Daniel DiCapua

Response of patients with refractory myasthenia gravis to rituximab: a retrospective study

Introduction: Myasthenia gravis, an autoimmune disorder of neuromuscular transmission, is treated by an array of immunomodulating therapies. A variable response is observed with certain patients being medically refractory. Methods: We report the results of 14 refractory generalized myasthenia gravis patients (6 AChR+; 8 MuSK+) treated with rituximab. Results: Sustained clinical improvement was observed in all patients as well as a reduction of conventional immunotherapies. Prednisone dose decreased a mean of 65.1%, 85.7%, and 93.8% after cycle 1, 2, and 3 of rituximab therapy, respectively. A statistically significant reduction in plasma exchange sessions was seen after cycle 1 with all patients being off of plasma exchange after cycle 3. Acetylcholine receptor antibody titers decreased a mean of 52.1% (p = 0.0046) post-cycle 2. Conclusion: Our results support the hypothesis that rituximab is beneficial and well tolerated in managing refractory myasthenia gravis and nearly doubles published cases. We propose that B-cell-directed therapies may become an attractive option and suggest pursuit of a prospective trial.

Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients

Despite the efficacy of standard immunotherapy, a subset of myasthenia gravis (MG) patients remains medically refractory. Muscle-specific kinase autoantibody positive (MuSK+) patients, in particular, do not respond well to treatment, exhibit more bulbar symptoms and have more frequent exacerbations as compared to acetylcholine receptor antibody positive (AChR+) patients.1 ,2 Autoreactive B cells are appropriate candidates for targeted drug therapy as they play an important role in the pathogenesis of MG.2–4 Rituximab, a chimeric monoclonal antibody that targets the CD20 antigen on B lymphocytes, is the only B cell–directed biologic currently approved for clinical use. Several groups, including our own, have observed the benefits of rituximab in both AChR+ and MuSK+ patients.2–7 The durability of this positive response has varied among different reports. One group reported sustained benefit after a mean follow-up of 31 months in the combined AChR+ and MuSK+ cohort and 40 months in the MuSK+ subpopulation.3 Here, we report our experience with the sustained effects of rituximab in nine refractory MuSK+ patients in a follow-up period ranging from 2 to 5.5 years. A retrospective study was performed of generalised MuSK+ MG patients referred to our neuromuscular clinic from 2003 to 2011. Nine MuSK+ patients were identified with refractory disease and treated with rituximab. The group consisted of eight females and one male with a median age of 40. Patients were defined as refractory when they: (1) could not lower …

Durability of the Rituximab Response in Acetylcholine Receptor Autoantibody–Positive Myasthenia Gravis

Importance Myasthenia gravis (MG), an autoimmune disorder of neuromuscular transmission, is treated by an array of immunotherapeutics, many of which are nonspecific. Even with current therapies, a subset of patients has medically refractory MG. The benefits of B-cell–targeted therapy with rituximab have been observed in MG; however, the duration of these benefits after treatment is unclear. Objective To evaluate the durability of response to rituximab in the treatment of acetylcholine receptor autoantibody–positive (AChR+) generalized MG. Design, Setting and Participants This retrospective case series study included 16 patients with AChR+ MG referred to an MG clinic from January 1, 2007, to December 31, 2015. The patients were treated with rituximab and followed up for 18 to 84 months after treatment. Main Outcomes and Measures Assessment of long-term clinical response, durability of response and/or relapse rate, AChR autoantibody levels, adverse effects, and inflammatory markers. Results In the 16 patients (6 men and 10 women; median age, 42 [range, 18-69] years), clinical improvement was observed in parallel with complete withdrawal or reduction of other immunotherapies, with all patients achieving complete stable remission, pharmacologic remission, or minimal manifestations based on the Myasthenia Gravis Foundation of America postintervention status criteria. Nine patients (56%) had a relapse during a mean follow-up of 36 (range, 24-47) months. Seven patients (44%) remained relapse free with a mean follow-up of 47 (range, 18-81) months since the last rituximab treatment. All values were normalized to a pretreatment anti-AChR antibody level of 100% and the mean levels after each rituximab cycle were calculated. A 33% decrease was seen after cycle 1 of rituximab treatment (100% vs 67%; P = .004); 20% after cycle 2 (compared with cycle 1) (67% vs 47%; P = .008); and 17% after cycle 3 (compared with cycle 2) (47% vs 30%; P = .02). However, the serum cytokine levels measured were found to be unchanged. Conclusions and Relevance Rituximab therapy appears to be an effective option in patients with refractory AChR+ MG, who were observed to have a durable response after treatment. Identification of markers of disease relapse and sustained remission are critical next steps in the development of pathophysiology-relevant, evidence-based practice parameters for rituximab in the treatment of MG.

