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.

[Cutaneous manifestations of Lyme disease : Pitfalls in the serological diagnostic workup]. / Kutane Lyme-Borreliose : Fallstricke der serologischen Diagnostik.

Serology, the detection of B. burgdorferi-specific IgM and IgG serum antibodies, is the most common laboratory test to diagnose cutaneous manifestations of Lyme disease. In a two-tiered approach, an ELISA is used as a screening test. A positive or equivocal ELISA result needs confirmation by a specific immunoblot. The sensitivity of this approach reaches 80-95%. The diagnosis of erythema migrans is based on its typical clinical appearance. Serology is only indicated in atypical cases. In contrast, serology is mandatory in the diagnostic workup of borrelial lymphocytoma and acrodermatitis chronica atrophicans. A positive serology can persist for many years, even after adequate antibiotic treatment. A positive serology is no indication for antibiotic treatment if typical symptoms of Lyme disease are absent.

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.

[Skin infections in pregnancy]. / Hautinfektionen in der Schwangerschaft.

The article outlines examples of a viral (varicella-zoster virus, VZV), a bacterial (Lyme borreliosis) and a parasitic (scabies) infection in pregnancy with their risk for the mother and/or child as well as their management. VZV infections cause various clinical scenarios depending on the maternal immune status and the time of infection. Herpes zoster usually poses no risk to the pregnant woman and there is no need for antiviral therapy. VZV infection of a seronegative mother, however, may lead to severe varicella in the pregnant woman and to congenital malformations (congenital varicella syndrome) in case of early infection or neonatal varicella in case of perinatal infection. Prompt therapy with acyclovir or administration of VZV immunoglobulin for prophylaxis is mandatory in those patients. In case of Lyme borreliosis of the mother, adequate antibiotic therapy with amoxicillin prevents harm to the fetus. Doxycycline is contraindicated during pregnancy. Scabies represents an important differential diagnosis of pruritic dermatoses in pregnancy and should be treated with permethrin 5% cream.

Autoantibodies against desmocollins in European patients with pemphigus.

BACKGROUND: Autoimmune bullous disorders of the pemphigus group are characterized by autoantibodies targeting desmoglein (Dsg)1, Dsg3 and Dsg4 and occasionally, desmocollin (Dsc)1, Dsc2 and Dsc3. Both Dsg and Dsc are components of desmosomal adhesion complexes. AIM: To investigate the presence of IgG and IgA autoantibodies against Dsc1, Dsc2 and Dsc3 in a cohort of patients with bullous disorders. METHODS: IgG and IgA autoantibodies against Dsc1, Dsc2 and Dsc3 were investigated by ELISA and immunoblotting analysis in a cohort of European patients with pemphigus vulgaris (PV; n = 74), IgA pemphigus (n = 3), paraneoplastic pemphigus (PNP; n = 3) and two cases of atypical pemphigus (n = 2). RESULTS: Of the two cases with atypical pemphigus, one showed IgA reactivity against Dsc1 and Dsc3 and weak reactivity against Dsc2, and the other showed both IgG and IgA reactivity against Dsc1. One patient with IgA pemphigus had IgA autoantibodies against Dsc1, Dsc2 and Dsg1, and one patient with PNP had IgG reactivity against with Dsc3. In contrast, all the PV sera showed IgG reactivity against Dsg3 but not against Dsc1-3. Thus, IgG and IgA reactivity against Dsc was restricted to cases of PNP, IgA pemphigus and atypical pemphigus. CONCLUSIONS: These findings support the concept that desmocollins are not important autoantigens in PV.

Differential expression of cytokine mRNA in skin specimens from patients with erythema migrans or acrodermatitis chronica atrophicans.

