Robert Carruthers

IgG4-Related Disease and Hypertrophic Pachymeningitis

AbstractHypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4-related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP.To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD.Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4-RD.This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis.

Effect of vitamin D on MS activity by disease-modifying therapy class.

Objective: To determine whether vitamin D status predicts disease activity in patients with multiple sclerosis (MS) taking interferon-β (IFN), glatiramer acetate (GA), and fingolimod (FTY). Methods: Participants (n = 324) with relapsing-remitting MS on IFN (96), GA (151), or FTY (77) were identified from the Comprehensive Longitudinal Investigation of MS at Brigham and Womens Hospital (CLIMB) Study at the Partners MS Center. FTY-treated participants were analyzed separately because of differences in selection. Serum vitamin 25(OH)D concentration was adjusted for season. We evaluated the relationship between 25(OH)D tertile and time to relapse or gadolinium-enhancing lesion using a Cox model adjusted for age, sex, and disease duration. Results: Higher 25(OH)D was associated with longer time to the combined endpoint in the overall IFN/GA cohort (p for trend = 0.042; hazard ratio [HR] = 0.77) and in the IFN subgroup (HRIFN = 0.58; pIFN = 0.012), but not in GA-treated participants (p = 0.50; HR = 0.89). For gadolinium-enhancing lesions alone, there was a significant association observed in GA and IFN subgroups, although the effect was more pronounced on IFN (HRGA = 0.57; pGA = 0.039 vs HRIFN = 0.41; pIFN = 0.022). No significant associations were found for relapses. For FTY, higher 25(OH)D was associated with longer survival for the combined endpoint (HRFTY = 0.48; pFTY = 0.016) and for relapses (HRFTY = 0.50; pFTY = 0.046), but not for gadolinium-enhancing lesions. Conclusions: Disease activity generally improved with higher 25(OH)D, but this study raises the question of effect modification by treatment class.

An observational comparison of natalizumab vs. fingolimod using JCV serology to determine therapy

Background: The lack of prospective trial data comparing certain multiple sclerosis (MS) therapies could be addressed with observational research. Objective: The objective of this paper is to investigate outcomes of natalizumab versus fingolimod treatment in an MS cohort using a novel method of patient selection. Methods: We reviewed entries from our clinic’s database for all relapsing–remitting MS patients started on fingolimod and natalizumab where JCV serology was used to determine treatment. We analyzed each group for time to first relapse and in a second analysis, time to first relapse or gadolinium-enhancing lesion. Results: Sixty-nine patients on natalizumab and 36 on fingolimod met our inclusion criteria and had adequate follow-up for analysis. The baseline clinical characteristics at the time of treatment switch were similar. With a mean follow-up of 1.5 years for both treatment groups, there was a trend favoring natalizumab in time to first relapse, although this was not statistically significant (2.20 (0.87, 5.55) p = 0.095). There was a significant difference in the secondary outcome, time to relapse or gadolinium-enhancing lesion (2.31 (1.03, 5.17) p = 0.041), favoring natalizumab. Adjusted analyses favored natalizumab for both outcomes (p < 0.05). Conclusion: This work employed an observational study design where treatment allocation by JCV serology allowed for treatment groups with well-balanced characteristics.

Progressive multifocal leukoencephalopathy and JC Virus-related disease in modern neurology practice

The natural history and clinical import of Progressive Multifocal Leukoencephalopathy has changed enormously in the last thirty years. After a resurgence of PML during the HIV/AIDS epidemic, advances in the treatment of multiple sclerosis created another group of at risk patients. With a focus on issues pertaining to the multiple sclerosis patient population, this review covers pathophysiology of the JC virus, causes of PML, mechanisms by which natalizumab increases the risk of PML, determinants of PML risk in natalizumab-treated patients, risks of natalizumab discontinuation, PML prevention and surveillance, PML imaging features, PML diagnosis and stumbling blocks to making the diagnosis, PML and PML-Immune Reconstitution Inflammatory Syndrome (IRIS) treatment.

MS arising during Tocilizumab therapy for rheumatoid arthritis

Background: Interleukin-6 (IL6) blockage is a treatment strategy used in many inflammatory conditions. Trials in Neuromyelitis Optica Spectrum Disorder (NMOSD) are ongoing. Secondary auto-immunity affecting the central nervous system (CNS) is well described with some biologic agents, mainly tumor necrosis factor (TNF)-alpha inhibitors. These treatments can also aggravate patients with known multiple sclerosis (MS). Objectives: To describe a case of a patient who developed MS using another biologic, IL6 receptor antibody Tocilizumab. Results: A 48-year-old woman developed MS while on treatment with Tocilizumab for Rheumatoid Arthritis (RA). This is the first published report of this association. It has obvious implications for NMOSD patients receiving anti-IL6 therapy. Development of new white matter lesions suggestive of MS in a patient treated with anti-IL6 therapy might represent an important complication of therapy. Conclusion: This case illustrates that Tocilizumab might cause secondary auto-immunity in CNS. It is important to be aware of this potential complication as anti-IL6 therapy might become an option for the treatment NMOSD.