Autoantibodies Produced at the Site of Tissue Damage Provide Evidence of Humoral Autoimmunity in Inclusion Body Myositis

Inclusion body myositis (IBM) belongs to a group of muscle diseases known as the inflammatory myopathies. The presence of antibody-secreting plasma cells in IBM muscle implicates the humoral immune response in this disease. However, whether the humoral immune response actively contributes to IBM pathology has not been established. We sought to investigate whether the humoral immune response in IBM both in the periphery and at the site of tissue damage was directed towards self-antigens. Peripheral autoantibodies present in IBM serum but not control serum recognized self-antigens in both muscle tissue and human-derived cell lines. To study the humoral immune response at the site of tissue damage in IBM patients, we isolated single plasma cells directly from IBM-derived muscle tissue sections and from these cells, reconstructed a series of recombinant immunoglobulins (rIgG). These rIgG, each representing a single muscle-associated plasma cell, were examined for reactivity to self-antigens. Both, flow cytometry and immunoblotting revealed that these rIgG recognized antigens expressed by cell lines and in muscle tissue homogenates. Using a mass spectrometry-based approach, Desmin, a major intermediate filament protein, expressed abundantly in muscle tissue, was identified as the target of one IBM muscle-derived rIgG. Collectively, these data support the view that IBM includes a humoral immune response in both the periphery and at the site of tissue damage that is directed towards self-antigens.

Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small-fiber neuropathy

Perineural granulomas in cutaneous sarcoidosis have been rarely reported and their clinical significance has yet to be evaluated. Recently, a 27‐year‐old male presented with multiple pink papules on the flank and lower back, accompanied by a painful, burning sensation. Biopsies revealed well‐defined granulomas, consistent with sarcoidosis, in the dermis and involving small cutaneous nerves. We hypothesized that perineural granulomas may be an under‐recognized feature of cutaneous sarcoidosis and may be responsible for sensory disturbances. We reviewed cases from 29 consecutive patients with cutaneous sarcoidosis. Perineural granulomas were identified in 18/29 (62%) patients and in 22/40 (55%) biopsies. Perineural granulomas were identified in 7/9 biopsies from the proximal upper extremity, 1/3 from the distal upper extremity, 7/12 from the head and the neck, including 4/4 from the nose, 5/9 from the back, 1/2 from the flank and 1/1 from the proximal lower extremity and 0/4 from the distal lower extremity. The anatomical distribution is similar to sarcoidosis small‐fiber neuropathy (SSFN), in which sarcoidosis patients without evident skin lesions experience sensory disturbances of unknown etiology involving the face, the proximal extremities and the trunk. Our results indicate perineural granulomas in cutaneous sarcoidosis are more common than previously appreciated, primarily involve the head, the proximal upper extremities and the back, and may be responsible for neurological manifestations.

Guillain-Barre syndrome mimics primary biliary cirrhosis-related myopathy.

Guillain–Barré syndrome (GBS) is an immune-mediated disorder characterized by acute polyneuropathy, ascending paralysis and post infectious polyneuritis. Two-thirds of patients present with a history of recent upper respiratory tract or gastrointestinal infection. The clinical history, neurologic examination and laboratory assessment allow for a straightforward diagnosis in the majority of cases. However, primary biliary cirrhosis (PBC) is known to cause clinically detectable muscular weakness. It is therefore critical to differentiate between PBC-associated muscular weakness and GBS-induced paralysis. Here, we report a patient with a longstanding history of PBC who developed progressive weakness and respiratory failure due to GBS, which clinically mimicked PBC myopathy. This is the first reported association between GBS and PBC.

