Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial.

BACKGROUND: Fumaric acid esters (FAEs; Fumaderm® ) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi® ) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. OBJECTIVES: To compare risankizumab treatment to FAEs in patients with psoriasis. METHODS: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. RESULTS: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. CONCLUSIONS: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

Fumaric acid ester-induced T-cell lymphopenia in the real-life treatment of psoriasis.

BACKGROUND: Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes. OBJECTIVE: To evaluate the influence of long-term FAE (Fumaderm® ) treatment on peripheral blood CD4+ and CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells in psoriasis. METHODS: In this single-centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. RESULTS: FAEs significantly reduced the numbers of CD4+ T, CD8+ T, CD19+ B and CD56+ NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD8+ T cells, with a peak of 55.7% after 2 years of therapy. The risk of T-cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T-cell lymphopenia enhances the effectiveness of FAE therapy. CONCLUSIONS: Monitoring distinct T-cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4+ and CD8+ T-cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence-based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAEs and who develop low absolute T-cell counts.

Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study.

BACKGROUND: Fumaric acid esters (FAEs) are an established systemic treatment for moderate-to-severe psoriasis. However, the long-term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established. OBJECTIVE: To examine the long-term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany. METHODS: This monocentric, retrospective observational study, with a follow-up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate. RESULTS: Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2-point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001). CONCLUSION: According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long-term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration.

The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide in the treatment of hypertension.

INTRODUCTION: Hypertension is a leading cause of cardiovascular morbidity and mortality, and uncontrolled hypertension remains common despite the availability of several classes of effective antihypertensive medications. Combination therapy with antihypertensive agents of complementary actions has been advocated in the management of hypertension to maximize efficacy and minimize side effects. AREAS COVERED: This review summarizes the current data on the triple combination therapy of aliskiren with amlodipine and hydrochlorothiazide, and discusses the clinical use of single pill triple combination of aliskiren, amlodipine and hydrochlorothiazide in the treatment of hypertension and associated cardiovascular conditions. EXPERT OPINION: Combination therapy with antihypertensive agents of complementary actions is more effective than monotherapy in the management of hypertension. Combining an agent in renin-angiotensin blockade with a dihydropyridine calcium channel blocker (CCB) and a thiazide diuretic has plausibility in maximizing blood pressure reduction and minimizing side effects. The combination of aliskiren with amlodipine and hydrochlorothiazide has shown effective blood pressure lowering and noteworthy tolerability. The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide offers five different formulations of escalating dosages of the three agents, allowing dosing flexibility. The decreased pill burden and simplified treatment options with the single pill triple combination provide an opportunity to improve blood pressure control through improved adherence and reduced treatment inertia.

[Clinical aspects of antimicrobial therapy used in patients with urogenital infections].

AIM: To study the clinical aspects of using the furasidine potassium in combination with basic magnesium carbonate (furamag) and phosphomycin trometamol (monural) as antimicrobial agents most frequently used in outpatient practice during combination therapy for acute and chronic urinary tract (UT) diseases. SUBJECTS AND METHODS: To study the specific features of therapy for UT infections, 60 patients were randomized to 2 groups: 1) 30 patients received a course therapy with furasidine potassium (furamag) in a dose of 50 mg t.i.d. for 7 days (a study group) and 2) 30 had phosphomycin trometamol (monural) in a single dose of 3 g for pulse therapy (a comparison group). The clinical efficacy of the drugs, symptom disappearance rates, bacterial changes, and laboratory and instrumental findings were assessed. The patient's opinion was mainly used to evaluate outpatient pharmacoeconomic efficiency. Patient compliance with the given therapy was estimated by taking into account the specific features of prehospital care. RESULTS: During therapy, both groups showed positive clinical changes. In the study group, the symptoms of dysuria resolved 0.5 days more quickly and a complete clinical remission was achieved 0.8 days more promptly; the latter within the first 72 hours was achieved by 7.5% more of the patients; the symptoms of bacteriuria resolved 0.6 days more rapidly. With the similar average price of the packs of furasidine potassium (furamag) 50 mg (30 capsules) and phosphomycin trometamol (monural) 1 g (a sachet) being 350 and 370 rubles, the average costs of required treatment were 482 and 546 rubles, respectively. No case of adverse reactions was recorded during the study. CONCLUSION: Patients with infectious and inflammatory diseases of UT should be given furasidine potassium in the standard dose of 50 mg t.i.d for 7 days.

