Tuesday, 30 August 2016

ResearchSpeak: low lymphocyte counts in MSers

Do you have a normal lymphocyte count? Do you know your lymphocyte counts? #ResearchSpeak #MSBlog #MSResearch

"The retrospective study below found that 1 in 10 DMT-naive MSers had low lymphocyte counts and in the majority of these no obvious cause could be found. The authors' suggest the lymphopaenia is due to autoimmunity, or is stress-induced through increased cortisol production or Epstein-Barr activation."

"I live and learn something new every day of the week about MS. I had no idea that ~10% of MSers had idiopathic (no apparent cause found) lymphopaenia. What is interesting that in this study low lymphocyte counts at baseline predicted low lymphocyte counts on treatment. Clearly these findings needs to be confirmed and explained. Who knows it may provide interesting insights into the pathogenesis of MS. I like the suggestion that it may be linked to stress and/or EBV reactivation."

"Lymphopaenia is one of the key battlegrounds in the marketing of DMTs. Low lymphocyte counts are an important risk factor for several serious adverse events on DMTs. Understanding MS-related lymphopaenia may help de-risk some of these DMTs. I am interested to know how many of you know what your latest lymphocyte counts are? If you don't you should find out and keep a record of it for yourself."

A lymphocyte: image source Wikipedia

Lim et al. Lymphopenia in treatment-naive relapsing multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016 Aug 12;3(5):e275. doi: 10.1212/NXI.0000000000000275. eCollection 2016.

Background: Lymphopenia accompanies some autoimmune diseases. Several studies, but not others, have suggested that lymphopenia occurs in treatment-naive multiple sclerosis (MS), so the issue remains unresolved.

Methods: Data were collected retrospectively during an institutionally approved service evaluation of blood test monitoring of patients with relapsing MS in a regional MS service in Southampton, UK, over a 2-year period (2012–2014). Control lymphocyte data were derived from preoperative blood counts of age- and sex-matched individuals undergoing septoplasty in the same hospital for structural reasons, excluding neoplastic and infective operative indications.

Results:  Seven hundred sixty-four patients were identified with blood test data (table). Baseline and post-treatment blood tests were available in 466 and 247 patients, respectively. Average blood test frequency was 4 per year. Lymphocyte counts were relatively stable with time, with a coefficient of variation of 7.5%. The mean lymphocyte count in treatment-naive patients with MS was 2.18 × 109/L with an SD of 0.66 × 109. Lymphopenia was present in 10% (48 patients; 46 grade I, one grade II, one grade III). In only 3 cases steroids were administered in the month before lymphopenia. There was no association between pretreatment lymphocyte count and any patient characteristic or month or season. 

Discussion: Since the lymphocyte reference range covers 95% of values in a healthy population, lymphopenia is expected in 2.5%. In our treatment-naive relapsing MS population, we found lymphopenia in 10%. Moreover, lymphopenia was not associated with relapsing activity. Hence, the lymphopenia in patients with MS is unlikely to be related to autoimmunity. A more likely explanation is stress-induced lymphopenia in both cohorts, through cortisol or Epstein-Barr activation.

Metabolic problems in immune cells can cause autoimmunity

Immunol Cell Biol. 2016 Aug 26. doi: 10.1038/icb.2016.77. [Epub ahead of print]

"Immunometabolism and autoimmunity".

Freitag J, Berod L, Kamradt T, Sparwasser T.


A continuous increase in the prevalence of autoimmune diseases is to be expected in the aging societies world-wide. Autoimmune disorders not only cause severe disability and chronic pain, but also lead to considerable socio-economic costs. Given that current treatment options are not curative, have substantial side effects and a high percentage of non-responders, innovative options to the existing therapeutic armament against autoimmune diseases are urgently required. Accumulating evidence suggests that changes in the metabolism of immune cells are associated with and contribute to the pathogenesis of autoimmunity. Additionally, some autoimmune diseases share alterations in metabolic pathways, key metabolites or metabolic byproducts such as reactive oxygen species. Other examples for metabolic changes in autoimmune settings include modifications in amino acid and cholesterol levels or glucose catabolism. Thus, the emerging field of immunometabolism may hold the potential to discover new therapeutic targets. Here, we discuss recent findings describing metabolic changes in autoimmune arthritis, multiple sclerosis.

Mounting an immune response requires changes to metabolic processes (i.e. the chemical transformations that are needed for survival). Immune cells have different metabolic requirements depending on their activation state (in order to meet the demands of the activation state) and differentiation state (into effector T cells, which include helper, cytotoxic or regulatory T cells).