Erythema migrans, the characteristic skin manifestation of acute Lyme borreliosis, is a self-limited lesion. In contrast, acrodermatitis chronica atrophicans, the typical cutaneous manifestation of late Lyme borreliosis, is a chronic skin condition. In an effort to understand pathogenic factors that lead to different outcomes in dermatoborrelioses, skin biopsy samples from 42 patients with erythema migrans and 27 patients with acrodermatitis chronica atrophicans were analyzed for mRNA expression of five pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interferon-gamma, and interleukin-2) and two anti-inflammatory cytokines (interleukin-4 and interleukin-10) by in situ hybridization with cytokine-specific riboprobes. Among the 27 patients who had erythema migrans alone with no associated signs or symptoms, the major cytokines expressed in perivascular infiltrates of T cells and macrophages were the pro-inflammatory cytokine interferon-gamma and the anti-inflammatory cytokine interleukin-10. In the 15 erythema migrans patients who had associated signs and symptoms, including headache, elevated temperature, arthralgias, myalgias, or fatigue, a larger number of macrophages and greater expression of macrophage-derived pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6, were also found. In comparison, infiltrates of T cells and macrophages in the skin lesions of acrodermatitis chronica atrophicans patients had very little or no interferon-gamma expression. Instead, they usually expressed only the pro-inflammatory cytokine tumor necrosis factor alpha and the anti-inflammatory cytokine interleukin-4. Thus, the activation of pro-inflammatory cytokines in erythema migrans lesions, particularly interferon-gamma, seems to be important in the control of the spirochetal infection. In contrast, the restricted pattern of cytokine expression in acrodermatitis chronica atrophicans, including the lack of interferon-gamma, may be less effective in spirochetal killing, resulting in the chronicity of this skin lesion. J Invest Dermatol 115:1115-1123 2000

Topical treatment with liposomes containing T4 endonuclease V protects human skin in vivo from ultraviolet-induced upregulation of interleukin-10 and tumor necrosis factor-alpha.

Exposing human skin to ultraviolet radiation causes DNA damage, sunburn, immune alterations, and eventually, skin cancer. We wished to determine whether liposomes containing a DNA repair enzyme could prevent any of the acute effects of irradiation when applied after ultraviolet exposure. Fifteen human patients with a prior history of skin cancer were exposed to two minimal erythema doses of ultraviolet radiation on their buttock skin. Liposomes containing T4 endonuclease V or heat-inactivated enzyme were applied immediately and at 2, 4, and 5 h after ultraviolet irradiation. Transmission electron microscopy after anti-T4 endonuclease V-staining and immunogold labeling on biopsies taken at 6 h after ultraviolet exposure revealed that the enzyme was present within cells in the skin. Immunohistochemical DNA damage studies suggested a trend toward improved DNA repair at the active T4 endonuclease V liposome-treated test sites. Although the active T4 endonuclease V liposomes did not significantly affect the ultraviolet-induced erythema response and microscopic sunburn cell formation, they nearly completely prevented ultraviolet-induced upregulation of interleukin-10 and tumor necrosis factor-alpha RNA message and of interleukin-10 protein. These studies demonstrate that liposomes can be used for topical intracellular delivery of small proteins to human skin and suggest that liposomes containing DNA repair enzymes may provide a new avenue for photoprotection against some forms of ultraviolet-induced skin damage.

Phenotypic markers, sunlight-related factors and sunscreen use in patients with cutaneous melanoma: an Austrian case-control study.

Sunscreens have been advocated to prevent burning in the hope that this will decrease the chance of developing melanoma. In a single-centre case-control study in Styria, Austria, we examined the risk of cutaneous malignant melanoma in relation to phenotypic markers, sunlight-related factors and sunscreen use. In total, 193 melanoma patients and 319 control subjects answered a comprehensive questionnaire regarding phenotypic markers, a variety of sunlight-related factors and sunscreen use. Risk factors for melanoma were examined through the use of unconditional logistic regression analysis, controlling for age and sex. Screening for confounding factors was done by forward and backward elimination of non-significant variables (P < 0.05). The resulting set of factors were investigated further for effect modification by introducing interactions into the model. The factor most significantly associated with increased melanoma risk was the use of sunscreens. Subjects who often used sunscreens had an increased odds ratio (OR) of 3.47 (95% confidence interval [CI]1.81-6.64) compared with subjects who never used sunscreens (P = 0.001), after adjustment for sex, age and other significant sunlight-related factors. Skin colour and higher numbers of sunbaths were significant protective factors. Subjects with medium skin colour had an adjusted OR of 0.63 (95% CI 0.41-0.99) compared with subjects with light skin colour (P = 0.0022). Subjects who took more than 30 sunbaths per year and subjects who took 20-30 sunbaths per year had, in the absence of sunburn(s), a decreased OR of 0.09 (95% CI 0.02-0.39) and 0.28 (95% CI 0.13-0.64), respectively, compared with subjects who took less than 20 sunbaths per year (P = 0.0002). However, sunbaths had no protective value when they were associated with sunburns. Although we cannot exclude the presence of an unknown confounding factor, our results suggest that the use of sunscreens does not help prevent melanoma.

