Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus.

Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.

Comparing Clinical Outcomes of Steroid-Sparing Therapy With Rituximab Versus Rituximab Alone in Pemphigus.

BACKGROUND: Previous clinical trials have demonstrated that rituximab therapy combined with conventional steroid-sparing therapy (SST) has increased rates of disease control for mucous membrane pemphigoid compared with rituximab alone. However, limited data is available regarding the role of SST with rituximab therapy in pemphigus. OBJECTIVE: This study aimed to examine clinical outcomes in pemphigus patients treated with rituximab with SST versus without the addition of SST. METHODS: A retrospective chart review was performed for adult pemphigus patients in the Southeastern US at Emory between January 1, 2011, and December 31, 2021. Primary outcomes, including time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, and time to relapse after a rituximab cycle, were compared between patients on SST and patients without SST.  Results: Following rituximab therapy, there was no difference in time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, or time to relapse for patients with or without SST. LIMITATIONS: Our study is limited by its retrospective decline, setting at a single academic center, and inclusion of a high proportion of patients with moderate disease. CONCLUSIONS: The use of SST with rituximab dosing did not improve clinical outcomes related to time to remission, reduction in prednisone dosing, or relapse. These data provide further evidence for the use of rituximab in the majority of pemphigus patients without the need for SST. J Drugs Dermatol. 2024;23(3):e97-e99    doi:10.36849/JDD.7949e.

An oral lesion masquerading as lichen planus.

Proliferative verrucous leukoplakia (PVL) is a rare, aggressive form of oral leukoplakia with a substantial risk of malignant transformation. The slowly progressive course and the lack of a single defining histopathologic characteristic for PVL make this entity a diagnostic challenge. We report on a patient who presented with a 7-year history of worsening oral lesions.

Implementation of the Enhanced Transtheoretical Model Intervention (ETMI) for Low Back Pain Patients in Primary Care: Study Protocol.

BACKGROUND: Self-management, an active life routine, and adherence to physical activity are effective in the management of low back pain (LBP). However, delivering effective education and reassurance to patients can be a difficult for practitioners. The enhanced transtheoretical model intervention (ETMI) has shown to be successful and cost effective. The intervention focuses on educating practitioners to reassure patients, empower them to increase physical activity, and improve their self-efficacy. OBJECTIVES: To assess whether ETMI can be implemented among primary care practitioners and to examine whether it reduces pain, disability, and fear avoidance as well as decreasing healthcare utilization. This protocol outlines the methodology for the implementation of ETMI through a hybrid implementation-effectiveness design. METHODS: Two qualitative and mixed-method studies provided a basis for an implementation prospective cohort study. Discussions are followed by a prospective cohort study with pre-and post-intervention measures as well as descriptions retrieving economic and therapeutic outcome data from the Maccabi Healthcare Services (MHS) databases. In addition, a fourth qualitative study was conducted at the midpoint of the implementation to evaluate the process by measuring the perceptions and practice of practitioners. The intervention group was 220 primary care practitioners and their patients (~n=10,000) from the central district of MHS. The control data was provided by other care districts with similar socioeconomic makeup (~n=40,000). CONCLUSIONS: We evaluated the process and outcomes of the implementation of ETMI. We investigated the relationship between the care received (ETMI against treatment as usual) and healthcare utilization, costs, and patient-clinical outcomes.

Distinct compartmentalization of immune cells and mediators characterizes bullous pemphigoid disease.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by recruitment of leucocytes into skin and release of damaging enzymes, resulting in epidermal detachment and blister formation. To better understand the role of leukotriene B4 (LTB4) and other inflammatory factors in BP pathophysiology, we conducted microscopic and immunohistochemical analyses of preserved skin biopsy sections and conducted flow cytometry and ELISA analyses of matched blood and blister fluid from BP patients. Neutrophils predominated in BP blister fluid, which also contained monocytes/macrophages and T cells, but few to no eosinophils and B cells. In contrast, BP skin histology showed a different pattern, with abundant neutrophils but eosinophils being the predominant immune cell type. LTB4 pathway and neutrophil activation markers were prevalent in BP skin lesions and strongly associated with perivascular neutrophils. Blister fluid neutrophils, monocytes/macrophages and eosinophils all exhibited increased surface expression of leukotriene A4 hydrolase and neutrophil elastase (P = .002 for both). Blister fluid was also enriched in interleukins (IL)-1α, IL-1ß, IL-8, IL-10, IL-18, monocyte colony-stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF). Our findings suggest differential leucocyte recruitment from blood into dermis and from dermis into blister, which correlates with disease activity, and presents potential new treatment opportunities for BP.

Diagnosis and management of pemphigus: Recommendations of an international panel of experts.

BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.

