersome problem for the patient and the physician. Adequate compression therapy that reduces venous pressure is the cornerstone of treatment. For each patient treatment of superficial venous insufficiency should be considered. Adjuvant surgical, physical or biologic interventions can stimulate healing in case of refractory ulcers Treatment of a venous ulcer needs a tailored approach.

Microvascular proliferations in arteriovenous malformations relate to high-flow characteristics, inflammation, and previous therapeutic embolization of the lesion.

BACKGROUND: Episodes of microvascular proliferation associated with volume expansion have been observed in arteriovenous malformations (AVMs) of skin and soft tissue. OBJECTIVE: We sought to investigate the relationship between a microvascular proliferative response and flow velocity in AVMs. METHODS: Resection specimens of 80 AVMs were clinically categorized as either high- or low-flow lesions, and histopathologically screened for the presence of microvessels, inflammation, thrombosis, or a combination of these. Immunohistochemistry was performed with endoglin (CD105), von Willebrand factor, and fibrinogen antibodies. RESULTS: Clinically, 37 AVMs were classified as high-flow lesions and 43 as low-flow lesions. In 81% of high-flow lesions microvascular proliferations were seen versus in 14% of low-flow lesions (P < .005). In high-flow lesions, which were embolized before surgery (30% of all), 88% showed microvascular proliferation, 88% inflammation, and 33% thrombosis. However, similar vasoproliferative responses were also observed in nonembolized AVM (69% high-flow and 14% low-flow lesions). Endoglin was more frequently expressed in high-flow lesions. Extracellular von Willebrand factor staining was found in most lesions, irrespective of flow type or presence of microvascular proliferations. LIMITATIONS: The study was carried out at a single tertiary referral center. CONCLUSIONS: Microvascular proliferative masses in AVMs appear to be strongly associated with high-flow characteristics. This could be explained to some extent by previous therapeutic embolization and/or inflammation in the lesion. However, occurrence of similar microvascular responses in AVM that were not embolized before surgery suggests that the biomechanical effects of high flow in these lesions may also have an angiogenic effect.

The off-label treatment of severe hidradenitis suppurativa with TNF-α inhibitors: a systematic review.

To provide an overview of the current evidence regarding off-label treatment of hidradenitis suppurativa (HS) with TNF-α inhibitors, a systematic search was performed in MEDLINE, EMBASE and CENTRAL. Any type of original article concerning HS patients treated with infliximab, etanercept and/or adalimumab was included. No language restriction was applied. After full-text screening 65 studies involving 459 patients met the inclusion criteria and were subjected to data extraction. Four randomized controlled trials (RCTs) were available, and the remainders were case series or reports. Only RTCs were subjected to methodological quality assessment. Based on efficacy data extracted from the case reports, a moderate to good response was seen in 82% of the patients treated with infliximab, 76% of the patients treated with adalimumab, and 68% of the patients treated with etanercept. Due to the moderate level of evidence only a weak recommendation can be provided. If conventional treatment options fail, the use of TNF-α inhibitors can be a useful supplement for the treatment of recurrent severe HS. Infliximab should be preferred based on the most encouraging results regarding efficacy and expenses. Also adalimumab seems promising when administered in higher doses. The use of etanercept should be discouraged.

Comparing treatment outcome of infliximab and adalimumab in patients with severe hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic relapsing skin disease. Recent studies have shown promising results of anti-tumor necrosis factor-alpha treatment. OBJECTIVE: To compare the efficacy and safety of infliximab and adalimumab in the treatment of HS. METHODS: A retrospective study was performed to compare 2 cohorts of 10 adult patients suffering from severe, recalcitrant HS. In 2005, 10 patients were treated with infliximab intravenous (i.v.) (3 infusions of 5 mg/kg at weeks 0, 2, and 6). In 2009, 10 other patients were treated in the same hospital with adalimumab subcutaneous (s.c.) 40 mg every other week. Both cohorts were followed up for 1 year using identical evaluation methods [Sartorius score, quality of life index, reduction of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), patient and doctor global assessment, and duration of efficacy]. RESULTS: Nineteen patients completed the study. In both groups, the severity of the HS diminished. Infliximab performed better in all aspects. The average Sartorius score was reduced to 54% of baseline for the infliximab group and 66% of baseline for the adalimumab group. CONCLUSIONS: Adalimumab s.c. 40 mg every other week is less effective than infliximab i.v. 5 mg/kg at weeks 0, 2, and 6.

[Treatment options in severe hidradenitis suppurativa]. / Behandelopties bij ernstige hidradenitis suppurativa.

