Manisha Lamba

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis

BACKGROUND Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland. METHODS The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases. RESULTS The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sjögrens syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sjögrens syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sjögrens syndrome), oligoclonal rearrangement in the other. INTERPRETATION Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.

Evaluation of the Effect of Tofacitinib Exposure on Outcomes in Kidney Transplant Patients

Tofacitinib fixed‐dose regimens attained better kidney function and comparable efficacy to cyclosporine (CsA) in kidney transplant patients, albeit with increased risks of certain adverse events. This post‐hoc analysis evaluated whether a patient subgroup with an acceptable risk‐benefit profile could be identified. Tofacitinib exposure was a statistically significant predictor of serious infection rate. One‐hundred and eighty six kidney transplant patients were re‐categorized to above‐median (AME) or below‐median (BME) exposure groups. The 6‐month biopsy‐proven acute rejection rates in AME, BME and CsA groups were 7.8%, 15.7% and 17.7%, respectively. Measured glomerular filtration rate was higher in AME and BME groups versus CsA (61.2 and 67.9 vs. 53.9 mL/min) at Month 12. Fewer patients developed interstitial fibrosis and tubular atrophy (IF/TA) at Month 12 in AME (20.5%) and BME (27.8%) groups versus CsA (48.3%). Serious infections occurred more frequently in the AME group (53.0%) than in BME (28.4%) or CsA (25.5%) groups. Posttransplant lymphoproliferative disorder (PTLD) only occurred in the AME group. In kidney transplant patients, the BME group preserved the clinical advantage of comparable acute rejection rates, improved renal function and a lower incidence of IF/TA versus CsA, and with similar rates of serious infection and no PTLD.

Differentiated thyroid carcinomas with vascular invasion: a comparative study of follicular, Hürthle cell and papillary thyroid carcinoma

Aim: Non‐medullary thyroid carcinomas arise from follicular cells. The purpose of this study is to correlate clinical and pathological properties of these tumours with the rate of distant metastasis from a series of thyroid tumours excised at one institution. Methods: A total of 311 non‐medullary thyroid tumours were identified and divided into: 29 follicular carcinoma (FC), 12 Hürthle cell carcinoma (HC), 13 Hürthle cell papillary thyroid carcinoma (HPTC) with vascular invasion (VI), 32 papillary thyroid carcinoma (PTC) with VI and 225 PTC without VI. The mean follow‐up was 6.5 years with a range of 1‐17 years. The tumours were histologically subdivided into minimal or wide invasion for FC and HC and focal or extensive invasion for PTC and HPTC, and stratified according to status of VI. Results: The rate of distant metastasis was similar for FC, malignant Hürthle cell tumours and PTC with VI, and increased with extent of invasion. VI was seen in 12% of all PTC and 0% of HPTC in this study. PTC without VI were associated with a much lower potential of distant metastasis, were smaller in size and occurred in patients of younger age than PTC with VI. In addition, there was a tendency for increased potential for distant metastases with increased tumour size and patient age for all groups of tumours in the study. Patient age and tumour size appeared to play a smaller role than that of VI in predicting distant metastasis. Conclusions: Our study suggests that the rate of distant metastasis relates to VI, patient age and tumour size, regardless of Hürthle cell, FC or PTC differentiation. PTC of large size, and in patients older than 45 years, have a high propensity for vascular invasion.

Salivary Gland Lymphoproliferative Disorders: A Canadian Tertiary Center Experience

Salivary gland lymphoproliferative disorders (SGLD) are very rare tumors and clinicopathological data is sparse. In a Canadian series of 30 cases, extracted from the surgical pathology files of The Ottawa Hospital between 1990 and 2010, a clinical, histopathological, and immunophenotypic analysis was conducted. Tumors were staged using the Ann Arbor staging and classified using the World Health Organization 2008 classification. There were 15 salivary gland (SG) primary lymphomas with localized disease, predominantly mucosa associated lymphoid tissue type marginal zone lymphoma (MALT-L), but with a significant incidence of low grade follicular lymphoma (FL) and diffuse large B cell phenotype as well. There were 7 systemic SG lymphomas and 5 patients were diagnosed with lymphoproliferative disorders originating from intra-parotid lymph nodes. Finally, the remaining 3 cases represented reactive sialadenitis. A literature review was conducted and our primary lymphoma group was compared to those from other countries. SGLDs are predominantly B cell lymphomas that develop in older adults. Primary tumors, which have MALT-L and low grade FL characteristics, have a favorable survival, however MALT-L have a high rate of relapse. A minority of SG lesions are excised secondary to lymphomas that definitely arose from intra-parotid lymph nodes.

Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended‐release (XR) formulation has been designed to provide a once‐daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice‐daily immediate‐release (IR) formulation. We conducted 2 randomized, open‐label, phase 1 studies in healthy volunteers. Study A characterized single‐dose and steady‐state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single‐dose and steady‐state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high‐fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half‐life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) after single‐ and multiple‐dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies.