Rituximab therapy in patients with bullous pemphigoid: A retrospective study of 20 patients.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease requiring treatment with immunosuppressive medications; however, finding a therapy that has a sustained durable response and an acceptable side effect profile has been challenging. OBJECTIVE: Our study aimed to evaluate the clinical outcomes of patients with BP treated with rituximab therapy at a single academic center. METHODS: A retrospective chart review was performed on 20 patients who received at least 1 dose of rituximab therapy, either as initial therapy for severe BP or as therapy for recalcitrant disease after having failed conventional immunotherapies. RESULTS: Within our cohort, 75% of patients (n = 15) achieved remission an average of 169 days following rituximab therapy. There were no rituximab-related deaths and significantly fewer adverse events following rituximab therapy. LIMITATIONS: This study was limited by its retrospective nature, focus on a single academic center, and small sample size. CONCLUSION: Use of rituximab therapy demonstrated high rates of remission, steroid-sparing activity, and an acceptable safety profile in our cohort of patients with severe BP or disease refractory to conventional therapies.

Bilateral keratoprostheses in a patient with ocular mucous membrane pemphigoid.

Mucous membrane pemphigoid (MMP) with ocular involvement, also referred to as ocular cicatricial pemphigoid, is a rare, autoimmune blistering disease that can have devastating effects for patients. The resulting corneal neovascularization, recurrent corneal abrasions, and ulceration can ultimately result in severe vision loss. We present a 64-year-old man with recalcitrant ocular MMP and consequently advanced corneal involvement that received bilateral keratoprostheses. This case highlights an aggressive but successful placement of bilateral keratoprostheses in recalcitrant ocular MMP, which restored his vision and ultimately his quality of life.

Autoimmune Sequelae Following Rituximab Therapy: A Review of the Literature and Potential Immunologic Mechanisms.

Rituximab is an anti-CD20 antibody used to deplete B lymphocytes in lymphoma and autoimmune disease. Case reports in the literature describe patients who paradoxically develop autoimmune disease in response to rituximab therapy. We review the reports of autoimmune pathology in response to rituximab treatment and the proposed mechanisms of this reaction. These autoimmune diseases manifest in various organ systems, most frequently the skin and lungs, and involve distinct mechanisms of pathogenesis mediated by potential alterations in B and T lymphocytes, innate immune system, and specific environmental factors. Those clinicians utilizing rituximab should be aware of this unusual phenomenon.

Developing biomarkers for predicting clinical relapse in pemphigus patients treated with rituximab.

BACKGROUND: Rituximab is an effective therapy for pemphigus, although relapses are common. OBJECTIVE: To identify biomarkers to predict relapse of pemphigus following rituximab treatment. METHODS: In this retrospective cohort study, 62 patients with pemphigus treated with 99 rituximab cycles provided longitudinal clinical scoring and biomarker data, including levels of CD19+ B cells, CD4+ T cells, and desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) autoantibodies. An extended time-variant Kaplan-Meier estimator and extended Cox model were applied. RESULTS: Relapse was rare before B-cell repopulation. Univariate analysis revealed low CD4 count (<400 cells/µL) to predict relapse (P < .001). A positive result of testing for Dsg1 (>20 IU) was predictive of relapse among patients with mucocutaneous disease (hazard ratio, 6.40; P = .019); a positive result of testing for Dsg3 (>20 IU) was predictive in patients with mucocutaneous and mucosal disease (hazard ratio, 32.92; P < .001). Multivariable analysis revealed that every CD4 value increase of 200 decreases the hazard ratio for relapse by 35% (P = .029). A positive result of testing for Dsg1 increases the risk for relapse by a factor of 12.32 in patients with mucocutaneous disease (P = .001); positive result of testing for Dsg3 increases risk for relapse by 28.38 in patients with mucosal and mucocutaneous disease (P = .006). LIMITATIONS: Limitations include the retrospective design and inconsistent follow-up. CONCLUSION: Relapse is associated with B-cell repopulation, low CD4+ T -cell count, and positive result of testing for Dsg1 and Dsg3.

Rituximab combined with conventional therapy versus conventional therapy alone for the treatment of mucous membrane pemphigoid (MMP).

BACKGROUND: The use of rituximab for refractory autoimmune blistering diseases is increasing. Data related to rituximab for the treatment of mucous membrane pemphigoid (MMP) are limited. OBJECTIVE: We sought to compare the efficacy of adding rituximab with traditional immunosuppressive therapies in the treatment of MMP. The primary outcome was achievement and time to disease control. METHODS: Patients with a diagnosis of MMP from August 2001 to June 2015 who had greater than 6 months of follow-up after the initiation of therapy were reviewed. RESULTS: In all, 24 patients were treated with rituximab and 25 were treated with conventional immunosuppression. Of patients, 100% in the rituximab group achieved disease control compared with 40% in the conventional group (P < .01), with a mean time to disease control of 10.17 months and 37.7 months (P = .02). Adverse events were seen in 33% of patients after rituximab, compared with 48% of patients in the conventional group (P = .2). LIMITATIONS: Rituximab dosing was not uniform and the 2 groups were not matched in terms of disease severity, nor were they randomized. CONCLUSIONS: Our study indicates that the addition of rituximab to conventional therapy in patients with MMP results in more rapid and sustained disease control with potentially fewer adverse events.

