Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

Real-world effectiveness of anti-interleukin-23 antibodies in chronic plaque-type psoriasis of patients from the Austrian Psoriasis Registry (PsoRA).

With the introduction of the latest class of biologic drugs targeting interleukin (IL)-23p19, three new, highly effective drugs can be used for the treatment of chronic plaque psoriasis. However, poorer skin improvement as well as higher rates of serious adverse events have been reported for patients under real-world conditions (outside clinical trials). This accounts especially for patients who have already been treated with biologic drugs. We therefore aimed to determine effectiveness and safety of IL-23p19 inhibitors in real-world patients by analysing data from the Psoriasis Registry Austria (PsoRA) in this observational, retrospective, multicentre cohort study. Data for 197 patients (52.3% biologic-non-naïve), who were treated with anti-IL-23p19 antibodies (127 guselkumab, 55 risankizumab and 15 tildrakizumab) for at least 3 months, were eligible for analysis. In general, biologic-non-naïve patients displayed a less favourable response to anti-IL-23 treatment as compared to biologic-naïve patients. However, after correction for previous biologic exposure, few differences in PASI improvement were detected among biologic-naïve and -non-naïve patients treated with different IL-23p19 inhibitors. This indicates that treatment effectiveness is not related to the class of the previously administered therapy in biologic-non-naïve patients. Therefore, IL-23p19 inhibitors represent a promising treatment alternative for patients who have not responded to previous biologics. However, as with other biologic agents (including IL-17 inhibitors), we did not observe an entirely satisfactory treatment response (i.e. PASI < 3 and/or PASI 75) to anti-IL-23 treatment in one out of four to five patients. Adverse events (mainly non-severe infections) were observed in 23 (11.7%) patients with no major differences regarding the administered IL-23 inhibitor or previous biologic exposure.

Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

[Etiology, nomenclature and pathophysiology of chronic venous insufficiency]. / Ätiologie, Nomenklatur und Pathophysiologie der chronisch venösen Insuffizienz.

This article presents current notions and conceptions of the aetiopathogenesis of primary varicosis and chronic venous insufficiency, as well as an updated version of the nomenclature and terminology of venous disorders, which was recently agreed on in an international consensus conference. Furthermore, both CEAP-classification and venous severity score system are discussed.

Methotrexate vs. fumaric acid esters in moderate-to-severe chronic plaque psoriasis: data registry report on the efficacy under daily life conditions.

OBJECTIVE: To compare the clinical efficacy of methotrexate (MTX) vs. fumaric acid esters (FAE) in psoriasis treated under daily life conditions. METHODS: Data were extracted from a registry (http://www.psoriasisregistry.at) of 272 adult patients with moderate-to-severe chronic plaque psoriasis treated primarily with MTX (n = 72) or FAE (n = 200) between 2004 and 2011. Data from all patients, including those who did not complete at least 3 months of monotherapy, were included in an intention-to-treat (ITT) worst-case analysis. RESULTS: Thirty of 72 (41.7%) patients treated with MTX and 85 of 200 (42.5%) patients treated with FAE discontinued early, mainly due to side-effects or lack of response. Among patients who completed at least 3 months of treatment, the response to primary treatment with MTX vs. FAE did not differ significantly at any time point. In the ITT worst-case analysis at month 3, complete remission rate, PASI90, PASI75 and PASI50 rates were 6%, 7%, 24% and 39% in MTX-treated patients vs. 1%, 5%, 27% and 44% in FAE-treated patients. Overall mean PASI reduction score improved significantly in response to primary MTX and FAE treatment (by 10.6% and 12.6%, respectively) between 3 and 6 months (P = 0.0005; exact Wilcoxon test), but not between 6 and 12 months (P = 0.16). A subset of 32 patients who did not respond satisfactorily to primary treatment with FAE responded better to subsequent MTX therapy (P < 0.0001; paired Wilcoxon test). CONCLUSIONS: As shown by retrospective analysis, the primary efficacy of FAE was similar to that of MTX under daily life conditions.

Case presentation of moderate-severe psoriasis.

