Emergence of rheumatoid arthritis following exposure to natalizumab

We report a patient with relapsing-remitting multiple sclerosis, who developed rheumatoid arthritis after exposure to natalizumab. While some multiple sclerosis therapies are known to unmask autoimmune conditions, natalizumab is rarely implicated as a cause of alternative autoimmunity. This case illustrates an unusual clinical scenario which may support recent scientific work suggesting that, when natalizumab blocks T helper 1 cells from entering the central nervous system, T helper 17 cells may continue to migrate into immune-privileged spaces and cause pathologic inflammation. BRIEF BACKGROUND: Multiple sclerosis (MS) patients often suffer from concurrent autoimmune conditions, and may be at increased risk for developing rheumatoid arthritis (RA) (Langer-Gould et al., 2010; Tseng et al., 2016). While alemtuzumab and rituximab are known to unmask underlying autoimmune disorders, natalizumab is not commonly associated with autoimmunity. Here, we report a patient with relapsing-remitting MS who developed acute autoimmune arthropathy following exposure to natalizumab. CASE REPORT: A 45-year-old woman with autoimmune thyroiditis presented after episodes of left arm and right leg numbness. MRI showed multiple supratentorial and spinal cord demyelinating lesions. Lumbar puncture yielded CSF with a lymphocytic pleocytosis (11 leukocytes, 97% lymphocytes), normal protein, normal glucose, elevated immunoglobulin G index (2.24), and multiple unmatched oligoclonal bands. Her initial autoimmune workup revealed elevated anti-thyroid peroxidase antibody and rheumatoid factor (22 IU/mL, reference value < 14 IU/mL). The remainder of the patient's rheumatologic evaluation was normal, including aquaporin-4 antibody, anti-nuclear antibody, complements 3 and 4, and Sjogren's antibodies. She fulfilled 2017 McDonald Criteria for multiple sclerosis, and was started on dimethyl fumarate. Three months later, she developed left foot numbness and urinary incontinence. MRI spine showed a new lesion at C7, and her therapy was escalated to natalizumab. Immediately after her initial natalizumab infusion, she experienced transient neck and shoulder pain with decreased range of motion. She had no history of arthropathy. After her second natalizumab infusion, she developed persistent shoulder and hip pain. Her arthralgias resolved after a course of oral steroids. Two weeks after her second natalizumab infusion, she was seen by a rheumatologist who noted mild synovitis of both elbows and wrists on exam, but no significant inflammation involving her shoulders, fingers, knees, ankles, or feet. This time, she had significantly elevated anticyclic citrullinated peptide IgG (> 300 U/mL, reference value < 3 U/mL) and rheumatoid factor (71 IU/mL). Based on the number of small joints involved, and her positive serology, she met 2010 American College of Rheumatology Criteria for rheumatoid arthritis. Natalizumab was discontinued, and the patient was started on methotrexate, with which her rheumatoid arthritis has been controlled for the past two years.