Francesco Logullo

Subcutaneous immunoglobulin in polymyositis and dermatomyositis: A novel application

OBJECTIVES To describe the feasibility and safety of subcutaneous immunoglobulin (SCIg) in polymyositis (PM) and dermatomyositis (DM). METHODS Since 2009, we used SCIg to treat patients with severe idiopathic myositis (4 with DM, 3 with PM), diagnosed according to the Bohan and Peters criteria. SCIg (Vivaglobin®; CSL Behring) was administered by a programmable pump at the patients usual IVIg monthly dose fractioned into equal doses given subcutaneously at weekly intervals. A standardized protocol was used to evaluate patients and to assess disease activity, treatment response and quality of life. RESULTS Seven female patients were studied. All were Caucasians, with a median age of 53 years and a median disease duration of 72 months. The median follow-up period was 14±4 months. During treatment period, no relapse of the disease occurred. All patients showed a favourable clinical response and reported a good tolerance to the treatment with an improved quality of life. CK serum levels decreased over time with a concomitant improvement in MRC and Rankin modified scores. Three patients were able to discontinue the immunosuppressant and all to reduce the daily maintenance prednisone dose. CONCLUSIONS Our experience demonstrates the beneficial effect and the safety of SCIg administration in active and refractory inflammatory myopathies.

Influence of early high-dose steroid treatment on Bell's palsy evolution

Abstract. The objective of this double-blind, randomized, placebo-controlled study was to test the efficacy of high-dose prednisone, administered as early as possible, in modifying the natural progression of Bells palsy. Sixty-two consecutive patients, enrolled within 72 hours of facial palsy onset, were assigned to high dose intravenous prednisone in combination with intramuscular polyvitaminic therapy (group A) or polyvitaminic therapy alone (group B). Clinical grading of facial muscle strength and length of absence from work were evaluated. An early worsening of facial muscle strength was observed in controls, leading to the divergence in the trends of the grading scores in the two groups; this result was not confirmed in the long-term follow-up. Treated patients returned to work earlier than controls. In conclusion, early treatment based on high-dose corticosteroids slightly accelerates spontaneous improvement in Bells palsy.

Intravenous immunoglobulin as add on treatment with mycophenolate mofetil in severe myositis

OBJECTIVES To report the use of intravenous immunoglobulin (IVIg) and mycophenolate mofetil (MMF) in polymyositis (PM) and dermatomyositis (DM). METHODS We performed an open study in PM and DM with active disease. Indications for treatment were: steroid-dependency, refractoriness to steroid and/or immunosuppressants, and life-threatening disease. IVIg was used at 2 g/kg in monthly cycles for six months and then each other month for other three cycles. MMF was slowly titrated to 30 mg/kg/day orally. Parameters employed to follow patients were the Medical Research Council (MRC) scale, the modified Rankin score, CK serum levels and daily prednisone dose. RESULTS Seven patients were studied (4PM, 3DM). All were females, with a mean age of 49 years. All of them achieved a complete remission and, at the last follow-up visit, significant differences in MRC score, modified Rankin score, CK levels, and the daily maintenance prednisone dose were documented. No relevant side effects were observed. CONCLUSION IVIg as add on treatment with MMF is effective in severe and refractory myositis, moreover as safe and steroid-sparing agent.

Usefulness of hand rehabilitation after carpal tunnel surgery

The purpose of this randomized trial was to assess the clinical evolution after carpal tunnel release in subjects with long‐term carpal tunnel syndrome. The evaluation criteria were symptom occurrence, motor performance, and delay in returning to work. A total of 100 subjects were assessed four times (prior to surgery, and 12 days, 1 month, and 3 months after surgery) using the Boston carpal tunnel questionnaire, the nine‐hole peg test (NHPT), and the Jebsen–Taylor test (JTT). Subjects were randomized to a rehabilitation program or to a progressive home exercise program. No difference in symptom occurrence between the two groups was detected after 1 and 3 months. One month after surgery, only patients in the first group showed motor dexterity improvement according to NHPT and JTT scores. At the 3‐month follow‐up, the two groups did not differ but the group undergoing rehabilitation showed a shorter return‐to‐work interval. A rehabilitation approach after hand surgery is clinically relevant to accelerate recovery but neither modifies functional recovery nor reduces symptom occurrence.