Hidradenitis suppurativa is a chronic skin disease, characterized by painful, deep-seated inflamed lesions, mainly in areas bearing apocrine sweat glands, most commonly the axillary and inguinal regions. Pain leads to mechanical problems, and bacterial growth in the lesions produces a foul-smelling discharge, which reduces the quality of life. In this type of hidradenitis the infection occurs around hair follicles and sebaceous glands, in contrast to what the name would suggest (hidradenitis = sweat-gland inflammation); hidradenitis suppurativa can, therefore be regarded more as a form of acne. The aetiology of hidradenitis is still unknown, but associated factors are smoking, obesity and familial predisposition.The syndrome can take a severe and disabling course. It is worthwhile implementing aggressive treatment at an early stage. Tumour necrosis factor-alpha inhibitors are now employed in the treatment of severe and treatment-resistant forms of hidradenitis suppurativa; under certain conditions this treatment will be reimbursed by the health insurance company. This development means that there are more treatment possibilities in hidradenitis than there were 5 years ago. The best results are achieved with a combination of antibiotic, anti-inflammatory and surgical treatment, tailored to the patient's individual situation.

Increased incidence of hypercoagulability in patients with leg ulcers caused by leukocytoclastic vasculitis.

Vasculitis is a rare cause of leg ulceration. It is unclear why severe skin infarction develops in some patients with vasculitis, whereas others have only mild symptoms such as purpura, erythema, or urticaria. A coincidence of vasculitis and hypercoagulability may lead to more extensive thrombotic occlusion and hence explain the occurrence of large ulcers in a subset of patients. Our aim was to investigate whether patients with vasculitis ulcers have an increased incidence of hypercoagulability. Thirteen consecutive patients admitted to the hospital with necrotic ulcers caused by histologically confirmed vasculitis were screened for clotting disorders. In 7 of 13 patients (53%), hypercoagulable conditions were found. Five patients had factor V Leiden (38%), and 2 had lupus anticoagulant (15%). The normal frequency of these conditions is 5% to 6% and 3.6%, respectively. These data indicate that there is an increased incidence of hypercoagulable disorders in patients with vasculitis ulcers. We recommend screening these patients routinely for hypercoagulability.

Laboratory tests and identified diagnoses in patients with physical and chronic urticaria and angioedema: A systematic review.

BACKGROUND: The value of laboratory tests in chronic urticaria is still controversial. OBJECTIVE: Our aim was to assess this value in clinical studies, and to identify factors explaining the variation in the number of identified causes. METHODS: A total of 4 electronic databases were searched, and a manual literature search was performed. Only unselected patient series with more than 50 adult patients were included. From each included study predefined items were recorded to assess their quality (consecutive patients, use of standardized diagnostic criteria) and validity (follow-up, assessment of treatment effects, level of evidence). RESULTS: A total of 29 studies were included, involving 6462 patients. The verification of the validity of the results and the level of evidence of the included studies were limited. CONCLUSION: No relationship between the number of identified diagnoses and the number of performed laboratory tests, the different settings, the study design, or the publication period was found. On the basis of this systematic review and the relevant literature, a clinical guideline in the form of a flowchart is presented.

Evaluation of a clinical guideline for the diagnoses of physical and chronic urticaria and angioedema.

In this retrospective study, the feasibility and implementation of a clinical guideline was evaluated in 130 consecutive patients with chronic urticaria. We analysed how often a questionnaire was used, how often routine laboratory tests were performed and on what information (history-taking, detailed questionnaire, laboratory or provocation tests) the diagnosis was made. In this validation sample, the number of identified diagnoses was compared with the number of identified diagnoses of a prospective study previously performed in the same hospital. A cause was identified in 58 patients (45%): 43 of these had physical urticaria and 15 had chronic urticaria. In 50 of the 58 patients (86%) the cause was identified by history-taking and in 8 patients by additional use of the questionnaire. In 38 patients the questionnaire was not in the patient's file. In 89 of 130 patients (68%), laboratory tests were performed without a reason suggested by the patients' history. This did not reveal a cause in any patient. In general, the diagnostic guideline was followed reasonably well. In identifying a cause of urticaria, careful history-taking was important; routine laboratory tests were not helpful. A detailed questionnaire is presented in an appendix.

Allogeneic fibroblasts in dermal substitutes induce inflammation and scar formation.