THU0178 Relationship Between NK Cell Count and Important Safety Events in Rheumatoid Arthritis Patients Treated with Tofacitinib

Background Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Cytokines (eg interleukin [IL]-2, -4, -7, -15, -21) involved in lymphocyte development, function and homeostasis are known to signal through JAK. Objectives To characterise changes in natural killer (NK) cell counts following tofacitinib treatment and evaluate the relationship between NK counts and rates of infection and malignancy. Methods Lymphocyte subset data, enumerated by flow cytometric analyses, were pooled from 3 double-blind, placebo-controlled, Phase 2 (P2) studies (two monotherapy and one background methotrexate [MTX]) in MTX inadequate responders, and from a sub-study of an ongoing long-term extension (LTE) study (study is ongoing; database not locked). RA patients (pts) received tofacitinib (1 to 30 mg twice daily [BID]) or placebo for 6 to 24 weeks in P2 and tofacitinib 5 or 10 mg BID for 22 months (median) in LTE. 928 and 161 pts contributed NK cell data in P2 and LTE, respectively. Correlations between baseline or nadir NK cell count and serious infection (SIE, any infection that requires hospitalisation for treatment or parenteral antimicrobial therapy), herpes zoster (HZ) and malignancy (excluding non-melanoma skin cancer) were assessed by sub-dividing NK cell data into deciles and calculating incidence rate (events/100 pt-years) of adverse events for each decile. Results Following tofacitinib administration, NK cell counts decreased in a dose-dependent manner by Week 2 (Figure 1A). Median NK cells counts returned to baseline 2 to 6 weeks after treatment discontinuation (dc). At the 5 mg BID dose, pts with the largest (>90th percentile) decrease in NK cell counts recovered from ∼70% below baseline to ∼18% by 6 weeks after treatment dc (n=4). The estimated median decrease for 5 mg BID at Week 24 was ∼35%. Cross-sectional analyses in different groups of pts showed similar median NK cell count in the LTE (141 cells/μL) compared to pre-treatment baseline (135 cells/μL). No clear association between baseline or nadir NK cell counts (predominantly collected within first 6 months of treatment) and the incidence of SIE, HZ or malignancy (Figure 1B) was seen over the period of observation (median duration 1.9 years). Conclusions Tofacitinib treatment is associated with a dose-dependent decrease in NK cell counts. No association between baseline or nadir NK cell counts and the incidence of SIE, HZ or malignancy was observed. Long-term lymphocyte subset data are being collected in the ongoing LTE study to confirm these relationships. Acknowledgements Previously presented (van Vollenhoven R et al. Arthritis Rheum 2014; 66(11): S220 abs 508) and reproduced with permission from Arthritis and Rheumatism. All aspects of this work were funded by Pfizer Inc. Editorial support under the direction of the authors was provided by Amanda Pedder, of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest R. F. van Vollenhoven Grant/research support from: Pfizer, Consultant for: Pfizer, Y. Tanaka Consultant for: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB Japan, GlaxoSmithKline, Bristol-Myers Squibb, Speakers bureau: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB Japan, GlaxoSmithKline, Bristol-Myers Squibb, M. Lamba Shareholder of: Pfizer, Employee of: Pfizer, M. Collinge Shareholder of: Pfizer, Employee of: Pfizer, T. Hendrikx Employee of: Pfizer, T. Hirose Shareholder of: Pfizer, Employee of: Pfizer Japan, S. Toyoizumi Employee of: Pfizer Japan, A. Hazra Shareholder of: Pfizer, Employee of: Pfizer, S. Krishnaswami Shareholder of: Pfizer, Employee of: Pfizer

Population Pharmacokinetic Analysis of Mycophenolic Acid Coadministered With Either Tasocitinib (cp-690,550) or Tacrolimus in Adult Renal Allograft Recipients

Tasocitinib (CP-690,550) is an orally active Janus kinase inhibitor that is in development for prophylaxis of acute rejection after kidney transplantation and for the treatment of select autoimmune diseases. The current study was conducted to evaluate the systemic exposure of mycophenolic acid (MPA) in de novo kidney transplant patients when coadministered with tasocitinib compared with exposure in patients receiving tacrolimus, which has no effect on MPA pharmacokinetics. Plasma MPA concentrations were obtained from 17 adult patients who received either 15 mg or 30 mg tasocitinib twice daily (eight patients) or tacrolimus (nine patients) after kidney transplantation. All patients also received concomitant mycophenolate mofetil, prednisone, and basiliximab induction. The median mycophenolate mofetil dose was 1000 mg twice daily. A two-compartment population pharmacokinetic model estimating oral clearance, between-patient variability in oral clearance, central volume of distribution, and residual variability in combination with historical estimates of first-order absorption rate constant, intercompartmental clearance, and peripheral volume of distribution adequately described the sparse MPA data. Based on individual estimates oral clearance from the population pharmacokinetic model, mean steady-state area under the concentration-time curve values for a mycophenolate mofetil dose of 1000 mg twice daily were 63 mg·hr/L (22%) and 59 mg·hr/L (36%) for the tasocitinib and tacrolimus groups, respectively. These results indicate that tasocitinib does not influence systemic MPA exposure.

