Secukinumab efficacy and safety in indian patients with moderate-to-severe plaque psoriasis: Sub-analysis from FIXTURE, a randomized, placebo-controlled, phase 3 study.

TITLE: Secukinumab efficacy and safety in Indian patients with moderate-to-severe plaque psoriasis: sub-analysis from FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), a randomized, placebo-controlled, phase 3 study. BACKGROUND: Evidence has suggested Interleukin (IL)-17A to be an important effector cytokine in the pathogenesis of psoriasis. Here, we report results for an Indian sub-population from a multinational study FIXTURE, designed to assess the safety, tolerability, and long-term efficacy of fully human anti-IL-17A monoclonal antibody secukinumab in patients with moderate-to-severe plaque psoriasis. MATERIALS AND METHODS: In this double-dummy, placebo controlled, 52-weeks phase 3 study FIXTURE, 149 Indian patients were randomized 1:1:1:1 to receive secukinumab at a dose of 300 mg or 150 mg, etanercept, or placebo. The study objective was to show the superiority of secukinumab over placebo at week 12, vis-à-vis proportion of patients achieving a reduction of 75% or more from the baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (IGA mod 2011) (co-primary end points). RESULTS: At week 12, 61.0% and 55.9% patients in secukinumab 300 mg and 150 mg groups, respectively, achieved PASI 75 response compared to 20.0% in the etanercept and 7.1% in the placebo groups. Similarly, IGA mod 2011 0 or 1 response was achieved by 43.9% and 20.6% in patients in the secukinumab 300 mg and 150 mg group, respectively, vs. 13.3% in the etanercept and 2.4% in the placebo groups at week 12. Likewise, higher proportions of patients in secukinumab 300 mg (41.5%) and 150 mg (20.6%) group were PASI 90 responders at week 12 than those in the etanercept (10.0%) or placebo (0.0%) groups. The incidences of adverse events (AEs), during the induction period were similar in all the treatment groups. Overall secukinumab was well-tolerated at both doses in the Indian sub-population. CONCLUSION: The results from the Indian sub-population suggest that secukinumab is an efficacious and safe drug for use in moderate-to-severe chronic plaque psoriasis.

Association of tumor necrosis factor-alpha and interferon gamma gene polymorphisms and their plasma levels in leprosy, HIV and other peripheral neuropathies.

OBJECTIVE: Mycobacterium leprae and Human Immunodeficiency Virus (HIV) are causative agents known to be involved in nerve damage in leprosy and HIV-peripheral neuropathy (HIV-PN) respectively. Among other peripheral neuropathies the most common is diabetic neuropathy, which is metabolically induced. The proinflammatory cytokines TNF-α and IFN-γ have been implicated in the pathogenesis of peripheral neuropathy. The association between the plasma levels of these cytokines and their single nucleotide polymorphisms (SNPs) were investigated in leprosy neuropathy (LN), HIV-PN and other peripheral neuropathies (OPN). METHODS: Eighty-eight individuals with LN (PB=36; MB=52), 39 with HIV-PN, 52 patients with OPN, 101 HIV positive individuals without neuropathy (HIV) and 113 healthy subjects (HS) were included in the study. Plasma cytokine levels were measured by sandwich ELISA and one way ANOVA was carried out among the groups. SNPs of TNF-α- 308 G/A, -238 G/A and IFN-γ +874 T/A were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Their frequencies were compared between groups by Pearson's chi squared test. RESULTS: Plasma TNF-α and IFN-γ was significantly increased in LN (p<0.05), HIV-PN (p<0.05) and OPN (p<0.05) as compared to HS. A significant association was found between IFN-γ +874 A/A genotype in LN (p<0.05; OR=7.9), HIV-PN (p<0.05; OR=8.9) and OPN (p<0.05; OR=8.9) as compared to HS. CONCLUSION: Elevated levels of plasma TNF-α and IFN-γ and the association of IFN-γ +874 A/A genotype SNP in LN, HIV-PN and OPN suggests a common involvement of these cytokines in susceptibility/pathogenesis of peripheral neuropathy.

Changes in the size and number of skin lesions in PB leprosy on treatment and follow-up.