Aliskiren: beyond blood pressure reduction.

IMPORTANCE OF THE FIELD: Hypertension is one of the most important risk factors and causes of cardiovascular disease (CVD). From some years, renin-angiotensin-aldosterone system (RAAS) inhibitors such angiotensin converting enzyme (ACE) and angiotensin receptor blockade (ARB) have been of interest, not only for better blood pressure (BP) control but also for their involvement in the mechanisms of various organ functions. AREAS COVERED IN THIS REVIEW: The aim of this review is to focus on the effectiveness and safety of aliskiren beyond the treatment of hypertension. WHAT THE READER WILL GAIN: Aliskiren, the first approved renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic non-peptide molecule that blocks angiotensin I generation. Because of its mechanism of action, aliskiren may offer the additional opportunity to inhibit progression of atherosclerosis at tissue level and the potential to be useful in a wide spectrum of conditions. However, we will discuss how it might become a reasonable therapeutic choice also in a broad number of clinical conditions, sharing an increased cardiovascular risk as stable coronary artery disease (CAD), microvascular and cardio-renal disease, diabetes, and peripheral arterial disease (PAD). TAKE HOME MESSAGE: Therapy of hypertension through a better blockade of RAAS may be the first step in also achieving interesting results in the complications that hypertension causes in several organs.

Long-term safety, tolerability and efficacy of combination therapy with aliskiren and amlodipine in patients with hypertension.

OBJECTIVE: Most patients with hypertension require antihypertensive combination therapy to achieve BP control. This study investigated the safety and efficacy of the direct renin inhibitor aliskiren combined with the calcium channel blocker amlodipine. METHODS: Overall, 556 patients with hypertension (msDBP > or =95-<110 mmHg) received open-label aliskiren/amlodipine 150/5 mg for 2 weeks, followed by forced titration to aliskiren/amlodipine 300/10 mg for 52 weeks. Add-on hydrochlorothiazide (HCT) was permitted from week 10 to achieve BP control (<140/90 mmHg). The primary objective of the study was to evaluate the long-term safety and tolerability of aliskiren/amlodipine combination therapy; the BP-lowering efficacy of the combination was also assessed (week 54 endpoint; last observation carried forward). TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00402103. RESULTS: In total, 452 patients completed 54 weeks' treatment with aliskiren/amlodipine 300/10 mg, with or without add-on HCT. The most frequently reported adverse events (AEs) were peripheral edema, upper respiratory tract infection, headache and bronchitis. Peripheral edema (the most common AE), occurred in 22.7% of treated patients, and was generally mild or moderate in intensity and transient in nature. Few patients exhibited laboratory abnormalities. Aliskiren/amlodipine combination therapy provided a mean BP reduction from baseline to week 54 of 24.2/15.5 mmHg; 74.3% of patients achieved BP control. In the subgroup of patients with stage 2 hypertension (baseline msSBP > or =160 mmHg and/or msDBP > or =100 mmHg), the mean BP reduction at week 54 was 29.1/17.1 mmHg, and 67.0% of patients achieved BP control. CONCLUSION: In this open-label study, aliskiren/amlodipine 300/10 mg combination therapy, with or without add-on HCT, effectively reduced BP, particularly in patients with stage 2 hypertension. The most common AE was peripheral edema, consistent with the known AE profile of high-dose (10 mg) amlodipine. Further studies comparing the aliskiren/amlodipine combination with the component monotherapies and other antihypertensive combinations are warranted.

