Patient Demographics
A total of 5058 patients were reported in the USIDNET registry at the time of data query. Among those, 278 (5.49%) patients had both IEI and at least one rheumatologic disease diagnosis (Table 1). Caucasian ethnicity was the most reported race in our cohort. 62% of patients were female.
Distribution of rheumatologic diseases in USIDNET cohort
We first investigated the frequency of rheumatologic diseases in the USIDNET population (Figure 1). Inflammatory joint disease (includes RA, JIA and psoriatic arthritis) was the most common rheumatologic condition reported (2.08%) (table 2). ALPS was reported to have the highest rate of inflammatory arthritis (4.11%) (table 3). Following arthritis, the second most common rheumatologic condition in our cohort was vasculitis (1.01%). As expected, interferonopathies and WAS were the IEIs with the highest rate of vasculitis reported.
In addition to frequently seen rheumatologic conditions, rare rheumatologic diseases were also reported in the USIDNET registry. Among these, SLE and Sjogren’s showed similar rates (0.67% and 0.69%, respectively). Interestingly, the rate of SLE was highest in chronic mucocutaneous candidiasis (CMC) (7.41%) followed by complement deficiencies (3.57%). In contrast, Sjogren’s was not reported in these conditions. Instead, IgG subclass deficiencies and ALPS had the highest reported rate of Sjogren’s (7.41% and 6.85%, respectively). As expected, systemic sclerosis and inflammatory myopathies had the lowest report rate in the cohort (0.19% and 0.24%, respectively). Reported systemic sclerosis rate was highest in familial HLH, whereas inflammatory myopathies had the highest frequency in agammaglobulinemia (2.99% and 1.65%, respectively) (table 3).
After identifying the rates of rheumatologic diseases in our cohort, we next investigated the specific IEI diagnosis and associated rheumatologic diseases. Interestingly, certain IEIs were noted to have higher rate of specific rheumatologic conditions.
Distribution of rheumatologic diseases in specific IEI populations
Immunodeficiencies affecting cellular and humoral immunity:
Overall, rheumatologic disease frequency in this group was noted to be 1.7%. At the time of the query, the USIDNET cohort had 339 severe combined immunodeficiency (SCID), 92 nonspecific combined immunodeficiency (CID) and 156 hyper IgM syndrome (HIGM) patients. Among those, 1 SCID (0.29%) patient was reported to have inflammatory arthritis. No other rheumatologic diagnoses were reported in this group. Interestingly, nonspecific CID patients were reported to have a higher rate of arthritis (3.26%), followed by vasculitis (2.17%), SLE (1.09%) and inflammatory myopathies (1.09%). Rheumatologic disease rate in HIGM patients was 1.28%, evenly distributed between inflammatory arthritis and vasculitis.
Combined immunodeficiency with associated or syndromic features
The USIDNET cohort included 246 WAS, 102 Hyper IgE syndrome (HIES) and 523 DiGeorge syndrome patients. The rheumatologic condition with highest rate was vasculitis (6.5%) in WAS. Systemic sclerosis and arthritis were reported with lower rates in this group (0.41% and 0.41% respectively). DiGeorge syndrome patients had a lower rate of arthritis (0.19%) and systemic sclerosis (0.19%) and none had vasculitis. It was noted that 1.96% of HIES patients were diagnosed with SLE and 0.98% of HIES patient were reported to have vasculitis.
Predominantly antibody deficiencies:
Our query included 82 SAD, 425 agammaglobulinemia, 1739 CVID and 60 specific IgA deficiency patients (SIgAD). Patients with SIgAD had a lower rate of rheumatologic disease in our cohort with one case (1.67%) of reported arthritis. Interestingly, patients with agammaglobulinemia showed an impressively different profile with highest rate of inflammatory myopathies in the entire cohort (1.65%). This was followed by arthritis (1.41%), systemic sclerosis (0.47%), vasculitis (0.47%) and SLE (0.24%).
CVID was the predominant immunodeficiency (34.4%) reported in the USIDNET cohort. Among patients with CVID, 7.36% had at least one type of rheumatologic disease. The most common rheumatologic disease reported was inflammatory arthritis (4.03%), followed by Sjogren’s (1.27%), systemic sclerosis (0.92%) and vasculitis (0.86%). Moreover, inflammatory myositis (0.17%) and SLE (0.12%) were also reported in patients with CVID. Similar to CVID, arthritis was also the most common rheumatologic disease in SAD patients (3.66%), followed by Sjogren’s (2.44%) and SLE (1.22%). Additionally, arthritis remained the most common rheumatologic disease in patients with hypogammaglobulinemia (3.45%). Similar to other antibody deficiencies, Sjogren’s and vasculitis were also reported in this group (0.99% and 0.99% respectively).
Disease of immune dysregulation:
Patients with immune dysregulation were reported to have arthritis (3.37%), vasculitis (3.37%), Sjogren’s (2.24%) and systemic sclerosis (1.12%). Among 64 patients with HLH, 3 patients (4.68%) were reported to have a rheumatologic disease with 2 having systemic sclerosis and one patient with arthritis. Interestingly, 13.69% of ALPS patients had a rheumatologic condition and the majority of these cases were reported to be Sjogren’s syndrome (50%).
Congenital defects of phagocyte number, function or both:
Chronic granulomatous disease (CGD) was the second most commonly reported IEI in the USIDNET registry. We found that 2.05% of CGD patients had been diagnosed with a rheumatologic disease. SLE was the most common (1.49%) rheumatologic condition in CGD patients followed by vasculitis (0.37%) and arthritis (0.19%).
There were 57 reported cases of GATA2 defects in USIDNET. Among those, 4 patients (7.02%) were reported to have a rheumatologic diagnosis. Reported conditions were vasculitis (50%), arthritis (25%) and systemic sclerosis (25%). In contrast to CGD, there were no reported cases of SLE in patients with GATA2 defect.
Defects in intrinsic and innate immunity:
The USIDNET cohort included 27 CMC patients. Interestingly, SLE was the only rheumatologic condition reported in patients with CMC (7.41%).
Auto-inflammatory disorders:
Three patients were reported to have interferonopathies in the USIDNET cohort. Interestingly 2 of them (66.67%) were reported to have vasculitis. No other rheumatologic diseases were reported in this group.
Complement deficiencies:
The USIDNET cohort had 28 patients with reported complement deficiencies. The overall frequency of rheumatologic disease was 7.14 % with reported SLE (3.57%), vasculitis(3.57%) and arthritis (3.57%).
Our query did not have patients with a rheumatologic diagnosis from IEI groups of defects in bone marrow failure and phenocopies of IEI.