Background/Purpose: To assess the efficacy and safety of abatacept (ABA) for the treatment of IgG4-related disease (IgG4-RD). To date, there are no FDA-approved treatments available for IgG4-RD. The efficacy of ABA in the context of IgG4-RD has been reported in a single case report but not yet studied further.

Methods: We conducted a prospective, open-label trial of ABA in 10 patients with active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD and had active disease based on an IgG4-RD responder index (RI) of  ≥2 with disease manifestations in at least one organ system at the time of screening. Patients received subcutaneous ABA 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but was required to be discontinued by week 4.  The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD RI score of 0 and a secondary endpoint, disease response, was defined as improvement of > 1 point in the IgG4-RD RI score from baseline. Achieving either outcome required no glucocorticoid use beyond week 4 and no disease flares. PBMCs were collected at baseline, 1-month and 3-month time points and B and T cell subsets were quantitated using a 25-parameter flow cytometry panel.

Results: Ten subjects were enrolled in the study between December 2018 and August 2019. Median age was 67.5 years, 70% were male and 90% Caucasian.  Eight subjects had both orbital and salivary gland involvement, while five subjects had lung involvement. All patients had elevated serum IgG4 concentrations of at least 2-fold the upper limit of normal (range 170 to 1,359.5 mg/dL, median 480.5 mg/dL). Two subjects received prednisone with ABA. Three subjects (30%) achieved the primary endpoint of complete remission and two subjects (20%) had a disease response at week 24. ABA was stopped early in the remaining five subjects (50%) due to flare (N=1) or lack of response by week 12 (N=4). Although serum IgG4 concentrations declined in only two of the five subjects with any response, serum IgE concentrations declined in all five (baseline median 802 IU/mL, IQR 260-4981 IU/mL, 24 week median 470 IU/mL, IQR 138-2417 IU/mL). Response to treatment correlated most strongly with a reduction in circulating plasmablasts (p=0.016) with a trend towards significant reduction in HLA-DR⁺ CD4⁺ T cells (p=0.056). There was also a trend toward significant correlation between the change in plasmablast numbers and serum IgE but not with IgG4. Surface expression of CD86 on memory B cells was less detectable among responders as compared to non-responders (p=0.016). PD1⁺CXCR5⁺CD4⁺ T cells did not correlate with clinical response, plasmablasts, serum IgE or serum IgG4. There was one adverse event (grade 2 thrombocytopenia) attributed to ABA.

Conclusion: Although subcutaneous ABA was associated with a high rate of treatment failure in patients with IgG4-RD, some patients had excellent clinical responses that correlated well with measures of immunologic response. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, activated CD4⁺ T cells, and detectable surface expression of CD86. It is possible that the higher dose of ABA offered by intravenous administration may be more effective.  

ACR Meeting Abstracts - https://acrabstracts.org/abstract/abatacept-for-the-treatment-of-igg4-related-disease/