BACKGROUND: The increase in size of existing skin lesions and appearance of new skin lesions are considered important signs of clinical activity both in untreated and treated leprosy. To confirm such activity, the number and size of lesions need to be recorded methodically prior to therapy and on follow-up, especially in PB leprosy where clinical signs alone define the reactivation of the disease. However, no systematic follow-up studies are available on changes in size and number of skin lesions in PB leprosy before and after therapy. OBJECTIVES: To measure changes in the number and size of skin lesions in PB leprosy patients before starting MDT PB and after 18 months follow-up in order to evaluate their relevance in assessing clinical improvement and identifying possible relapses. DESIGN: In 32 untreated leprosy patients with 1-5 skin lesions, the number of skin lesions were recorded on body charts and their size measured using a grid chart method to arrive at total area of involvement in each patient prior to starting MDT PB and after 18 months. Skin smears and skin biopsies were performed at entry and follow-up to assist the clinical evaluation. RESULTS: Twenty three patients had single skin lesion (SSL), followed by three each with two and three skin lesions respectively, two with four and one with five skin lesions. The area of involvement ranged from six to 1686 sq cm. Few patients with SSL had higher areas of involvement than those who had multiple skin lesions. On follow-up at 18 months, in 14 (44%) patients skin lesions were not measurable, while in 18 (56%) they were measurable, with eight (25%) patients showing no change, three (9%) showing decrease and seven (22%) showing increase in area of involvement. Of the seven patients showing increase, in three it was due to the spread of existing skin lesions alone, in one it was due to a new skin lesion alone and in three due to the spread of existing skin lesions and the appearance of new skin lesions. New skin lesions were multiple (> 3) in two patients. T1R was observed in three out of four patients with new skin lesions, and this was persistent at 18 months in one patient. When histopathology at the entry and 18 month follow-up was compared, in one patient with persistent T1R with appearance of multiple new skin lesions, there was increase in GF from 10 to 40% with histological features of T1R and a BI of granuloma of 1+. CONCLUSIONS: In 32 treated patients of PB leprosy on 18 month follow-up for changes in size and number of skin lesions, of six patients showing increase in area of involvement of existing skin lesions, 3 (50%) developed new skin lesions, indicating persistent disease activity. The new lesions which were associated with T1R increased the total number of skin lesions to > 5 in two of these patients requiring a change of drug regimen from PB to MB MDT, with one of them fulfilling clinical and histopathological criteria for relapse of leprosy. Hence, although new lesions are known to occur as part of T1R in PB patients, they are events of great significance which need to be assessed in a methodical manner for their influence on classification and therapy of leprosy.

Efficacy and safety of topical halometasone in eczematous dermatoses in Indian population: an open label, noncomparative study.

BACKGROUND: Topical steroids remain the mainstay of treatment in eczema, an inflammatory skin reaction characterized by pruritus, redness, scaling, and clustered oozing papulovesicles. Halometasone is a new potent corticosteroid approved in the Indian market for topical application in the treatment of dermatitis. AIMS: To evaluate the efficacy and safety of halometasone in the treatment of acute or chronic noninfected eczematous dermatosis in Indian population. MATERIALS AND METHODS: A prospective, open, multicentric, phase 3, noncomparative clinical trial conducted at outpatient departments of seven centres. Two hundred endogenous eczema patients meeting study criteria were enrolled. Halometasone 0.05% cream was applied twice daily for 30 days in chronic and 20 days in acute eczema patients. Calculation of eczema area and severity index, and assessment of investigator's global assessment of severity of eczema and severity of pruritus score were done at each visit and compared with baseline. All adverse events (AE) were captured and documented. Laboratory investigations including haematological tests, urinalysis, renal and liver function tests were performed at baseline and at end of treatment. RESULTS: Of the 200 patients enrolled, 180 were chronic and 20 were acute eczema patients. It was found that there was a significant (P<0.001) improvement in all efficacy parameters compared with baseline. The treatment was shown to be successful in 91% patients. AE were reported in 30 patients and there was no serious AE reported. There was no clinically significant difference in laboratory investigations with treatment. CONCLUSIONS: Halometasone was shown to be safe and very effective in Indian patients with acute and chronic eczema and the drug was well tolerated.

Comparative study of uniform-MDT and WHO MDT in Pauci and Multi bacillary leprosy patients over 24 months of observation.

STUDY DESIGN: An open comparative study between WHO MDT and U-MDT regimen in all types of leprosy over 24 months of observation was carried out at Gandhi Hospital, Secunderabad, India. Periodic assessment of clinical and histopathological parameters at 6 monthly intervals was performed in both groups of patients for grading response to the treatment regimens. PATIENTS AND METHODS: One hundred and twenty-seven newly diagnosed, untreated leprosy patients classified into PB (< or = 5 skin lesions) and MB leprosy (> 5 skin lesions) were alternately allocated into Study (U-MDT for 6 months) and Control groups (WHO MDT) at entry. Out of the 127 patients included, 64 patients (M-44, F-20; PB leprosy 32 & MB leprosy 32) could be followed-up regularly. These 64 patients were clinically assessed and graded into Good, Moderate and Poor response at 6, 12 and 18 months of the study, and 44 of these patients were also assessed at 24 months of the study. Histopathological assessments were also done at the above intervals. RESULTS: PB PATIENTS: The control and study groups comprised of 14 and 18 patients respectively. When clinical grades were compared, the numbers of Moderate and Good responses were 78% and 61% at 6 months, 86% and 94% at 18 months and 82% and 100% at 24 months in the PB Control and Study groups respectively, suggesting better progressive improvement in the Study group compared to Control group, but the differences were not significant (At 6 months P = 02195, at 18 months 0.7305, at 24 months P = 0.3500) Histopathological assessment at 12 months, showed higher percentage of Good responses (100%) in the PB-Study group than in the PB-Control group (86%). MB PATIENTS: The MB Control and Study groups comprised of 22 and 10 patients respectively. In clinical improvement grades, Good responses in the Control group was 36%, 45% and 77% at 12, 18 and 24 months of study, whereas the Study group did not have a single Good response at 12 and 18 months with the Poor responses being 50%, 67% and 75% at 12, 18 and 24 months. These differences between the groups were significant at all periods of assessment. (At 12 months P = 0.0465, at 18 months P = 0.0014, at 24 months P = 0.0064). Histopathological assessment showed higher the percentage of Good responses in Control group (100%) compared to Study group (50%) at 18 months. CONCLUSION: U-MDT of 6 months duration was well tolerated and effective in patients with PB leprosy but was too short a regimen adequately to treat patients with MB leprosy.