Resolution of granulomatous rosacea after eradication of Helicobacter pylori with clarithromycin, metronidazole and pantoprazole.

The aetiopathogenetic role of Helicobacter pylori in rosacea remains controversial. We report a 27-year-old man with a 4-year history of intractable rosacea. Histopathology showed epithelioid granulomas. H. pylori infection was proven directly on gastroscopy and by serological testing. Treatment with clarithromycin, metronidazole and pantoprazole eradicated H. pylori. Skin changes were markedly improved by the end of this therapy and had resolved completely 2 months later. The patient has been followed up, and has remained free of symptoms for 3 years. We suggest that H. pylori may be involved in the aetiopathogenesis of granulomatous rosacea.

Is serological follow-up useful for patients with cutaneous Lyme borreliosis?

Serologic follow-up examinations are frequently performed in patients with erythema migrans, borrelial lymphocytoma, and acrodermatitis chronica atrophicans (the 3 dermatoborrelioses) to evaluate treatment efficacy. There is, however, substantial proof in the literature that antibody titer development after therapy is unpredictable and variable, and moreover it is largely uncorrelated with the clinical course and mode of antibiotic treatment. For example, persistent positive IgG and/ or IgM antibody titers do not indicate treatment failure. Thus, repeated serologic testing is of very limited value for assessing therapy efficacy, and therefore not recommended in the follow-up of dermatoborrelioses patients. Since cultivation of the etiologic agent, Borrelia burgdorferi sensu lato, and polymerase chain reaction are also inadequate for this purpose, the assessment of patients with cutaneous manifestations of Lyme borreliosis in the follow-up rests primarily on the clinical picture.

The impact of immunosuppression on erythema migrans. A retrospective study of clinical presentation, response to treatment and production of Borrelia antibodies in 33 patients.

BACKGROUND: Little is known about the potential influence of immunosuppression on erythema migrans, the hallmark of early Lyme borreliosis. METHODS: We performed a retrospective study to assess the impact of immunosuppression on erythema migrans in 33 patients with a malignant or autoimmune disease, chronic infection, or immunosuppressive therapy for organ transplantation. Only patients with active disease status and/or current immunosuppressive therapy were included. Pre-treatment clinical parameters, such as presentation of the skin lesion and presence of extracutaneous signs and symptoms, the disease course during a median follow-up of 9 months after therapy and serum anti-Borrelia burgdorferi antibodies before therapy and by the end of follow-up in the 33 immunosuppressed patients were statistically compared with 75 otherwise healthy patients with erythema migrans. The 75 control patients were matched for sex, age and antibiotic therapy. RESULTS: With the exception of the site of erythema migrans lesions, which were found more often on the trunk than on the legs in the immunosuppressed patients (vice versa in immunocompetent patients), we found no significant differences for all investigated parameters between the two groups. CONCLUSIONS: It appears that immunosuppression does not influence clinical presentation, response to therapy, or production of anti-B. burgdorferi antibodies of patients with erythema migrans. It is thus not necessary to treat immunosuppressed patients with erythema migrans differently from immunocompetent patients.

Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients.