Points of metabolic dysregulation in immune function may prove to be therapeutic targets of the future. For example, the natural antioxidant from the green tea plant, EGCG has been shown to promote suppressive Treg cells whilst inhibiting Th1/Th17 formation (proinflammatory cells). This is currently being evaluated in a clinical trial in MS (Sunphenon in progressive forms of multiple sclerosis, NCT00799890).

Leptin is another. Also popularly known as the anti-obesity hormone, leptin has been found to promote CD4 T cell expansion as well as secretion of proinflammatory molecules, such as TNFalpha. Levels of leptin have been sound to be elevated in MS, leading to activation of leptin-mTOR pathway in suppressive Treg cells and as a consequence their impaired expansion. For therapeutic purposes rapamycin-mediated blockade of mTOR activation facilitates Treg expansion and significantly ameliorates EAE (the murine version of MS). Current clinical trials in MS are NCT00228397 (Temsirolimus) and NCT00095329 (Sirolimus).

Statins which lower cholesterol have been proven to be beneficial in MS by inhibiting the formation of proinflammatory Th1 and Th17 responses but favouring Treg responses. In fact the MS-STAT (NCT00647348) showed benefits with regard to brain atrophy measures in SPMS.

These therapeutic targets may therefore prove to be highly attractive options in the near future.

Monday, 29 August 2016

SurveySpeak: Impact, or lack of it

How do you feel about research, or academic, IMPACT? It is a sad fact of life in the modern university. #SurveySpeak #MSBlog 

"One of our successes this year has been our medical school investing in Alison Thomson our designer; she has officially been appointed as a lecturer. This is the first time our University has embedded a designer within a biomedical research environment. As always we need to justify our existence; this means metrics and impact. We now have to build a case for Alison's work having impact. It would help us enormously if you could please complete a short survey (9 questions and ~1 minute of your time) to help show that Alison's work in relation to the Barts-MS Blog is having impact. The survey is not only for people with MS, but anyone who reads this blog. Thank you!"

Safety of daclizumab: 3-year results from the SELECTED study

Background: This paper reports early results from a clinical trial evaluating a new drug for relapsing-remitting Multiple Sclerosis (MS)1. The drug – daclizumab – is a designer antibody manufactured to dampen down the activity of the immune system by inhibiting a signal called interleukin-2. In Multiple Sclerosis, the immune system goes awry and attacks cells in the brain. For this reason, several clinical trials are looking at whether daclizumab is a safe and effective treatment for MS. The available evidence suggests that daclizumab is effective2-4, but is it safe to use in the long term?

Methods: The SELECTED trial aimed to answer this question. Researchers followed 410 patients across 8 countries who received 150mg of subcutaneous daclizumab injections every 4 weeks. On average, the patients had been receiving the treatment for just over 2 years. It follows on from two earlier trials, SELECT and SELECTION, which were mainly interested in the effectiveness of daclizumab.

Results: Over the 3-year study period, 76% experienced an adverse event of some kind. 26% experienced serious adverse events, of which the most common were MS relapse, disturbances of liver function, pneumonia, and ulcerative colitis. 12% of patients experienced an adverse event which led them to stop receiving the treatment, but no patients died during the study period. It is important to note that the chance of experiencing a side effect with daclizumab may be slightly underestimated by these results. This is because patients were excluded from the trial if they had already left because of a previous adverse event.

Conclusion: The take home message of the SELECTED trial is that daclizumab appears to have a similar risk-benefit profile to commonly-used MS drugs such as beta-interferon. However, we will have to wait a few more years until the end of the 8-year study period to confirm that daclizumab is safe for clinical use. We will also need to find out how daclizumab compares to other drugs in head-to-head trials looking at long-term safety and efficacy.

  1. Gold, Ralf, et al. "Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study." BMC Neurology 16.1 (2016): 1.
  2.  Gold, Ralf, et al. "Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial." The Lancet 381.9884 (2013): 2167-2175.
  3. Giovannoni, Gavin, et al. "Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial." The Lancet Neurology 13.5 (2014): 472-481.
  4. Kappos, Ludwig, et al. "Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis." New England Journal of Medicine 373.15 (2015): 1418-1428.

Pregnancy and Natalizumab

Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M.
Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study.BMC Neurol. 2016 Aug 24;16(1):150. doi: 10.1186/s12883-016-0674-4.

BACKGROUND: Patients with multiple sclerosis (MS) or Crohn's disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes.
METHODS:The Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects.
RESULTS:A total of 369 patients with MS and 7 patients with CD were enrolled, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3-12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9-8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g.
CONCLUSIONS: Although the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population.
If you are planning to start a family make sure that you consult with your MS team for advice and monitioring of your treatment status