Obsessive Compulsive Disorder associated with Autoimmunity in Youth: Clinical Course before and after Rituximab+/- Adjunctive Immunomodulation.

Background: Multiple lines of evidence suggest that some cases of OCD are underlain by autoimmune and/or inflammatory processes that act on the brain to create neuropsychiatric symptomatology. However, studies of immunomodulatory treatments for such cases are sparse. Here we present consecutive cases of presumed-neuroimmune OCD in youth that have been treated with rituximab +/- adjunctive immunomodulatory treatments.

Methods: Of the 458 cases evaluated by our clinic between September 15, 2012 and January 6, 2023, 23 patients were treated with rituximab +/- adjunctive immunomodulation orchestrated by our team (based on evidence of autoimmunity) and were followed routinely by the outpatient clinic team. Patients who presented for a second opinion and were not diagnosed, treated, and/or followed by our outpatient clinic (n=5) or did not have OCD (n=1) are not included. We present the immunological and psychiatric profiles (prior to treatment), selection criteria for use of rituximab, rituximab treatment protocol, recovery status, and reasons for discontinuation (if applicable). Data was obtained from chart review of clinical records. Determination of recovery status was confirmed by the clinical team caring for the patients; patients were classified as: did not recover, partial recovery (PR), or full recovery (FR). Since multiple treatments (psychotherapy, psychiatric medication, and immunomodulation) together contributed to recovery, the team additionally assessed attribution of response to rituximab and details are documented.

Results: Patients were between ages of 4 and 20 at initiation of rituximab treatment. All suffered from severe, debilitating neuropsychiatric symptoms prior to rituximab initiation in the context of evidence for systemic autoimmunity. Approximately 70% had an unequivocal recovery following treatment with rituximab (+/- induction and adjunctive immunomodulation) which in most cases allowed the patients to achieve normal levels of function and cease psychotropic medications. Interpretation of attribution in many cases is complicated by the use of induction and adjunct immunomodulation. Most patients experienced transient increases in symptoms before improving; 11 experienced mild self-limited infusion-related reactions, and 14 experienced hypogammaglobulinemia. No patient had an organ or life-threatening reaction or infection following rituximab. One patient developed recurrent sinusitis following rituximab and thus rituximab was stopped despite neuropsychiatric improvements, then rituximab was restarted later due to recrudescence of psychiatric symptoms; the approval to use rituximab with IVIG permitted its use. Patients who received adjunctive immunomodulation (IVIG, methotrexate, leflunomide, etc.) had a higher likelihood of achieving recovery (FR or PR) after rituximab (Fisher's Exact Test, one-sided, p<0.0001).

Discussion And Conclusions: For a small fraction of our patients, systemic autoimmunity and severe, debilitating psychiatric symptoms (including but not limited to OCD) led to a trial of rituximab. A randomized placebo-controlled trial will be necessary to objectively determine efficacy with regards to OCD/complex neuropsychiatric disease in the setting of systemic autoimmunity. Patients may have better responses to rituximab when given with adjunctive immunomodulation (IVIG, methotrexate, etc.). Reasons for the benefit of adjunctive immunomodulation is likely multifactorial: controlling infections, addressing inflammation driven by immune pathways beyond T& B cells (i.e. proinflammatory monocytes which have been linked to OCD), and preventing anti-rituximab antibodies.