Aliskiren: clinical experience and future perspectives of renin inhibition.

BACKGROUND: Aliskiren, the first renin inhibitor with sufficient bioavailability for oral use, is now available to clinicians treating hypertension. OBJECTIVE: The novel mechanism by which aliskiren works was used to provide understanding of its therapeutic and adverse effects. METHODS: After reviewing physiology and preclinical studies, human studies of aliskiren in hypertension were reviewed. Effects of aliskiren on serum levels and enzymatic activity of renin were explored. RESULTS/CONCLUSIONS: Aliskiren has antihypertensive efficacy similar to existing medications such as thiazide diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and can be used in drug combinations. Preclinical studies indicate possible cardioprotective and renoprotective effects, similar to other inhibitors of the renin-angiotensin cascade, but future studies are needed in humans.

Side effects of oral iron prophylaxis in pregnancy--myth or reality?

BACKGROUND: It is a common belief among women that iron compounds have unpleasant gastrointestinal side effects. OBJECTIVE: To assess the gastrointestinal side effects of iron prophylaxis in pregnancy. METHODS: A randomized, double-blind study comprising 404 healthy pregnant women allocated to four groups taking ferrous iron supplement (as fumarate) in doses of 20 (n = 99), 40 (n = 100), 60 (n = 102) and 80 mg (n = 103) daily from 18 weeks of gestation to delivery. Iron supplement was predominantly taken at bedtime. Gastrointestinal symptoms (nausea, vomiting, epigastric pain, eructation, pyrosis, meteorism, borborygmi, colic pain, flatulence, constipation, thin feces, diarrhea), black feces, and use of laxatives were recorded by interview at 18, 32 and 39 weeks of gestation. RESULTS: The frequencies of gastrointestinal symptoms were not significantly different in the four iron supplement groups either at inclusion or at 32 and 39 weeks of gestation and thus not related to the iron dose. CONCLUSION: This study shows that a supplement of 20-80 mg ferrous iron (as fumarate), taken between meals, has no clinically significant gastrointestinal side effects. The implementation of iron prophylaxis to pregnant women should not be compromised by undue concern of non-existing side effects.

Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks.

Psoriasis is a chronic, recurrent disease that affects between 1% and 3% of the population. Patients with moderate to severe disease generally require phototherapy (e.g. narrowband ultraviolet B radiation), photochemotherapy (oral psoralen plus ultraviolet A radiation) or systemic agents (e.g. ciclosporin, methotrexate, oral retinoids, fumaric acid esters) to control their disease adequately. In general, these therapeutic modalities have proven to be highly effective in the treatment of psoriasis. However, potentially serious toxicities can limit their long-term use. Given that there is no standard therapeutic approach for patients with moderate to severe psoriasis, the benefits and risks of phototherapy, photochemotherapy and systemic therapy must be weighed carefully for each patient, and treatment individualized accordingly. This review summarizes the benefits and risks of traditional, nonbiological therapies for moderate to severe chronic plaque psoriasis.

[Immunomodulating therapy of psoriasis vulgaris]. / Immunmodulierende Therapie bei Psoriasis vulgaris.

BACKGROUND: Newest studies have shown that psoriasis is not primarily a skin disorder but an immunological disturbance under the skin. The skin manifestations are a result of overstimulation of superficial skin cells (Langerhans cells) due to increased production of interleukin 2, 6 and 8 as well as transforming growth-factor-alpha. Interleucin-10 production is diminished. In a recent study (11 German University Skin Clinics) fumaric acid was shown to improve the skin leasons in 80% of treated patients. OWN EXPERIENCES: Our own studies on 54 patients which where treated in addition with intravenous thymus extract (Thymoject) and selenium (Selenase) showed a faster healing rate with fumaric acid alone. From these results one can postulate that the above treatments (fumaric acid, thymus and selenium) have a synergystic effect. CONCLUSIONS: Internal immunmodulating treatments should therefore have preference over external symptomatic treatments like UV-light, ointments, salt water bath, etc.