Discussion
CVID represents one of the most common primary antibody deficiency which is associated with a broad spectrum of non-infectious complications including various autoantibody-mediated autoimmune diseases. Several studies reported the presence of various antibodies directed against “self-antigens”, such as feritin, thyreoglobulin or DNA in the therapeutics used for IRT (12). Antierythrocyte alloantibodies or anti-Ro (SS-A) were even associated with clinical manifestation – self-limiting hemolysis (11) and sicca syndrome (13). Thefore, we initiated the prospective observational study focusing on the prevalence, clinical significance and the origin of selected spectrum of autoantibodies in a cohort of 38 CVID patients treated with regular IRT.
Anti-GAD and anti-TPO were the most prevalent autoantibodies found in the majority of CVID patients on regular IRT (68.4% and 55.3%, respectively). All other investigated autoantibodies including ANA, anti-dsDNA, anti-EMA, RF, ACLA, anti-F-actin, anti-SLA, anti-LKM1, anti-LC1, anti-AMAM2, anti-MPO, anti-PR3, anti-Sm, anti-RNP, anti-SS-A, anti-SS-B, anti-Scl70, anti-Jo-1, anti-IAA, anti-IA2 and anti-TG were negative in all patients, with exception of anti-TG, anti-IAA and anti-IA2 found in patients with previously diagnosed T1D and AIT at the screening visit, who were excluded based on exclusion criteria. Interestingly, both excluded CVID patients with T1D were anti-GAD negative. However, the titers of anti-GAD observed in our cohort of CVID patients were significantly lower in comparison to newly diagnosed T1D patients. The cohort of CVID patients was prospectively followed to assess the T1D development. This included regular measurements of fasting C-peptide as a marker of inzulin production and g-Hgb reflecting long-term glycemia. No differences were found in serum concentration of C-peptide and g-Hgb between anti-GAD negative and positive CVID patients, as well as between the baseline and end-of-study visits in anti-GAD positive patients. On the other hand, the serum levels of C-peptide were significantly higher and the levels of g-Hgb significantly lower in comparison to newly diagnosed T1D patients suggesting an undisturbed inzulin production and glucose metabolism.
Similarly, the serum titers of anti-TPO autoantibodies in CVID patients were also significantly lower than in newly diagnosed AIT patients. However, no differences were found in the serum levels of TSH and fT4 between anti-TPO positive, anti-TPO negative CVID patients and AIT patients. Both paramters were within referential limits in all groups. Therefore, the thyroid gland USG was performed to evaluate the presence of predictive signs of subclinical AIT (14). Based on the USG, the diagnosis of AIT was considered in three out of 26 anti-TPO positive patients and in one patient without AIT specific autoantibodies.
The same spectrum of autoantibodies was also assessed in IRT therapeutics. Surprisingly, all solutions contained high amount of anti-GAD and anti-TPO autoantibodies. Other investigated autoantibodies were uniformly negative. The possible explanation for this phenomenon may be found in population-based studies investigating the prevalence of anti-GAD and anti-TPO. Anti-GAD autoantibodies were present in 0.9 – 1.7% of healthy donors, the highest prevalence 3.2% was observed in age group 30-34 years (15). Even higher prevalence was reported for anti-TPO antibodies – up to 31.7% of healthy donors (16, 17). Based on our findings and the previously published reports, we therefore suggest that these autoantibodies may be passively transfered into blood circulation via the immunoglobulin solutions. Our findings are also consistent with previous observations that T1D and AIT are predominantly T-cell-mediated diseases (18-21). Correspondingly, both T1D and AIT may develop in the abscence of specific autoantibodies. The autoantibody negative cases comprise 3.5-19% from all T1D patiens (22, 23), moreover, several seronegative T1D patients were also desribed amongst the CVID patients (10). Autoantibody negative AIT represents approximately 5% of all patients with AIT (24). While the tissue specific autoantibodies may not constitute the principal pathophysiological mechanisms in T1D and AIT, they represent a commonly used diagnostic and prognostic marker. The physicians should therefore be sensitized to the fact, that in CVID patients on regular immunoglobulin subtitution therapy neither serum anti-GAD nor anti-TPO are suitable tools for the screening or diagnosis of T1D or AIT.
The authors are aware, that due to the limitations of this pilot study, the results must be interpreted with caution. The strength of the study is particularly in its prospective design and the utilization of routine and certified laboratory methods. On the other, the limited number of included patients and the relatively short trial follow up time are its main limitations. Further multicentric and longer follow up studies are warranted to confirm these findings.