The use of biologic agents has greatly improved psoriasis treatment. However, some individuals fail to respond to treatment or loose initial efficacy, and it may be difficult to find the optimal treatment for these patients. We present a patient with long-standing, moderate-severe plaque psoriasis, who had received UVB therapy as well as classical systemic therapies without sufficient response previously. Alefacept only gave a moderate response with quick recurrence after the end of treatment. Adalimumab was working for some time, but finally the patient experienced a slow loss of efficacy and was especially hampered by severe involvement of his hands. This caused him great distress as his work involved a high level of customer contact. The decision was taken to change therapy to ustekinumab. After one injection of ustekinumab psoriasis was greatly improved and it was almost completely resolved after the second injection, and arthritis was no longer active. The efficacy of ustekinumab treatment could be maintained up to now; there is only minimal disease activity and the patient is extremely satisfied. In conclusion, the decision to change to another biologic with different mode of action proved to be successful, and it helped the patient to forget his disease for most of the time and to fulfil the responsibilities of his job.

Treatment with 311-nm ultraviolet B enhanced response of psoriatic lesions in ustekinumab-treated patients: a randomized intraindividual trial.

BACKGROUND: Treatment with the interleukin-12/23 antibody ustekinumab produces a satisfactory response [i.e. 75% reduction in Psoriasis Area and Severity Index (PASI) compared with baseline (PASI 75)] in the majority of patients with moderate to severe chronic plaque-type psoriasis. OBJECTIVES: To determine whether concomitant 311-nm ultraviolet (UV) B therapy can further enhance the response in patients with psoriasis treated with ustekinumab. METHODS: Ten patients (five women and five men; mean age 58years, range 48-66) with moderate to severe plaque-type psoriasis were treated with ustekinumab at a standard dosage of 45 or 90mg subcutaneously depending on body weight (below or above 100kg) at weeks 0 and 4. Within 2days after ustekinumab initiation, the minimal erythemal dose (MED) was determined and suberythemal MED 311-nm UVB-based phototherapy was thereafter administered to one randomly selected body half (left or right, excluding the head) three times weekly for 6weeks. Treatment response was monitored weekly in terms of half-body PASI. RESULTS: Nine patients completed the study. Analysis of their data showed that 311-nm UVB significantly accelerated the therapeutic response. At baseline (i.e. start of 311-nm UVB therapy), the mean PASI was similar in both irradiated and unirradiated body halves (13·6 vs. 13·3). At week 6, however, it was lower on irradiated body halves (2·5 vs. 6·1). This difference of 3·6 (95% confidence interval 1·3-5) was statistically significant and corresponded to an overall mean PASI reduction from baseline of 82% vs. 54%, respectively. At week 6, PASI 75 was achieved significantly more often on UV-irradiated body halves than on unirradiated body halves [7/9 patients (78%) vs. 1/9 (11%)] (McNemar test, P=0·007). At week 12, this synergistic effect of 311-nm UVB was still apparent although not significantly so. CONCLUSIONS: Treatment with 311-nm UVB accelerates the clearance of psoriatic lesions in ustekinumab-treated patients.

Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry.

BACKGROUND: Few studies have directly compared the clinical efficacy of psoralen plus ultraviolet A (PUVA) vs. biologics in the treatment of psoriasis. OBJECTIVES: To compare the clinical efficacy of PUVA and biologic therapies for psoriasis under daily life conditions. METHODS: Data from a psoriasis registry (http://www.psoriasis-therapieregister.at) of 172 adult patients with moderate to severe chronic plaque psoriasis treated between 2003 and 2010 were analysed retrospectively. These patients had received oral PUVA [118 treatment courses including 5-methoxypsoralen (5-MOP; n = 32) and 8-methoxypsoralen (8-MOP; n = 86)] and/or biologic agents [130 treatment courses including adalimumab (n = 18), alefacept (n = 32), efalizumab (n = 17), etanercept (n = 38), infliximab (n = 7) and ustekinumab (n = 18)]. Treatment responses were analysed in terms of Psoriasis Area and Severity Index (PASI) improvement, including complete remission (CR) and reduction of PASI by at least 90% (PASI 90) or 75% (PASI 75), at treatment completion for PUVA (median time 10·3 and 9·2 weeks, for 8-MOP and 5-MOP, respectively) and at week 12 for biologics. RESULTS: Intention-to-treat-as observed CR, PASI 90 and PASI 75 rate was 22%, 69% and 86% for PUVA compared with 6%, 22% and 56% for adalimumab (P = 0·0034 by adapted Wilcoxon test), 3%, 3% and 25% for alefacept (P = 0·000000002), 6%, 6% and 59% for efalizumab (P = 0·000053), 6%, 29% and 39% for etanercept (P = 0·0000086), 29%, 71% and 100% for infliximab (P = 0·36) and 6%, 39% and 67% for ustekinumab (P = 0·028). When applying a more conservative post-hoc modified worst-case scenario analysis, with CR of 15%, PASI 90 of 58% and PASI 75 of 69%, PUVA was superior only to alefacept (P = 0·000013), efalizumab (P = 0·015) and etanercept (P = 0·0037). There were no statistically significant differences in PASI reduction rates between PUVA and infliximab. CONCLUSIONS: Retrospective analysis of registry data revealed that the primary efficacy of PUVA was superior to that of certain biologics. Prospective head-to-head studies of PUVA and biologics are warranted to confirm these observations.

