Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.

Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis.

OBJECTIVE: We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now 'redundant' enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value. DESIGN: Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now 'redundant' IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity. RESULTS: The 'redundant kit', and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the 'redundant' kit had predictive utility. CONCLUSIONS: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.

A novel strategy to reduce the immunogenicity of biological therapies.

Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.

Teaching Spanish using the pharmacists' patient care process.

BACKGROUND AND PURPOSE: The Hispanic population of the United States now comprises the largest minority and is expected to increase. Student pharmacists must be prepared to care for this segment of the population. Efforts to learn medical Spanish will assist in these endeavors. EDUCATIONAL ACTIVITY AND SETTING: This paper describes the design and implementation of a novel course teaching Spanish for student pharmacists using the framework of the Pharmacists' Patient Care Process (PPCP). A two-credit hour elective course was developed to provide a focused course on practical Spanish used in the pharmaceutical care space. Lessons were framed with the various steps in the PPCP of collect, assess, plan, implement, and follow-up. FINDINGS: Interest in the course was high, with first through third professional year cohorts and varying Spanish experience represented. Student feedback from self-reflections and course evaluations revealed the course was helpful in increasing ability to work with patients of differing cultural backgrounds and in medical Spanish skill in pharmaceutical care. SUMMARY: Pharmacy programs can utilize the PPCP as an instructional method to increase offerings of medical Spanish in their curriculum with modest resource utilization.

B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis.

INTRODUCTION: Treatment with alemtuzumab is highly effective in relapsing-remitting multiple sclerosis; however, 30% of patients develop autoimmunity. Alemtuzumab (previously called Campath 1-H) induces a prolonged T-cell lymphopenia with memory cells dominating the reconstituting T-cell pool for at least 3 months. RESULTS: Here we show that B-cell recovery is rapid, returning to baseline by 3 months and rising to 165% of baseline by 12 months after treatment. Immature transitional 1 B cells are the predominant cell type 1 month after treatment. This coincides with a surge in serum B-cell activating factor (BAFF), which remains elevated by 33% for at least 12 months after alemtuzumab. BAFF is critical for transition to the mature naive B-cell phenotype, which dominates from 3 months after alemtuzumab. Differentiation to memory B cells is slow so there are radical and prolonged alterations to the B-cell pool after alemtuzumab.

Ovarian cancer in the elderly: outcomes with neoadjuvant chemotherapy or primary cytoreduction.

BACKGROUND: Recent studies have suggested inferior outcomes for elderly women with ovarian cancer. Our goal was to evaluate neoadjuvant chemotherapy versus primary cytoreduction in elderly women. METHODS: A retrospective chart review was performed for women aged 65+ diagnosed with ovarian cancer at our institution between 1997 and 2007. Univariate and multivariate logistic regression models were used to evaluate complication rates. Survival was evaluated with Cox regression and the Kaplan-Meier method. RESULTS: One hundred seventy-five patients were identified, 34 (19%) of whom were aged 80+. Those aged 65-79 and those 80+ received neoadjuvant chemotherapy with equal frequency (19% vs. 21%, p=0.92). Treatment with neoadjuvant chemotherapy was associated with odds ratios of 0.80 (95% CI 0.37-1.75) for surgical complications and 0.79 (95% CI 0.33-1.90) for chemotherapeutic complications. In those aged 80+, the frequency of surgical complications (OR 1.01, p=0.62) and chemotherapeutic complications (OR 1.04, p=0.78) did not differ compared to younger patients. Overall survival did not differ based on initial treatment regimen, with 34 months in the primary surgery group and 29 months in the neoadjuvant chemotherapy group (p=0.65). The median disease specific survival for those aged 65-79 was 35 months, and 24 months in those aged 80+ (p=0.15). Post-operative mortality for patients aged 80+ was zero. CONCLUSIONS: In our patient population, those aged 80+ have similar surgical and chemotherapy-related complication rates and comparable survival to those aged 65-79. The choice of initial treatment modality does not appear to impact survival when the decision is made in a selective fashion.