Performance comparison of secondary and tertiary treatment systems for treating antibiotic resistance

Rapid emergence of antibiotic resistance (AR) in developing countries is posing a greater health risk and increasing the global disease burden. AR proliferation mediated by treated/untreated discharges from sewage treatment plants (STPs) is a prime public health concern. Efficient sewage treatment is among our key defenses against the dissemination of infectious diseases. The present study aims to estimate the efficiency of aerobic [activated sludge process (ASP) and modified trickling filter (MTF)] and anaerobic reactors (anaerobic flow-through reactor) along with the three disinfection techniques (UV, ozone and chlorination) in reducing ARB and ARGs present in the domestic sewage. The three treatment systems were operated at different HRTs for 1 year and their performances in terms of treatment of conventional and emerging pollutants (ARB and ARGs) were assessed. The results indicated higher removal of ARB and ARGs in aerobic reactors compared to anaerobic reactor. Treatment studies in various bioreactors showed that the use of MTF along with UV/Ozone was superior to ASP and anaerobic flow-through reactor in reducing both the conventional and emerging pollutants. However, higher reduction of the pollutants was observed at higher HRTs. Though complete removal of coliforms and ARB was observed by treating the wastewater using MTF followed by UV or ozone but substantial levels of ARGs were observed in the effluent. Therefore, different advanced and effective treatment technologies such as filtration (RO), use of zero valent iron, TiO2 photocatalysis and other strong oxidizing agents which can ensure complete removal of ARGs along with ARB need to be evaluated. Though addition of these units will increase the treatment cost, but the increased cost would be negligible compared to the present disease burden of AR.

Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release Tofacitinib

Extended‐release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model‐informed, exposure–response (E‐R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E‐R analyses were conducted using validated clinical endpoints from phase II dose–response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration.

THU0143 Pharmacokinetics, Bioavailability and Safety of A Modified Release Once Daily Formulation of Tofacitinib in Healthy Volunteers

Background Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The efficacy and safety of an immediate-release (IR) formulation of tofacitinib, dosed twice daily (BID), has been assessed in patients with active moderate to severe RA. To facilitate once daily (QD) dosing, a novel modified-release (MR) formulation has been designed to achieve comparability of key systemic exposure parameters. Objectives To compare the extent of exposure between a single dose of tofacitinib MR 11 mg vs an IR 2x5 mg dose in healthy volunteers (HV). Methods This was a randomised, open label, 2-way cross-over study conducted in 26 HV. Following an overnight fast, HV were randomised to receive either a single dose of MR 11 mg (MR; test) or IR 2 x 5 mg (IR; reference). Treatments were separated by a 72-hour (h) washout. Pharmacokinetic (PK) parameters were calculated using non-compartmental analyses. The primary endpoint was extent of tofacitinib exposure, measured as area under the concentration-time curve from time zero extrapolated to infinite time (AUCinf). A mixed-effects model was used to generate adjusted geometric mean ratios (MR/IR) and 90% confidence intervals (CIs). The steady-state (SS) profiles of tofacitinib MR and IR were predicted using single-dose data from this study. Results All 26 HV completed the study and were included in the analyses. The study population had a mean age of 33.6 years, a mean body weight of 77.5 kg, and was 19% female. For the MR and IR formulations, geometric mean AUCinf (ng*h/mL) was 297.5 and 286.3, respectively, resulting in an MR/IR ratio of 103.91% (90% CI: 100.49%, 107.45%). Maximum plasma concentration (Cmax; ng/mL) adjusted for formulation was 40.75 and 44.10 for MR and IR, respectively, resulting in an MR/IR ratio of 92.40% (90% CI: 84.99%, 100.45%). For both parameters, 90% CI values were wholly contained within the 80–125% range of bioequivalence. Mean terminal half-life was 5.71 h and 3.41 h for MR and IR formulations, respectively. The most common adverse events (AEs) were nausea, abdominal pain, back pain and headache. The incidence of AEs was similar between treatment groups and no serious AEs were reported. Predictions following SS dosing indicate similar time above JAK1/3 half maximal inhibitory concentration signalling thresholds and similar AUC, peak concentration and minimum concentration values between MR and IR formulations. Conclusions This study demonstrates the single dose equivalence of AUCinf and Cmax of the MR and IR formulations of tofacitinib. Single doses of both formulations were well tolerated. This novel MR formulation of tofacitinib facilitates an opportunity to enable QD dosing, while maintaining systemic drug concentrations similar to the IR formulation (administered BID). Multiple-dose studies will be conducted to confirm the predictions of the SS PK profile and demonstrate equivalence between formulations following SS dosing. Acknowledgements This study was sponsored by Pfizer Inc. Pfizer personnel were involved in protocol development and data analysis. Editorial support was provided by Claire Cridland of CMC and funded by Pfizer Inc. Disclosure of Interest : M. Lamba Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Fletcher Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Alvey Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Hazra Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Kushner Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Larmann Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Stock Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.1521