PMC7905310_01
Time course depicting the clinical presentation of IgG4RD, laboratory results and treatment plans from 2009 to 2020. Chronic phase of the patient's disease: the upper part summarizes the specific features of clinical findings, biopsy, imaging, and immunological laboratory results; the lower part shows the therapy, specifying dose, duration, and dates for Rituximab infusions (deep red diamonds) and steroids (sky blue bars). Pulse treatment with methyl-prednisone (500mg i.v.) is represented by the bottom scale blue bars and was usually followed by oral Prednisone (top scale blue bars); the dashed bar corresponds to the period when the patient did not adhere thoroughly to the prescribed therapy.
fimmu-11-604759-g001.jpg
PMC7905310_01_fimmu-11-604759-g001.jpg
f1
She was treated with corticosteroids and rituximab but had multiple relapses, as summarized in Figure 1. Flow cytometry revealed increased peripheral blood plasmablast counts (3,010/ml, normal: < 900), while the serum IgG4 level was normal (1.1 g/l, Figure 1).
In the acute phase, the upper part shows the laboratory values for CFH (black, mug/ml), anti-CFH (pink, AU/ml), left y-axis, and thrombocytes (green, G/l) at the right y-axis. The normal reference values are shown with shades matching the colors of the different parameters. The lower part depicts the therapy including methylprednisolone/prednisone (sky blue bars, mg/d), plasma exchanges (deep blue arrows), and cyclophosphamide (purple triangles, 500 mg i.v.). The time when TMA and COVID-19 were diagnosed are shown with symbols. AU, arbitrary units; BM, bone marrow; Covid-19; coronavirus disease 2019; CT, computed tomography; CTX, cyclophosphamide; HPF, high-power field; IgA, immunoglobulin A; IgG4-RD, immunoglobulin G4-related disease; i.v., intra venous; PET-CT, positron emission tomography-computed tomography; PLEX, plasma exchange; RTX, Rituximab; SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; TMA, thrombotic microangiopathy.
fimmu-11-604759-g002.jpg
PMC7905310_01_fimmu-11-604759-g002.jpg
f2
Detectable complement factor H (CFH) levels were low at 49 microg/ml (400-800, Figure 2) with high levels of anti-CFH antibodies detected at 801 AU/ml (Normal < 30, Figure 2). Intriguingly, elevated levels of anti-CHF antibodies and decreased FH activity were already present in frozen stored samples from 4 months before the clinical manifestation of TMA (Figure 2), but not from 1 year earlier (data not shown). While waiting for the results of CFH and anti-CFH antibodies levels, the patient was treated with daily plasma exchanges (PLEX, 13 cures in total) by fresh frozen plasma twice the plasma volume and corticosteroids (methylprednisolone 500 mg iv, followed by oral prednisone 1 mg/kg/day) with gradual tapering until May 2020 (Figure 2).
Identification of IgG4 anti-factor H autoantibodies: Plasma samples were analyzed for anti-factor H antibodies by a previously reported specific ELISA which was developed using Horse Radish peroxidase (HRP)-labeled secondary antibodies specific for human IgG, IgG4, and IgA, respectively. Data are shown as optic density at 490 nm (OD). (A) The patient's serum was tested in duplicates at different dilutions 1:100, 1:400, and 1:1,000 for both IgG (black bars) and IgG4 (grey bars). Controls included a normal human serum (NHS), a serum with known elevated anti-CFH IgG levels, and a serum with elevated IgG4 but no anti-CFH activity. (B) Absence of IgA anti-factor H autoantibodies: Specific anti-CFH IgA antibodies were measured in the patient's serum (total IgA level of 6.4 g/l), NHS, and another serum with a high total IgA concentration of 12.4 g/l.
fimmu-11-604759-g003.jpg
PMC7905310_01_fimmu-11-604759-g003.jpg
f3
Results are presented in Figure 3A demonstrating a significant anti-CFH total IgG elevation mainly of IgG4 subclass. Results indicate an absence of specific anti-CFH IgA (Figure 3B).