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.     

New treatment strategies in multiple sclerosis

Multiple sclerosis is the most common, non-traumatic, disabling neurological disease of young adults, affecting an estimated two million people worldwide. At onset multiple sclerosis can be categorised clinically into relapsing remitting MS (RRMS — 85-90% of patients) or primary progressive MS (PPMS). Relapses typically present sub-acutely over hours to days with neurological symptoms persisting for days to weeks before they gradually dissipate. At first full recovery is the norm, later patients accumulate deficits and ultimately most convert to a secondary progressive phase (SPMS), characterised by deficits that increase in the absence of further relapses. The clinical picture reflects the complex interplay of focal inflammation, demyelination and axonal degeneration occurring within the central nervous system.Since the introduction of a genuine disease-modifying drug, interferon-beta1b in 1993, there has been a growing interest from academia and pharmaceutical companies alike in multiple sclerosis therapy. In part this effort has focused on investigating the “window of therapeutic opportunity” within the natural history of the disease: it is becoming increasingly clear that immunotherapies are not useful in the secondary phase of the disease but may offer long-term benefit if given early in the relapsing-remitting phase. In part, attention is being paid to the details of dosing and administration of the various licensed therapies, but there is also a significant research effort to explore new ways to treat the disease. In this review, we first sketch the landscape of novel therapies in multiple sclerosis and then discuss in detail approaches which are likely to emerge over the next few years.     

Psychological care of the haemodialysis patient

The psychological care of patients at the haemodialysis unit is becoming an increasingly important aspect of the overall treatment of patients with end-stage renal failure. As more is understood and reported regarding the impact of psychological factors on physical processes it becomes crucial that good quality psychological care is delivered to patients by nurses working at the haemodialysis unit. This study aimed to look at haemodialysis patients' perceptions of their treatment to discover if a dialysis centre in Southern England might benefit from a more formal system of psychological care. The data revealed four main themes that were of particular importance to the participants of this study: The New Self, Coping, Medical Concerns and Psychological Care. Within these areas of importance, the need for good quality information, the need for a suitable dialysis environment and the importance of social and family support were evident. Although the psychological care system that was in place at the unit appeared to be working well a more formal system of care might improve the patient experience.     

The New Injury Severity Score: Better Prediction of Functional Recovery after Musculoskeletal Injury

OBJECTIVES: Injury Severity Score (ISS) is the most widely used method of assessing severity of injury in blunt trauma. It has been recognized that, by only allowing the score to consider the worst injury for each body system, ISS underestimates the problems of multiple musculoskeletal injuries. The New ISS (NISS) allows the three most severe injuries to be scored, irrespective of region affected, and may give better prediction of functional recovery in these patients. METHODS: A prospective cohort study of 200 patients with musculoskeletal injuries, examining the predictive value of ISS and NISS on functional recovery as measured by patient-derived outcome measures (Short Form-36, Sickness Impact Profile, and Musculoskeletal Function Assessment). RESULTS: NISS was greater than ISS in 34 patients (17%). NISS showed closer correlation with total scores and subscores of the outcomes measures than did ISS (Spearman's rho ranked test, P < 0.05). CONCLUSIONS: NISS, a simple modification from ISS, better predicts functional outcomes in survivors of musculoskeletal trauma, and offers an improvement in the assessment of effectiveness of trauma care delivery.     

Further characterisation of a thromboembolic model of stroke in the rat

We have used magnetic resonance imaging (MRI) techniques to characterise a rat model of thromboembolic stroke. The consequences of acute perfusion deficit associated with a middle cerebral artery occlusion (MCAo) by a newly formed thrombus was mapped by interrogation of the tissue oxygenation status using gradient echo methods and production of T2* maps. Final infarct size was subsequently assessed at 24-h post-ischaemia by histology with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Animals displayed an infarct volume of 178.7+/-84.2 mm(3) (mean+/-S.D.) with a large coefficient of variation (47%) and range of values (85.6--265.5 mm(3)). This variability provided us with an opportunity to assess the relationships between early imaging observations and eventual infarct size. For a single cerebral slice, at the centre of the MCA territory, a relationship between the area of reduced T2* at 1 and 2 h post MCAo correlated highly with final lesion area (Spearman rank correlation, r=0.98, P<0.01, n=9). Lesion volumes in the thromboembolic MCAo model were compared with a 120-min occlusion, 22-h reperfusion protocol using an intraluminal thread MCAo approach. For the thromboembolic model, the total lesion volume was found to be smaller (178.7+/-84.2 vs. 243.3+/-50.1 mm(3), mean+/-S.D., Student's t-test P=0.046) and showed a greater variability (coefficient of variations: 47% vs. 21%). These data underline the relative variability of this embolic model and provide important preliminary information regarding the value of early changes in T2* in predicting eventual infarct size.