BACKGROUND: Polymorphic eruption of pregnancy (PEP; synonym: pruritic urticarial papules and plaques of pregnancy) is the most common specific dermatosis of pregnancy. However, its clinical characterization is controversial and its pathogenesis uncertain. OBJECTIVES: To evaluate clinical characteristics of and potential trigger factors for PEP in a large mixed ethnic population. METHODS: A retrospective analysis of epidemiological, clinical, immunopathological and obstetric findings in 181 patients with PEP seen at two university-based dermatological hospitals in Graz, Austria, and London, U.K. RESULTS: PEP mainly affected white (88%) primigravidae (70%) in late pregnancy (83%; mean +/- SD onset 34 +/- 5 weeks) or the immediate postpartum period (15%). The most commonly involved sites were the abdomen and proximal thighs (97%). Involvement of the whole skin, including the face, palms and soles, was only rarely observed. While pruritic urticarial papules and plaques were the main morphological features at disease onset (98%), more than one-half of the patients (51%) later developed polymorphous features including erythema, vesicles, and targetoid and eczematous lesions. Topical treatment with corticosteroids and emollients was sufficient to control symptoms in the majority of patients, and skin lesions resolved after a mean +/- SD of 4 +/- 3 weeks. Multiple gestation pregnancies were observed in 13% of cases, excessive maternal weight gain in 78%. CONCLUSIONS: Our data confirm the benign, self-limiting nature of PEP and its favourable outcome for both the mother and the fetus. For the first time, we have documented a characteristic change in morphology with disease progression. The evidence of polymorphous clinical features in more than one-half of the patients favours the use of the term PEP. Multiple gestation pregnancies and excessive maternal weight gain, but not fetal weight and sex, were found to be significantly associated with PEP.

Grover's disease associated with Sarcoptes scabiei.

An 83-year-old man presented with a 4-month history of discrete, itchy papules mainly distributed on the trunk and upper extremities. Histopathologic examination of two biopsies from lesions on the trunk revealed mainly focal suprabasal acantholysis and an inflammatory infiltrate composed mainly of lymphocytes with a few eosinophils. The overall clinical and histopathologic features were consistent with Grover's disease. However, scrapings taken from the skin lesions showed numerous mites of Sarcoptes scabiei. Subsequent treatment with an antiscabies cream led to a rapid complete cure, and no skin lesions have been observed during a 6-month follow-up. A review of the literature revealed 2 other cases of cutaneous lesions fulfilling the clinical and histopathologic features of Grover's disease in which mites of S. scabiei were demonstrated. Our observation further highlights the unusual association of Grover's disease with S. scabiei mites and emphasises the importance of excluding this easily treatable skin infestation in all patients with Grover's disease.

Lyme borreliosis of central nervous system (CNS) in children: a diagnostic challenge.

Within 24 months in a consecutive series of 84 children with neurological symptoms indicative of Lyme borreliosis of the central nervous system (CNS) 45 seronegative children (group III), 17 seropositive (group II), and 22 children with specific Borrelia burgdorferi results in cerebrospinal fluid (CSF)-i.e. B. burgdorferi antibodies and/or intrathecally produced B. burgdorferi antibodies and/or positive B. burgdorferi culture in CSF were observed. The results show that intrathecally produced B. burgdorferi antibodies are the most important marker for the diagnosis of neuroborreliosis (with 71.4% positives) and B. burgdorferi cultivation directly from CSF may be successful in the earliest phase of the disease. Since each of the specific CSF parameters may be false negative in some cases, a careful synopsis of laboratory parameters was done. It shows that CSF protein and CSF cell values are higher in group I than in II or III. Neither can seronegativity exclude nor can seropositivity confirm the diagnosis of neuroborreliosis as in only 71% of group I serum B. burgdorferi antibodies were detected. In view of these aspects clinical and laboratory results are discussed.

Penicillin G sodium and ceftriaxone in the treatment of neuroborreliosis in children--a prospective study.

A controlled clinical study was set up to examine whether penicillin G sodium (PG) or ceftriaxone (C) is superior in the treatment of acute neuroborreliosis in childhood. Within a time period of 18 months 77 children with symptoms indicative of Lyme borreliosis of the central nervous system (CNS) were seen. In 23 of these children Borrelia burgdorferi specific cerebrospinal fluid (CSF) parameters confirmed the diagnosis of a neuroborreliosis. These children were treated at random with intravenous (i.v.) PG 400,000-500,000 I.U./kg/day for 14 days (group I) or with i.v. ceftriaxone 75-93 mg/kg/day for 14 days (group II), respectively. Clinical examination and a set of diagnostic laboratory parameters were done at admission, right after therapy, three, six and partly 12 months after therapy. The general condition of all children in both groups improved dramatically during antibiotic therapy, and no relapse occurred within the observation period. Considering the clear and comparable decrease of B. burgdorferi serum titres and the clinical outcome (duration of disease and follow-up for at least six months) in children of both groups no difference between both antibiotic drugs can be demonstrated.