Cancer Risk in Patients with Multiple Sclerosis: Potential Impact of Disease-Modifying Drugs.

In the 1990s, the first disease-modifying therapies (DMTs) for multiple sclerosis (MS) were injectable immunomodulatory (IM) drugs, including four different interferon-ß preparations and glatiramer acetate. Since 2000, more than 15 immunosuppressant (IS) drugs have been used, with a more or less specific action on inflammation. These include monoclonal antibodies targeting CTL4, the integrin receptor, the interleukin (IL)-2 receptor, CD19, CD20, CD52, and the sphingosine 1 phosphate family. The association between MS and cancer has long been investigated but has led to conflicting results. No studies have reported an increased risk of cancer after long-term exposure to IM. Several reports suggest an increase in cancer risk among MS patients treated with IS such as mitoxantrone, azathioprine and cyclophosphamide. Because of their action on the immune system, and due to a lack of available long-term data, a special warning of the potential risk of cancer accompanies the use of recent IS such as cladribine, fingolimod, natalizumab or alemtuzumab. In most studies, factors such as diet, smoking, solar radiation, and hormone therapy, all of which influence cancer risk, have not been considered. For fingolimod, natalizumab, alemtuzumab, dimethyl fumarate, teriflunomide, daclizumab and ocrelizumab, risk management plans outlined by regulatory agencies are mandatory. They allow prospective detection of some red flags, in particular those for the increased risk of cancer. We review the current evidence behind the increased risk of malignancy in MS patients receiving DMTs, and provide an overview of the DMTs that are currently in use and those in clinical trials. The known risks and benefits of these therapies will be considered.

Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis.

Rituximab (RTX) has demonstrated efficacy in limiting relapses in myasthenia gravis (MG). We investigated the interest of CD27+ memory B cell monitoring in patients as a biological marker of clinical relapse. Twenty-four patients have been treated with RTX (375mg/m(2)/week-month as an induction treatment). Maintenance treatment consisted with either systematic treatment every 3months or only when CD27+ memory B cells were detectable. After the induction treatment, the mean infusions were 1.3/year compared with 4/year. We suggest that RTX administration frequency can be decreased safely by monitoring the re-emerging CD27+ memory B cells.

Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study.

IMPORTANCE: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge. OBJECTIVE: To collect data from patients with MS switching from natalizumab to fingolimod. DESIGN, SETTING, AND PARTICIPANTS: The Enquête Nationale sur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod. MAIN OUTCOMES AND MEASURES: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod. RESULTS: Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). CONCLUSIONS AND RELEVANCE: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study.

INTRODUCTION: Few data are available about the effect of rituximab (RTX) on refractory (RM) and non-refractory (NRM) myasthenia. METHODS: This retrospective multicenter study involved 13 RM and 7 NRM patients treated with sequential RTX infusions over 2 years, on average. RTX was used as a substitute for corticosteroids in NRM patients. Disability was assessed using the annualized relapse rate (ARR) and Myasthenia Gravis Foundation of America (MGFA) scores. RESULTS: RTX induction decreased the ARR from 2.1 to 0.3 (P < 0.001), and lowered MGFA scores from 5-3b to 4b-0 in RM patients, and from 1.9 to 0.1 (P < 0.001) and 4b-2b to 3b-0 in NRM patients. No side effects were reported in either group, except for 1 case of spondylodiscitis 1 year after the last RTX infusion. Within a year after RTX induction, complete corticosteroid withdrawal was obtained in 7 RM and 4 NRM patients. CONCLUSIONS: RTX is efficacious and well-tolerated. Its use allows for dose reduction or withdrawal of corticosteroids.

Increased risk of multiple sclerosis relapse after in vitro fertilisation.

BACKGROUND: Exogenous sexual steroids together with pregnancy have been shown to influence the risk of relapses in multiple sclerosis (MS). Treatments used during assisted reproductive techniques may consequently influence the short term evolution of MS by modifying the hormonal status of the patient. The objective of this study was to determine if there was an increased risk of developing exacerbations in women with MS after in vitro fertilisation (IVF). METHODS: MS and IVF data were either automatically extracted from 13 French university hospital databases or obtained from referring neurologists. After matching databases, patient clinical files were systematically reviewed to collect information about MS and the treatments used for IVF. The association between IVF and the occurrence of MS relapses was analysed in detail using univariate and multivariate statistical tests. FINDINGS: During the 11 year study period, 32 women with MS had undergone 70 IVF treatments, 48 using gonadotrophin releasing hormone (GnRH) agonists and 19 using GnRH antagonists. A significant increase in the annualised relapse rate (ARR) was observed during the 3 month period following IVF (mean ARR 1.60, median ARR 0) compared with the same period just before IVF (mean ARR 0.80, median ARR 0) and to a control period 1 year before IVF (mean ARR 0.68, median ARR 0). The significant increase in relapses was associated with the use of GnRH agonists (Wilcoxon paired test, p=0.025) as well as IVF failure (Wilcoxon paired test, p=0.019). INTERPRETATION: An increased relapse rate was observed in this study after IVF in patients with MS and may be partly related both to IVF failure and the use of GnRH agonists.