Treatment with 311-nm ultraviolet B accelerates and improves the clearance of psoriatic lesions in patients treated with etanercept.

BACKGROUND: Some patients with plaque-type psoriasis respond slowly to treatment with etanercept. In such cases combining etanercept with conventional treatments might be helpful. OBJECTIVES: To investigate whether treatment with 311-nm ultraviolet (UV) B can improve the therapeutic response in patients treated with etanercept. METHODS: Four women and one man (mean age 57 years, range 48-66) with moderate to severe plaque-type psoriasis who had received standard treatment with etanercept 50 mg twice weekly for 6 weeks without Psoriasis Area and Severity Index (PASI) reduction of 75% or greater (of initial mean PASI of 16.0, range 15.4-20.4) were enrolled in the study. Starting at 6 weeks, 311-nm UVB treatment was given to a randomly selected body half (left or right, excluding the head) for another 6 weeks, while all patients continued receiving etanercept. The patients were monitored by half-body PASI at weekly intervals. RESULTS: During the 6-week irradiation regimen, 311-nm UVB significantly bolstered the therapeutic response in the patients on etanercept treatment. After 6 weeks of 311-nm UVB, the patients had a mean PASI on their UV-irradiated body halves of 1.6 (range 0.6-3.3) vs. 4.7 (range 1.4-8.6) on nonirradiated body halves (P = 0.0192, paired two-tailed t-test), compared with 10.7 (range 6-16.4) and 10.5 (range 5.2-16.4) at start of 311-nm UVB treatment. The overall mean PASI reduction from baseline (i.e. at etanercept start) was 89% vs. 68%, respectively (P = 0.0009 and P = 0.0088). CONCLUSIONS: Treatment with 311-nm UVB significantly accelerates and improves the clearance of psoriatic lesions in patients responding slowly to etanercept monotherapy.

[Cryotherapy in discoid lupus erythematosus (DLE)]. / Kryotherapie bei diskoidem Lupus erythematodes.

Discoid lupus erythematosus (DLE) is a chronic, scarring, photosensitive autoimmune dermatosis that usually occurs in sun-exposed areas. While the face, chest, and extremities are often affected, involvement of the eyelid is rare. In cases of DLE lesions that are resistant to local or systemic recommended therapies, contact cryotherapy should be considered as an alternative treatment option.

High serum levels of antibodies against the recombinant 70 kDa ribonucleoprotein are useful for diagnosing mixed connective tissue disease.

BACKGROUND: Anti-Sm antibodies and anti-RNP antibodies are considered to be diagnostic markers of systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). However, cross-reactivity between the antibodies diminishes their discriminating specificity between these diagnoses. OBJECTIVE: We examined whether we could achieve better differentiation between these two disease entities using recombinant antigens to RNP70 and SmD and quantitative immunoassays. PATIENTS/METHODS: Sera from 51 patients with SLE and 10 patients with MCTD and from a control group of 59 patients were used in a cross-sectional setting. Semiquantitative ELISAs for the detection of antibodies to RNP-70, RNP-A, RNP-C, SmBB' and SmD were used and the results were compared to conventional ELISA tests using U(1)-snRNP and a mixture of SmBB' and SmD as antigenic substrates. RESULTS: Sera from MCTD patients showed higher levels of anti-RNP-70 antibodies than sera from SLE patients. Levels of anti-SmBB' or anti-SmD antibodies were not significantly different between SLE and MCTD sera. However, the presence of antibodies directed against SmD was more frequent in SLE. CONCLUSIONS: Our results suggest that the use of RNP-70 and SmD antigens may increase the practical value of immunoassays used to confirm a diagnosis of SLE or MCTD in patients with connective tissue disease.