'A challenge to my professional identity'- resisting the shift from over-management to self-management for back pain within an implementation trial: a qualitative study.

OBJECTIVE: The Enhanced Transtheoretical Model Intervention (ETMI) is based on behavioral models and focuses on guiding Chronic Low Back Pain (CLBP) patients to self-manage symptoms and engage in recreational physical activity. While there is promising evidence that ETMI benefits patients, it is unclear how challenging it might be to implement widely. This investigation focused on the perceptions of physiotherapists trained to deliver ETMI for CLBP. DESIGN: A Qualitative study comprised of semi-structured interviews (July to November 2023). Interviews were audio-recorded, transcribed, coded, and analyzed thematically by two independent researchers. SETTING: Data were obtained as part of a large implementation study evaluating the uptake and impact of ETMI amongst physiotherapists in a large public healthcare setting. PARTICIPANTS: 22 physiotherapists trained to deliver the ETMI approach and chose to use it with at least one patient. RESULTS: While physiotherapists acknowledged the evidence base behind ETMI and the clarity of the approach, they struggled to adapt it to routine delivery. Exploration of the reasons for this identified an overarching meta-theme, 'A challenge to my professional identity', and three main themes consisting of 1) interventions such as ETMI contradicted my training. 2) I am ambivalent/ do not accept evidence that contradicts my habitual practice, and 3) I am under-skilled in psychological and communication skills. CONCLUSION: This study highlights the reluctance of physiotherapists to implement evidence-based interventions such as ETMI, which fundamentally challenge their traditional practice and therapeutic identity. The shift from over-management by experts seeking cures to supporting self-management was not palatable to physiotherapists. The challenge of embracing a new professional identity must be addressed to enable a successful implementation of the approach. CONTRIBUTION OF THE PAPER.

Physiotherapists' perceptions of implementing evidence-based practice for patients with low back pain through the Enhanced Transtheoretical Model Intervention: a qualitative study.

BACKGROUND: Physiotherapists have been urged to implement evidence-based practice for the management of low back pain (LBP). However, recent evidence suggests that many fail to do so, specifically in accordance with eliciting and addressing psychosocial factors that impact pain. The Enhanced Transtheoretical Model Intervention (ETMI) for the Treatment of patients with LBP was developed in Israel according to the clinical guidelines and demonstrated clinically and cost-effectiveness. OBJECTIVES: This study's purpose is to explore physiotherapists' perceptions of implementing evidence-based practice through the ETMI approach. DESIGN: Qualitative study. METHODS: Qualitative semi-structured interviews were conducted with 26 physiotherapists. The interviews were audio-recorded, transcribed, coded, and analyzed thematically to identify prevalent themes. RESULTS: Three main themes were identified from the transcripts, consisting of barriers and facilitators of implementing the intervention, and a meta-theme referring to shifts in the perceptions of professional role and identity. CONCLUSION: The findings suggest that physiotherapists believed that implementing ETMI and adopting a psychosocial approach to LBP can be achieved by overcoming issues around communication skills, patient reassurance, and inter-professional collaboration. Therapists also highlighted the need for physiotherapy training to gain skills in combined physical and psychological approaches.

Impact of an Enhanced Transtheoretical Model Intervention (ETMI) Workshop on the Attitudes and Beliefs Regarding Low Back Pain of Primary Care Physicians in the Israeli Navy.

Low back pain (LBP) is a major cause of discomfort and disability. Physicians' attitudes and beliefs influence the way patients with LBP are diagnosed and treated. The objective of the study is the assessment of military primary care physicians' attitudes towards LBP and the effect of an enhanced transtheoretical model intervention (ETMI) workshop on them. We evaluated the impact of a 90-min ETMI workshop on the attitudes and beliefs of primary care physicians in the Israeli Navy on LBP. Outcomes were assessed using the Attitudes to Back Pain Scale in Musculoskeletal Practitioners questionnaire (ABS-mp). Participants responded before and after the workshop, and responses were compared to a control group of primary care physicians in the Air and Space Force. The intervention group included 22 participants and the control group included 18 participants. Both groups were heterogenic (gender, age, seniority). In both groups, primary care physicians reported the common use of non-steroidal anti-inflammatory drugs (NSAIDs) and over-the-counter (OTC) pain medications and often included physical activity and physiotherapy in the treatment plan. Physicians mentioned reassurance and suggestions of early return to physical activity as part of their appointment. There was a positive correlation between questionnaire items suggesting the physician tended to a biomedical approach and reporting the use of imaging modalities (r = 0.451, p = 0.005). After attending the workshop, physicians were significantly more likely to recommend an early return to physical activity (18 ± 0.48 vs. 16.4 ± 0.52, p = 0.04). An ETMI workshop had a minor impact on the attitudes and beliefs of primary care physicians regarding LBP, but a statistically significant impact was noted on return to physical activity recommendations. These findings may be important in the military setting.