The importance of suspecting superficial siderosis of the central nervous system in clinical practice.

Once the central nervous system surface is greatly encrusted with haemosiderin, even removing the source of bleeding will have little effect on the progression of clinical deterioration. Superficial siderosis of the central nervous system is rare and insidious, but magnetic resonance imaging has turned a previously late, mainly autoptical diagnosis into an easy, specific, in vivo, and possibly early one. Avoiding long diagnostic delay will be very important in those cases susceptible of causal treatment.

Spontaneous intracranial hypotension: the value of brain measurements in diagnosis by MRI.

Abstract Caudal brain displacement is inconstantly reported as an MRI feature of spontaneous intracranial hypotension (SIH). We reviewed the clinical data and MRI of eight patients diagnosed as having SIH and investigated the possibility of more precise assessment. On midsagittal images we measured four anatomical landmarks: the position of the cerebellar tonsils, fourth ventricle, and infundibular recess, plus the angle between the bicommissural line and a line tangential to the floor of the fourth ventricle; midsagittal images from 89 normal controls were also measured. On statistical analysis, all measurements differed in the two groups, and the difference was significant for the cerebellar tonsils, fourth ventricle, and infundibular recess. Some overlap between patients and controls was found for each measurement; however, all the patients had two (two patients) or more (six) values outside the range in normal controls range or not above their 1st quartile. Measurement of the position of the third ventricle seemed particularly sensitive. We suggest that examination of midsagittal images can help in diagnosing clinically suspected SIH.

CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients

Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n = 64) and apparently sporadic ALS (n = 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ∼ 1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs.

Impact of treatment on survival in polymyositis and dermatomyositis. A single-centre long-term follow-up study

OBJECTIVE To assess the long-term outcome in polymyositis (PM) and dermatomyositis (DM), with a particular emphasis on mortality and influence of treatment. METHODS Diagnosis was based according to the Bohan and Peters criteria. Patients have been followed up by a standardised protocol. Deaths were registered and causes of death were ascertained. Survival probability at 5 and 10years was estimated according to the Kaplan-Meier method, in the overall series and by a diagnostic group and an initial treatment. Mortality hazard ratios (95% CI) for major clinical and demographic features were estimated through univariate and multivariate Cox proportional hazard models. RESULTS 91 patients (43 PM and 48 DM) were available for the study. Baseline characteristics were not different from those previously reported. Twenty-two patients (24%) died after a median follow-up of 8.7years. As for idiopathic myositis, the survival probabilities at 5 and 10years from the diagnosis were 96.2% and 88.8% for PM respectively; and 93.9% for DM, whereas a higher mortality was documented for cancer-associated myositis and overlap myositis. Male sex [HR=2.4, 95% CI 1.0 to 5.6], heart involvement (HR=1.8), interstitial lung disease (HR=2.3) and arthritis (HR=1.8) increased the risk of mortality, these risk excesses were confirmed in the multivariate analysis. Independent of these features, a higher mortality was documented for patients treated with glucocorticoids (HR=2.3) or immunosuppressants (HR=2.1) when compared to patients treated with immunoglobulins. CONCLUSION Our study, with longitudinal and statistical analyses, suggests that survival has considerably increased in patients with PM/DM. Prognostic factors for mortality are male sex, and heart and lung involvement. Immunoglobulin treatment, intravenously or subcutaneously, is associated with a better survival.