Feasibility and acceptance of telemedicine for wound care in patients with chronic leg ulcers.

We examined the feasibility and acceptance of teledermatology for wound management of patients with chronic leg ulcers by home-care nurses. Forty-one chronic leg ulcers of different origin in 14 patients were included. After an initial in-person visit in which leg ulcers were assessed and classified, and underlying diseases noted, follow-up visits were done by home-care nurses. Once a week 1-4 digital images of the wound and surrounding skin and relevant clinical information were transmitted via a secure Website to an expert at the wound care centre. The experts provided an assessment of wound status and therapeutic recommendations. In 89% of the 492 teleconsultations, the quality of images was sufficient or excellent and the experts were confident giving therapeutic recommendations. Treatment modalities were changed or adapted in one-third of the consultations. There was a significant decrease in visits to a general physician or the wound care centre. The acceptance of teledermatology was high in patients, home-care nurses and wound experts. Teledermatology offers great potential for chronic wound care and seems to be accepted both by patients and health-care persons.

Two years' experience with Web-based teleconsulting in dermatology.

A non-commercial teledermatology network based on store-and-forward operation was established in April 2002. The aim was to create an easy-to-use platform for teleconsultation services, where physicians could seek diagnostic advice in dermatology from a pool of expert consultants and where they could present and discuss challenging dermatology cases with special emphasis on diagnosis and therapy. An online moderated discussion forum was added in October 2003. During the first two years, 348 health-care professionals from 45 countries registered to use the Website. A total of 783 requests for consultations were answered; 285 requests concerned pigmented skin lesions, 440 requests were from the whole range of clinical dermatology and 58 requests were about non-melanoma skin cancer. Of a total of 133 requests analysed, 80 (60%) were answered within one day, 47 (35%) within one week, five (4%) within two weeks and one (1%) consultation was answered in more than two weeks. Our experience with a discretionary, non-commercial, multilingual Website for open-access teleconsulting in dermatology appears to be successful. The Website represents an example of user-generated content, together with active interaction between users, who can present and discuss cases with remote colleagues.

Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.

Hereditary sensory and autonomic neuropathy type II (HSAN-II) is caused by recessive mutations in the HSN2 gene assigned to chromosome 12p13.33. The authors report three unrelated HSAN-II families with homozygous or compound heterozygous mutations resulting in the truncation of the HSN2 protein. Genotype-phenotype correlations indicated that HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs.

Penetration of piperacillin and tazobactam into inflamed soft tissue of patients with diabetic foot infection.

We investigated the pharmacokinetics of piperacillin and tazobactam in the extracellular space fluid of inflamed soft tissues of six patients with diabetic foot infection using in vivo microdialysis and found similar penetration for piperacillin but not for tazobactam into inflamed and noninflamed soft tissue.

Telepathology using immunofluorescence/immunoperoxidase microscopy.

We evaluated low-cost, store-and-forward telepathology interpretation of digital images of skin sections stained immunohistochemically, using immunofluorescence (IF) and immunoperoxidase (IP). The sample comprised 17 patients with skin diseases characterized by cutaneous deposition of immunoglobulins, fibrinogen or complement components. Up to 11 digital IF or IP images (median 3) were transferred via email to centres in Graz, Austria, and Kurume, Japan. Both remote centres had expertise in reading immunohistochemical specimens. Although image files were relatively small (approximately 100 kByte), the IF images were of high quality and they were well suited to static telepathology. There was agreement on the diagnoses made by the local and both remote centres by physicians experienced in IF/IP microscopy in 14 of 17 cases (82%). These results suggest that telepathology evaluation of immunohistochemical specimens may be a useful procedure for the discussion of unusual skin disorders, training purposes and second-opinion consultations on difficult cases from centres of excellence in immunohistochemical diagnosis.

Penetration of fosfomycin into inflammatory lesions in patients with cellulitis or diabetic foot syndrome.

We investigated the distribution of the broad-spectrum antibiotic fosfomycin in infected soft tissue of patients with uncomplicated cellulitis of the lower extremities or diabetic foot infection using in vivo microdialysis. Our findings suggest that fosfomycin exhibits good and similar penetration into the fluid in the interstitial space in inflamed and noninflamed soft tissue in patients.