Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches.

BACKGROUND: Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar. OBJECTIVES: To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. METHODS: This 51-week double-blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref-ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups. RESULTS: Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI -7·46 to 11·15) and key secondary end points (-60·7% and -61·5%, respectively; 95% CI -3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching. CONCLUSIONS: Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity.

A novel vaccine (Zostavax) to prevent herpes zoster.

Varicella-zoster virus is the causal agent of varicella and herpes zoster (HZ) in humans. HZ results from reactivation of latent varicella-zoster virus (VZV) within the sensory ganglia. The incidence and severity of HZ increase with advancing age; more than half of all persons in whom HZ develops are older than 60 years. The most frequent debilitating complication is postherpetic neuralgia, a neuropathic pain syndrome that persists or develops after the dermatomal rash has healed, and can be prolonged and disabling. There are many limitations of the current therapies for HZ and postherpetic neuralgia. A live attenuated VZV vaccine has been developed and recently approved by the United States Food and Drug Administration (FDA) and the European Union for the prevention of HZ in individuals 60 years of age and older. In a randomized, double-blind, placebo-controlled trial 38,546 adults of 60 years of age or older, the use of the HZ vaccine reduced the burden of illness due to HZ by 61.1% (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5% (P<0.001), and reduced the incidence of HZ by 51.3% (P<0.001). In this review, the authors will discuss the history of the use of the varicella vaccine in children, and the subsequent development of the new HZ vaccine.

Lipotoxicity.

Excess fatty acids accompanied by triglyceride accumulation in parenchymal cells of multiple tissues including skeletal and cardiac myocytes, hepatocytes, and pancreatic beta cells results in chronic cellular dysfunction and injury. The process, now termed lipotoxicity, can account for many manifestations of the 'metabolic syndrome'. Most data suggest that the triglycerides serve primarily a storage function with toxicity deriving mainly from long-chain nonesterified fatty acids (NEFA) and their products such as ceramides and diacylglycerols. In the kidney, filtered NEFA carried on albumin can aggravate the chronic tubule damage and inflammatory phenotype that develop during proteinuric states and lipid loading of both glomerular and tubular cells is a common response to renal injury that contributes to progression of nephropathy. NEFA-induced mitochondrial dysfunction is the primary mechanism for energetic failure of proximal tubules during hypoxia/reoxygenation and persistent increases of tubule cell NEFA and triglycerides occur during acute renal failure in vivo in association with downregulation of mitochondrial and peroxisomal enzymes of beta oxidation. In acute renal failure models, peroxisome proliferator-activated receptor alpha ligand treatment can ameliorate the NEFA and triglyceride accumulation and limits tissue injury likely via both direct tubule actions and anti-inflammatory effects. Both acute and chronic kidney disease are associated with systemic manifestations of the metabolic syndrome.

Morphoea of the breast in a young girl.

Localized morphoea is an uncommon sclerosing skin disorder. Prognosis is usually good but it may lead to contractures, perturbed limb growth, atrophy, pigmentary changes and cosmetic disturbance. We describe a case of morphoea that developed in one breast in a 9-year-old white female. Treatment comprised topical ammonium lactate 12% cream and tretinoin 0.025% cream but no topical corticosteroids were prescribed. One year later she was noted to have bilateral symmetrical breast development and, although signs of morphoea were still present in one breast, the plaque had softened and there was no breast deformity. It is important to remember that most cases of morphoea improve spontaneously, although a number of possible therapeutic options may be indicated in some patients.

The ocular manifestations of rosacea.

The ocular manifestations of rosacea are commonly nonspecific and variable. The etiology of the inflammation is unknown and there is no diagnostic test for the disease. Ocular rosacea is often underdiagnosed, despite the potential for serious sight-threatening sequelae. When evaluating patients with rosacea, dermatologists should obtain a careful history of eye complaints and examine the eyelid margins thoroughly. Treatment is aimed at controlling symptoms and is multifaceted. The foundation of treatment is good lid hygiene and oral tetracyclines. Those patients with moderate-to-severe ocular findings will benefit from a multidisciplinary approach, including evaluation by an ophthalmologist.

Short-duration oral terbinafine for the treatment of tinea pedis in HIV-positive patients.

Management of tinea pedis in patients who have the human immunodeficiency virus (HIV) is problematic; in those patients, dermatophytoses may be more difficult to treat than in the general population. This prospective, open-label, multicenter, randomized study evaluated the efficacy and safety of a short course of oral terbinafine for tinea pedis in patients who are HIV positive. Twenty-seven patients were randomized to receive oral terbinafine 250 mg once daily for 2 or 4 weeks; 17 patients with positive initial cultures and follow-up cultures were evaluable for efficacy at week 8. Mycological cure (defined as negative potassium hydroxide [KOH] microscopy and culture results) occurred in 47% (8) of patients; and modified mycological cure (defined as negative follow-up cultures) occurred in 65% (11) of patients. All 27 patients were evaluated for safety. Clinical cure (defined as minimal residual signs and symptoms) occurred in 82% (14) of patients. Oral terbinafine was well tolerated, indicating that regimens of 2 or 4 weeks are safe and effective for the treatment of tinea pedis in patients who are HIV positive.

Erythema elevatum diutinum in a patient with human immunodeficiency virus.

Erythema elevatum diutinum (EED) is a chronic cutaneous leukocytoclastic vasculitis. This rare disease is characterized by red, brownish-purple, and yellow papules, plaques, and nodules distributed symmetrically about the extremities. There have been recent reports of the disease in association with infection with the human immunodeficiency virus (HIV). We describe the case of a 51-year-old man with HIV who presented with EED, which was successfully treated with dapsone.

Energetic determinants of tyrosine phosphorylation of focal adhesion proteins during hypoxia/reoxygenation of kidney proximal tubules.

Anaerobic mitochondrial metabolism of alpha-ketoglutarate and aspartate or alpha-ketoglutarate and malate can prevent and reverse severe mitochondrial dysfunction during reoxygenation after 60 minutes of hypoxia in kidney proximal tubules.(34) The present studies demonstrate that, during hypoxia, paxillin, focal adhesion kinase, and p130(cas) migrated faster by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, their phosphotyrosine (pY) content decreased to approximately 5% of that in oxygenated tubules without changes in total protein, and the normally basal immunostaining of beta1 and alpha6 integrin subunits, pY, and paxillin was lost or markedly decreased. During reoxygenation without supplemental substrates, recovery of pY and basal localization of the focal adhesion proteins was poor. alpha-Ketoglutarate and aspartate, which maintained slightly higher levels of ATP during hypoxia, also maintained 2.5-fold higher levels of pY during this period, and promoted full recovery of pY content and basal localization of focal adhesion proteins during subsequent reoxygenation. Similarly complete recovery was made possible by provision of alpha-ketoglutarate and aspartate or alpha-ketoglutarate and malate only during reoxygenation. These data emphasize the importance of very low energy thresholds for maintaining the integrity of key structural and biochemical components required for cellular survival and reaffirm the value of approaches aimed at conserving or generating energy in cells injured by hypoxia or ischemia.