In the present study, we compared the use of autologous versus allogeneic fibroblasts in dermal skin substitutes in a porcine wound model. The allogeneic fibroblast populations were isolated from female and a male pig (allo-1, - 2 and - 3) and the controls, autologous fibroblasts, from female graft-recipient pigs (control). The histocompatibility of the three donor pigs with the recipient pigs was determined with a mixed lymphocyte reaction. In two pigs, full-thickness wounds were treated with the fibroblast-seeded dermal substitutes (n = 5 per animal) and immediately overgrafted with meshed split-skin autografts. After 6 weeks, wound contraction was measured by planimetry and scar formation was scored. At 2, 4, and 6 weeks biopsies were taken and evaluated for the presence of inflammatory reactions, myofibroblasts, and scar formation. The mixed lymphocyte reaction of both recipient pigs showed the highest responses on peripheral blood mononuclear cells of the allo-3 donor pig, and was low or negative for allo-1 and allo-2. In all "allogeneic" wounds, more inflammatory cells were observed over time along with inflammatory foci consisting of a mix of lymphocytes and granulomatous cells. After 4 weeks, myofibroblasts were absent in the control wounds, whereas in "allogeneic" wounds, myofibroblasts colocalized with inflammation foci. The final scar tissue of the "allogeneic" wounds showed granulating areas with thin, immature collagen bundles. In contrast, the control wounds showed a dermal tissue with mature collagen bundles organized randomly like in normal skin. The wounds treated with allo-3 fibroblasts showed in both pigs a significant increase in scar formation and wound contraction when compared with control wounds. In conclusion, for optimal restoration of dermal skin function with minimal scar formation, skin substitutes containing autologous fibroblasts are preferred over skin substitutes with allogeneic fibroblasts.

Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls.

Patients with diabetes mellitus experience impaired wound healing, often resulting in chronic foot ulcers. Healing can be accelerated by application of growth factors like platelet-derived growth factor (PDGF). We investigated the mitogenic responses, measured by 3[H]thymidine incorporation, of fibroblasts cultured from diabetic ulcers, non-diabetic ulcers, and non-lesional diabetic and age-matched controls, to recombinant human PDGF-AB, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor (IGF-I). We determined the optimal concentration of these factors and investigated which single factor, or combination of factors, added simultaneously or sequentially, induced the highest mitogenic response. For single growth factor additions, in all fibroblast populations significant differences in mitogenic response to different growth factors were observed, with PDGF-AB consistently inducing the highest response and IGF-I the lowest (p < 0.043). IGF-I produced only a 1.7-fold stimulation over control in diabetic ulcer fibroblasts, versus 2.95-fold for chronic ulcer, 3.2-fold for non-lesional (p = 0.007) and 5-fold for age-matched fibroblasts (p = 0.007). The highest mitogenic response induced by EGF was significantly less for chronic ulcer fibroblasts compared with age-matched and nonlesional controls (p < 0.03), chronic ulcer fibroblasts also needed significantly more EGF to reach this optimal stimulus (p < 0.02 versus age-matched and non-lesional controls). The simultaneous addition of FGF-IGF-I, PDGF-IGF-I and FGF-PDGF to diabetic ulcer fibroblasts always produced a higher stimulatory response than sequential additions (p < or = 0.05). Also the addition of bFGF, PDGF-AB and EGF prior to IGF-I induced a higher 3[H]thymidine uptake in all fibroblasts compared to the combination of each in reverse order. Significant differences were observed when comparing the combinations of growth factors with the highest stimulatory responses (PDGF-IGF-I, FGF-PDGF and EGF-PDGF added simultaneously) to a double dose of PDGF, with the highest mean rank for the combination PDGF-IGF-I (p = 0.018). In conclusion, combinations such as PDGF-AB and IGF-I may be more useful than PDGF-AB alone for application in chronic diabetic wounds.

Platelet involvement in cutaneous small vessel vasculitis.

BACKGROUND: Secretory products of platelets serve important functions in inflammation and thrombosis. Participation of platelets in the tissue reaction associated with cutaneous small vessel vasculitis has not yet been evaluated, so we systematically investigated the presence of platelet aggregates in inflamed microvessels. METHODS: Thirty-six biopsies containing vasculitis and 18 biopsies with perivascular or interface type dermatitis were reviewed and adjacent sections were immunohistochemically stained with anti-CD61 antibody recognizing GPIIbIIIa receptors on platelets and with anti-von Willebrand factor (anti-vWF) antibody. RESULTS: Platelet aggregates were observed in 27 (75%) of the vasculitis biopsies and three (16.7%) of the perivascular dermatitis biopsies, of which two (11%) had traumatic vessel damage. In all vasculitis cases, platelet clumps were associated with diffuse immunostaining of the perivascular stroma with the initiator of platelet aggregation anti-vWF. In the non-vasculitis type of dermatitis anti-vWF staining remained strictly limited to the cytoplasm of endothelial cells in 10 cases, and in eight cases there was also slight diffuse perivascular staining, albeit less extensively than in vasculitis cases. CONCLUSION: Formation of platelet aggregates appears to play a thus far unrecognized role in cutaneous small vasculitis. Secretory products of platelets will likely contribute to the inflammatory response and tissue damage in vasculitis. Moreover, platelet immunohistochemistry may be helpful in the diagnosis of microvascular damage in paraffin sections.