Relationship Between Cerebrospinal Fluid Protein Levels and Electrophysiologic Abnormalities in Guillain-Barré Syndrome.

Objectives: The cerebrospinal fluid (CSF) protein level is known to be elevated in patients with Guillain–Barré syndrome (GBS). This report correlates the degree of CSF protein elevation with the number of electrophysiologic abnormalities on nerve conduction study (NCS). Methods: We reviewed 38 patients admitted to our institution with a diagnosis of GBS and had both a measured CSF protein level and a NCS within 24 hours of each other. Results: CSF protein level correlates with the number of NCS demyelination criteria, as described by Cornblath, in patients with GBS. Conclusions: This retrospective study is the first to demonstrate a relationship between the CSF protein level and the electrophysiologic abnormalities that accompany GBS.

A Neurology Clerkship Curriculum Using Video-Based Lectures and Just-in-Time Teaching (JiTT)

Introduction Just-in-time teaching is an educational strategy that involves tailoring in-session learning activities based on student performance in presession assessments. We implemented this strategy in a third-year neurology clerkship. Methods Linked to core neurology clerkship lectures, eight brief video-based lectures and knowledge assessments were developed. Students watched videos and completed multiple-choice questions, and results were provided to faculty, who were given the opportunity to adjust the in-person lecture accordingly. Feedback was obtained by surveys of students and faculty lecturers and from student focus groups and faculty. Student performance on the end-of-clerkship examination was analyzed. Results Between October 2016 and April 2017, 135 students participated in the curriculum, and 56 students (41.5%) responded to the surveys. Most students agreed or strongly agreed that the new curriculum enhanced their learning and promoted their sense of responsibility in learning the content. Faculty agreed that this pedagogy helped prepare students for class. Most students watched the entire video-based lecture, although there was a trend toward decreased audience retention with longer lectures. There were no significant changes in performance on the end-of-clerkship examination after implementation of just-in-time teaching. In focus groups, students emphasized the importance of tying just-in-time teaching activities to the lecture and providing video-based lectures well in advance of the lectures. Discussion Just-in-time teaching using video-based lectures is an acceptable and feasible method to augment learning during a neurology clinical clerkship. We believe this method could be used in other neurology clerkships with similar success.

House Staff Communication Training and Patient Experience Scores

Objective: To assess whether communication training for house staff via role-playing exercises (1) is well received and (2) improves patient experience scores in house staff clinics. Methods: We conducted a pre–post study in which the house staff for 3 adult hospital departments participated in communication training led by trained faculty in small groups. Sessions centered on a published 5-step strategy for opening patient-centered interviews using department-specific role-playing exercises. House staff completed posttraining questionnaires. For 1 month prior to and 1 month following the training, patients in the house staff clinics completed surveys with Clinician and Group Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS) questions regarding physician communication, immediately following clinic visits. Preintervention and postintervention results for top-box scores were compared. Results: Forty-four of a possible 45 house staff (97.8%) participated, with 31 (70.5%) indicating that the role-playing exercise increased their perception of the 5-step strategy. No differences in patient responses to CG-CAHPS questions were seen when comparing 63 preintervention surveys to 77 postintervention surveys. Conclusion: Demonstrating an improvement in standard patient experience surveys in resident clinics may require ongoing communication coaching and investigation of the “hidden curriculum” of training.

Dermatoneuro syndrome: A full recovery after a second episode

Scleromyxedema is a chronic, idiopathic disorder associated with monoclonal gammopathy and characterized by dermal mucin deposition.1 A rare but severe complication of scleromyxedema is dermatoneuro syndrome (DNS), which presents with a flu-like prodrome, skin papules, fever, seizures, and coma. It can have catastrophic systemic effects with a substantial mortality rate of 21%2,3 requiring a multidisciplinary diagnostic approach for early detection and management.