Modeling probability of additional cases of natalizumab-associated JCV sero-negative progressive multifocal leukoencephalopathy

JCV serologic status is used to determine PML risk in natalizumab-treated patients. Given two cases of natalizumab-associated PML in JCV sero-negative patients and two publications that question the false negative rate of the JCV serologic test, clinicians may question whether our understanding of PML risk is adequate. Given that there is no gold standard for diagnosing previous JCV exposure, the test characteristics of the JCV serologic test are unknowable. We propose a model of PML risk in JCV sero-negative natalizumab patients. Using the numbers of JCV sero-positive and -negative patients from a study of PML risk by JCV serologic status (sero-positive: 13,950 and sero-negative: 11,414), we apply a range of sensitivities and specificities in order calculate the number of JCV-exposed but JCV sero-negative patients (false negatives). We then apply a range of rates of developing PML in sero-negative patients to calculate the expected number of PML cases. By using the binomial function, we calculate the probability of a given number of JCV sero-negative PML cases. With this model, one has a means to establish a threshold number of JCV sero-negative natalizumab-associated PML cases at which it is improbable that our understanding of PML risk in JCV sero-negative patients is adequate.

Effects of physical comorbidities on disability progression in multiple sclerosis

Objective To examine the association between physical comorbidities and disability progression in multiple sclerosis (MS). Methods We conducted a retrospective cohort study using linked health administrative and clinical databases in 2 Canadian provinces. Participants included adults with incident MS between 1990 and 2010 who entered the cohort at their MS symptom onset date. Comorbidity status was identified with validated algorithms for health administrative data and was measured during the 1 year before study entry and throughout the study period. The outcome was the Expanded Disability Status Scale (EDSS) score as recorded at each clinic visit. We used generalized estimating equations to examine the association between physical comorbidities and EDSS scores over time, adjusting for sex, age, cohort entry year, use of disease-modifying drugs, disease course, and socioeconomic status. Meta-analyses were used to estimate overall effects across the 2 provinces. Results We identified 3,166 individuals with incident MS. Physical comorbidity was associated with disability; with each additional comorbidity, there was a mean increase in the EDSS score of 0.18 (95% confidence interval [CI] 0.09–0.28). Among specific comorbidities, the presence of ischemic heart disease (IHD) or epilepsy was associated with higher EDSS scores (IHD 0.31, 95% CI 0.01–0.61; epilepsy 0.68, 95% CI 0.11–1.26). Conclusions Physical comorbidities are associated with an apparent increase in MS disability progression. Appropriate management of comorbidities needs to be determined to optimize outcomes.

IgG4-related disease and other causes of inflammatory meningeal disease.

Immunoglobulin-4 (IgG4-) related disease is a newly described treatable condition that has recently expanded the differential diagnosis of inflammatory meningeal disorders. This review will discuss the main clinical and pathophysiological features of IgG4-related meningeal disease in the context of meningeal inflammatory disorders in general. Particular attention will be dedicated to the differential diagnosis and the different therapeutic approaches.

Progression rates and sample size estimates for PPMS based on the CLIMB study population

Background: The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts. Objective: The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression. Methods: We studied PPMS (n = 73) and relapsing-onset MS (ROMS) patients (n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women’s Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression. Results: The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS (p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS (p < 0.001). PPMS patients progressed faster to EDSS 3 (p < 0.001) and from EDSS 3 to 6 (p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83–8.35), significantly faster than the RO group (p < 0.001). Conclusions: Our modern PPMS cohort is demographically similar to previously studied cohorts. PPMS is associated with faster disability accrual than ROMS. Current real-world observations of time to sustained progression will inform design of new clinical trials for PPMS.

Dysautonomia From Bilateral Carotid Artery Dissection

The mechanisms of dysautonomia from carotid artery dissection were discussed recently in Circulation . A case was presented of a 49-year-old woman with a history of hypertension and vasovagal syncope who developed abrupt slurred speech and left hemiplegia.1 She had a right internal carotid artery dissection and right cerebral hemispheric infarction involving the insular cortex. During her hospitalization, the patient had episodes of severe bradycardia that Dulay et al1 attributed to “mechanical pressure to an already sensitive carotid sinus from thrombus secondary to a dissection of the internal carotid.” Sarikaya et al2 argued that disrupted descending autonomic pathways from the infarcted insular cortex were responsible. Right-sided insular lesions are known to cause bradyarrhythmias.3 We present a case of bilateral carotid artery dissection in which dysautonomia occurred in the absence of cortical damage.nnA 47-year-old right-handed woman with rheumatoid arthritis experienced symptoms of an apparent upper respiratory infection with a persistent cough after the syndrome resolved. After …