CNS demyelination during anti–tumor necrosis factor alpha therapy

Sirs: Tumor Necrosis Factor alpha (TNFalpha) is a cytokine released by activated monocytes, macrophages, and T-lymphocytes. It is involved in several processes, but plays an important role particularly in inflammation [1]. Its overproduction is implicated in a wide range of pathological conditions, including rheumatoid arthritis (RA) [2] and multiple sclerosis (MS) [3]. High concentrations of TNFalpha are present in synovial fluid of RA patients [4] and in cerebro-spinal fluid (CSF) of MS patients [5]. Considering its role in inflammatory disease, numerous drugs have been developed to modulate its action on inflammation in recent years [6, 7]. Some are characterized by monoclonal antibodies against TNFalpha (Infliximab, Adalimumab), while others are soluble TNF-receptor fusionproteins (Etanercept, Lenercept), but all inhibit the TNFalpha effect [6, 7]. In the literature the effectiveness of TNFalpha therapy in experimental models and in studies of RA in humans is well known [8]. In addition several studies have shown its preventive role in experimental autoimmune encephalomyelitis (EAE), a well established experimental model of MS [9]. Despite these findings, antiTNFalpha treatment for MS worsens the disease. In a trial of antiTNFalpha-targeted therapy using Lenercept, treated patients had significantly more exacerbations than placebo-treated patients [7]. Moreover, other studies have demonstrated that Etanercept and Infliximab may also worsen preexisting MS and trigger de-novo CNS demyelination [10, 11]. The patient we report experienced CNS demyelination using Adalimumab, a new TNFalpha-blocker. A 40-year old woman with RA on methotrexate (10 mg i. m. once a week) treatment for several months started a therapy with Adalimumab (40 mg s. c. once 15 days), a TNFalpha-blocker. After two months she experienced diplopia, headache, nausea and dizziness with subacute onset. She had no family history of neurological disturbances and there was no evidence of a previous febrile episode or other previous neurological dysfunction. Neurological examination showed VI and VII right cranial nerve palsy, a tetrapyramidal syndrome, bladder voiding disorder, mild leg extremity sensory deficit. Immunological and infection investigations were normal, whereas CSF analysis showed barrier damage and several oligoclonal bands. VEPs, SEPs and BAEPs were abnormal. Brain and spinal cord MRI revealed several T2-hyperintensities in the hemispheric white matter, in the brainstem and in the spinal cord. Following gadolinium-DTPA (Gd) administration, some areas of enhancement were present in both hemispheres and in cervical spinal cord (Fig. 1A, B). Anti-TNFalpha therapy was stopped and methylprednisolone 1 g/day i. v. for five days was administered with a progressive improvement of the clinical picture. After six months brain and spinal MRI showed the persistence of T2-weighted hyperintensities (Fig. 1C), but there was no evidence of enhancement after Gd administration (Fig. 1D). After 6 and 14 months the clinical picture was normal except for mild hyperreflexia in all four limbs. Exacerbation of previously quiescent MS and new-onset demyelinating disease have been reported during Infliximab and Etenarcept therapy for RA. Moreover it has been well documented that another TNF-antagonist, Lenercept, increased the number of attacks of pre-existing MS [7, 10, 11]. The present data – in particular the temporal correlation of neurological symptoms onset with TNFalpha-blocker administration and the monophasic course – suggest that even Adalimumab, like other TNFalpha blockers, may trigger denovo CNS demyelination. Therefore, although a causal relationship between anti-TNFalpha therapy and CNS demyelination has not been well established, all reports make this association more plausible, indicating a possible protective role of TNFalpha in demyelinating diseases. Until further long-term safety data are available, we suggest that anti-TNFalpha therapy should not be administered to patients with MS or to patients with neurological signs or symptoms possibly arising from previous demyelinating episodes. Moreover it would be useful to look for MRI signs of leukoencephalopathy, possibly due to silent CNS demyelination, before starting a therapy with TNF-blockers.

Subcutaneous IgG in immune-mediate diseases: proposed mechanisms of action and literature review

Intravenous immunoglobulin (IVIg) constitutes a relevant treatment option in various immune-mediated disorders, such as chronic inflammatory neuropathies and idiopathic inflammatory myopathies (IIM). Several advantages are linked to IVIg immunomodulatory and steroid sparing effects and to the possibility to withdraw the immunosuppressant therapy. However, the use of IVIg is not always easy to manage. It is associated with the need of an intravenous route of administration, high costs, and the risk of serious systemic adverse effects. More recently, the subcutaneous administration of immunoglobulin (SCIg) has been used in immunological practice as an alternative to IVIg, administered at lower dosages and more frequent intervals. This results in higher and more stable IgG serum levels and may prevent end-of-dose reduction and adverse effects caused by sudden IgG serum elevation. Moreover, the use of SCIg is more feasible, patient-friendly and cost-effective compared to the intravenous administration. In this context we compared IVIg and SCIg long term efficacy in the treatment of chronic inflammatory neuropathies and IIM, by reviewing the current literature and reporting the data obtained from our clinical experience about the use of SCIg in patients with myositis. We also described the most recent evidence on the immunomodulatory role of immunoglobulin, the pharmacokinetic properties of SCIg compared to the IVIg treatment, and the consequent clinical, laboratory and immunological implications.