Using the Cholinergic Anti-Inflammatory Pathway to Treat Systemic Lupus Musculoskeletal Pain

Using the Cholinergic Anit-Inflammatory Pathway to Treat Systemic Lupus Musculoskeletal Pain

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune, inflammatory disease and musculoskeletal pain is one of the most common symptoms. This study will investigate whether transcutaneous stimulation of the vagus nerve will decrease lupus musculoskeletal pain. This study will additionally investigate the biologic effects of vagus nerve stimulation on inflammation. It will be the first clinical study using one of the body's own pathways of modulating the immune system and inflammatory response, the cholinergic anti-inflammatory pathway, in SLE.

Study Overview

• Status: Unknown
• Conditions: Musculoskeletal Pain; Lupus Erythematosus, Systemic
• Intervention / Treatment: Device: Vagus nerve stimulation; Device: Sham vagus nerve stimulation

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Manhasset, New York, United States, 11030
      • Feinstein Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years,
2. SLE (defined by the ACR or SLICC criteria),
3. Musculoskeletal pain ≥ 4 on a non-anchored VAS 10 cm scale
4. BILAG C on Musculoskeletal Domain of the BILAG 2004
5. If on corticosteroids, the dose must be stable and ≤ 10mg/day (prednisone or equivalent) for at least 28 days before baseline,
6. If on background immunosuppressive treatment the dose must be stable for at least 28 days before baseline
7. Able and willing to give written informed consent and comply with the requirements of the study protocol.

Exclusion Criteria:

1. Treatment with rituximab within one year of baseline (subjects with previous treatment with rituximab can enter study only with documentation of B cell repletion),
2. Treatment with cyclophosphamide within 2 months of baseline,
3. Expectation to increase steroids and/or immunosuppressive treatment,
4. Anti-phospholipid syndrome,
5. Fibromyalgia (fibromyalgia will be defined as a score > 13 on the Fibromyalgia Symptom Scale (FSS).
6. Treatment with an anti-cholinergic medication, including over the counter medications,
7. Implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators.
8. Current tobacco or nicotine user,
9. Joint replacement within 60 days prior to study enrollment or planned within the course of the study,
10. Any planned surgical procedure requiring general anesthesia within the course of the study,
11. Intra-articular cortisone injections within 28 days of the start of study,
12. Chronic inflammatory disorders apart from SLE affecting the joints,
13. Investigational drug and/or treatment during the 28 days or seven half-lives of the investigational drug prior to the start of study drug dosing (Day 0), whichever is the greater length of time,
14. Active infection including hepatitis B or hepatitis C at baseline,
15. Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to a study intervention,
16. Pregnancy or lactation,
17. Comorbid disease that may require administration of corticosteroid use,
18. Inability to comply with study and follow-up procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vagus Nerve Stimulation; Subjects randomized to this arm will receive transcutaneous vagus nerve stimulation for 5 minutes on 4 consecutive days.	Device: Vagus nerve stimulation; Patients will receive transcutaneous stimulation of the auricular branch of the left vagus nerve for 5 minutes daily for 4 consecutive days. The device is a handheld electrical pulse generator and a pair of electrodes to be placed at the ear for stimulation. The specific target at the ear will be the auricular branch of the vagus nerve which innervates the skin of the ear canal. Electrodes will be placed near/at the entrance to the canal of the ear to provide stimulation to the auricular branch.
Sham Comparator: Sham Vagus Nerve Stimulation; Subjects randomized to this arm will receive sham stimulation for 5 minutes for 4 consecutive days.	Device: Sham vagus nerve stimulation; Patients will receive sham transcutaneous stimulation of the auricular branch of the left vagus nerve for 5 minutes daily for 4 consecutive days. Sham stimulation will be performed in the identical manner as true transcutaneous stimulation except that the patient will not receive electrical stimulation of the vagus nerve.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Musculoskeletal pain.	Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SLE Disease activity	SLE disease activity will be assessed using the SLEDAI, a validated disease activity instrument for SLE.	5 days
Fatigue	Fatigue will be measured using the FACET F questionnaire which will be completed by each subject.	5 days
Fatigue	Fatigue will be measured using the FACET F questionnaire which will be completed by each subject.	12 days
Tender and swollen joint counts	The number of tender and swollen joints of the subject will be assessed by the investigator who will examine 68 potential tender joints and 66 potential swollen joints.	5 days
Tender and swollen joint counts	The number of tender and swollen joints of the subject will be assessed by the investigator who will examine 68 potential tender joints and 66 potential swollen joints.	12 days
SLE cutaneous activity	Cutaneous activity will be assessed using the CLASI, a validated index for SLE skin disease.	5 days
SLE cutaneous activity	Cutaneous activity will be assessed using the CLASI, a validated index for SLE skin disease.	12 days
Musculoskeletal Pain	Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.	12 days
Percentage of subjects with treatment emergent adverse events.	The percentage of participants with treatment emergent adverse events will be assessed using the NCI-CTAEversion4.	12 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
TNF, HMGB1, IL-6, Il1B, IFNα and IL10 levels	Levels of inflammatory cytokines (ie TNF, HMGB1, IL-6, Il1B, IFNα and IL10) will be measured in patients sera.	5 days
TNF, HMGB1, IL-6, Il1B, IFNα and IL10 levels	Levels of inflammatory cytokines (ie TNF, HMGB1, IL-6, Il1B, IFNα and IL10) will be measured in patients sera.	12 days
Lipopolysaccharide stimulated levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 in whole blood.	Whole blood will be taken from patients and stimulated by lipopolysaccharide. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.	5 days
Lipopolysaccharide stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood.	Whole blood will be taken from patients and stimulated by lipopolysaccharide. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.	12 days
Gardiquimod stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood.	Whole blood will be taken from patients and stimulated by gardiquimod.. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.	5 days
Gardiquimod stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood.	Whole blood will be taken from patients and stimulated by gardiquimod.. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.	12 days
CpG stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood.	Whole blood will be taken from patients and stimulated by CpG. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.	5 days

Collaborators and Investigators

• Sponsor: Northwell Health
• Collaborators: John and Marcia Goldman Foundation
• Investigators: Principal Investigator: Cynthia Aranow, M.D., Northwell Health

Publications and helpful links

General Publications

• Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3(3):CD007478. doi: 10.1002/14651858.CD007478.pub2.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): April 30, 2018
• Study Completion (Anticipated): November 1, 2020

Study Registration Dates

• First Submitted: May 26, 2016
• First Submitted That Met QC Criteria: July 5, 2016
• First Posted (Estimate): July 6, 2016

Study Record Updates

• Last Update Posted (Actual): September 9, 2020
• Last Update Submitted That Met QC Criteria: September 8, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Inflammation; Musculoskeletal Pain; Lupus Erythematosus, Systemic
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Pain; Neurologic Manifestations; Musculoskeletal Diseases; Connective Tissue Diseases; Muscular Diseases; Lupus Erythematosus, Systemic; Musculoskeletal Pain
• Other Study ID Numbers: 16-0171

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No