GPAs, PCATs, and Coupons: Wilting Quality in Pharmacy School Admissions and the Impact on Pharmacy Faculty.

INTRODUCTION: The number of available seats in US pharmacy schools has reached unprecedented numbers as applications are on the decline. A combination of forces signals that admissions to pharmacy school are becoming less selective. COMMENTARY: The conflict of balancing a need to fill the incoming class while maintaining selectivity is a growing problem in pharmacy education. Faculty may notice changes in the student quality and ultimately, program and graduate quality. Pressure from administration hinders faculty governance with negative consequences that impact faculty morale and the profession as a whole. Maintaining a firm position in the face of reduced applications is challenging but necessary if we are to protect the students we seek to support as faculty and stewards of the pharmacy profession. IMPLICATIONS: Faculty governance is at risk as pressure exists to admit less-prepared students into programs. Faculty must advocate for responsible leadership by initiating dialogue on admissions and selectivity. Furthermore, faculty mentorship programs need a new level of discussion that includes analysis and understanding of this paradigm in pharmacy academia.

Identifying opportunities for PharmD curricular reform by surveying oncology pharmacists about career preparedness and exposure.

INTRODUCTION: The primary objective of the study was to assess factors that predict pursuit of an oncology post-graduate year 2 (PGY-2) residency. Additional objectives included identifying the role of and exploring opportunities for PharmD curricula to increase student interest in the oncology field. METHODS: An anonymous 15-minute survey was developed and administered to oncology pharmacists and residents. Study participants were included if they were actively practicing as clinical pharmacists in an oncology setting in the US, maintained an active pharmacist license, and >18 years of age. Responses were analyzed using descriptive and inferential statistics. All results are reported in aggregate, with the exception of quotes obtained from open-ended responses. RESULTS: Eighty participants were included in analyses. After controlling for variance due to age, sex, race, years of practice, the number of oncology advanced pharmacy practice experiences (APPEs) correlated with pursuit of a PGY-2 residency in oncology (p = 0.047). Additionally, participants' perceived level of preparedness from didactic oncology training predicted pursuit of an oncology PGY-2 residency (p = 0.002). Emerging themes in pursuing oncology from open-ended items revealed that inclusion of supportive care in the didactic curriculum and having a family member or friend diagnosed with cancer were important factors. Additionally, participants' responses regarding PharmD curricula included recommendations to inform didactic and experiential education. CONCLUSIONS: The results support the need for reevaluation of oncology education in PharmD curricula. Further studies could explore specific aspects of didactic curriculum that impact the level of student preparedness, and which elements encourage a student pharmacist to seek further training in the oncology field.

IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H).

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.

Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis.

Following lymphocyte depletion, homeostatic mechanisms drive the reconstitution of lymphocytes. We prospectively studied this process in 16 patients for 1 year after a single pulse of treatment with Campath-1H, a humanised anti-CD52 monoclonal antibody. We observed two phases of lymphocyte reconstitution. In the first 6 months after treatment the precursor frequency and proliferation index of the patients' autologous mixed lymphocyte reaction increased; the depleted T cell pool was dominated by memory T cells, especially (CD4+)CD25high T cells, a putative regulatory phenotype; and there was a non-significant rise in peripheral mononuclear cell FoxP3 mRNA expression and fall in constitutive cytokine mRNA expression. In the later phase, from 6-to-12 months after Campath-1H, these changes reversed and there was a rise in ROG mRNA expression. However, total CD4+ numbers remained below 50% of pre-treatment levels at 12 months, perhaps reflecting a failure in homeostasis. This was not due to an impaired IL-7 response, as in rheumatoid arthritis, nor to a lack of IL-7 receptors, which are found on fewer human (CD4+)CD25high than naive cells. We speculate that CCL21 and IL-15 responses to lymphopaenia may be suboptimal in multiple sclerosis.