Endermology: a treatment for injection-induced lipoatrophy in multiple sclerosis patients treated with sub cutaneous glatiramer acetate.

OBJECTIVE: To evaluate sessions of endermology (LPG) on patients with lipoatrophy, due to GA injections in an open-labelled study. BACKGROUND: Glatiramer acetate (GA) is an immunomodulatory drug, with an excellent safety profile, that is currently used for treatment of multiple sclerosis and is administered as daily subcutaneous injections of 20 mg. The most common adverse effects, which occur in approximately 20-60% of the patients, include pain, inflammation and induration at the injection sites. Another adverse effect is frank panniculitis followed by localized lipoatrophy at the injection sites, which has been described in half of the patients receiving treatment with glatiramer acetate injections. No treatment has been found for established lipoatrophy. PATIENTS AND METHODS: All patients underwent LPG twice a week during 30 min. A cycle of two months was initially proposed. If the patient was satisfied with the result, sessions were continued with one session per week until the 4th month. RESULTS: Eight Patients treated with GA and presenting with lipoatrophy were prospectively recruited. None of them complained of any adverse events. After 8 weeks of treatment, all had a visible reduction of lipoatrophic area. MRI showed no major subcutaneous changes except for a reduction in and repartition of fatty tissues. CONCLUSION: The LPG cellu M6 keymodule is a mechanotransduction machine that stimulates the skin's surface in triggering cells to activate lipolysis and collagen production. It has never been used for treatment of lipoatrophy due to drug treatment or in specific diseases associated with lipoatrophy (diabetes, HIV). The prevention and management of lipoatrophy includes patient education, regular examination and manual palpation of all injection sites. LPG endermology can help patients to resolve this side effect and to continue immunomodulatory treatment.

Cancer and multiple sclerosis in the era of disease-modifying treatments.

Prior to the era of disease-modifying therapies (DMT), multiple sclerosis (MS) was linked to reduced rates of cancer. Early use of immunosuppressors (IS) in MS justifies the follow-up of patients to evaluate a possible increase in the incidence of cancer in these patients. We performed a descriptive study of MS patients with a documented oncological event. Among the 22,563 MS patients in the EDMUS databases, patients with a history of cancer were identified, and cancer risk in a multiple sclerosis cohort (CARIMS) was evaluated. Four groups were defined: (A) MS patients without cancer receiving DMT or not, (B) MS patients with cancer but without any history of DMT, (C) MS patients with cancer who received an immunomodulator (IM), and/or (D) MS patients treated with an IS. A total of 9,269 patients (44.1%) had a history of DMT (52% IM; 18% IS; 30% both); 253 patients with MS and cancer were identified, 182 had a history of DMT. The mean duration of DMT was longer for group D (A: 3.6 years vs. D: 4.9 years; P < 0.01). There was no increased risk of cancer among patients treated exclusively with IM. IS treatment (P = 0.043) and the duration of exposure (P < 0.001) significantly increased the risk of cancer, especially skin cancer, as observed in other autoimmune diseases. This result could influence the attitude of the medical profession with respect to the benefit to risk ratio when proposing DMT to MS patients.

Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis.

BACKGROUND: Prior to the era of immunomodulating or immunosuppressive (IS) treatments Multiple Sclerosis (MS) was linked to reduced rates of cancer. Method A descriptive study of MS patients with a documented oncological event was performed. From 1 January 1995 to 30 June 2006, we collected and studied the profile of 7,418 MS patients gathered from nine French MS centers. We evaluated the incidence of cancer in a Cancer Risk In MS Cohort. RESULTS: Thirty one patients (1.75%) with confirmed MS had a history of cancer: mean age at MS diagnosis of 37.9 years and a mean age at cancer diagnosis of 46.4 years. The most frequent cancers were breast (34.5%), gynecological (12.5%), skin (10.2%), acute leukemia and lymphoma (5.9%), digestive (8.8%), kidney and bladder (5.1%), lung (3.4%) and central nervous system (3%). Calculated standardized incidence rates were 0.29 (0.17-0.45) for men and 0.53 (0.42-0.66) for women. The incidence of cancer in this MS population was lower than that expected for the general population. Matched to age, gender and histology, cancers in MS were associated with a young age and exposure to IS treatments. When considering all patients, treated patients had a 3-fold higher risk of developing cancer, if they had a history of IS (P = 0.0035). For treated patients, the cancer sites were more likely the breast, the urinary tract, the digestive system and the skin. CONCLUSION: Our data suggest that MS patients do not have an increased risk of cancer. Rather for several types of cancer a significantly reduced risk was observed, except for breast cancer in women treated with IS. The relative increased risk of breast cancer in MS women under IS treatment warrants further attention.