Published: Nov 11, 2013 | Updated: Nov 12, 2013
By Nancy Walsh, Staff Writer, MedPage Today

Full Story:  http://www.medpagetoday.com/Rheumatology/GeneralRheumatology/42844

High levels of immunoglobulin G (IgG) in children — and particularly girls — were associated with the development of autoimmune disease, researchers found.

Among 442 patients seen over a 10-year period at a tertiary care center, 50% ultimately were diagnosed with an autoimmune or autoinflammatory disease, according to Mindy S. Lo, MD, and colleagues from Harvard University in Boston.

And girls with elevated IgG were three times as likely to develop autoimmunity as boys (OR 3, 95% CI 1.8-4.8, P<0.001), the researchers reported online in Pediatric Rheumatology.

Among adults, hypergammaglobulinemia most often signals hepatic disease, cancer, infection, or autoimmunity, but it’s not clear if the same pattern is true among children.

Understanding the causes of this laboratory finding in pediatric patients could be important, particularly for autoimmune disease, because of the rarity and wide range of clinical presentations of these disorders.

Therefore, Lo and colleagues conducted a retrospective study, identifying all patients who had IgG measurements of 2,000 mg/dL or higher between January 2000 and December 2009 at Boston Children’s Hospital.

Patients’ average age was 14.3 and mean follow-up was 3.48 years. Almost two-thirds of the patients were female, and 58% were white.

Diagnoses in the autoimmune group included systemic lupus erythematosus (SLE) in 48 and mixed connective tissue disease in 29.

“Hypergammaglobulinemia is well recognized as a key feature of SLE and lupus-related conditions. The diffuse B-cell activation and autoantibody production that is characteristic of SLE is also central to disease pathogenesis,” Lo and colleagues explained.

Arthritic-type autoimmune diseases were less common than lupus. Polyarticular juvenile idiopathic arthritis was diagnosed in 29, systemic-onset juvenile idiopathic arthritis in 15, and spondyloarthritis in 11.

Other types of autoimmune diseases included Crohn’s disease (10), ulcerative colitis (14), and autoimmune hepatitis (10), as well as several types of vasculitis.

Infections comprised 37% of diagnoses among children with hypergammaglobulinemia, primarily recurrent bacterial infections in those with cystic fibrosis. Streptococcal and post-streptococcal infections also were prevalent.

There also were small numbers of patients with malignancies, primary immunodeficiencies, drug reactions, and other diagnoses such as trisomy 21.

The two malignancies were both lymphoproliferative.

“Due to the small number of proliferative disorders in our cohort, we are unable to speculate whether lymphocyte dysregulation led to both hypergammaglobulinemia and development of the malignancy, nor can we identify risk factors for distinguishing autoimmune from malignant conditions,” Lo’s group cautioned.

A total of 10% of the children died during follow-up, with deaths being caused most often by malignancy (30%) and infection (18%).

Because of the high percentage of children with autoimmune disorders, the researchers then sought to identify risk factors that could be predictive.

In a univariate analysis, patients with autoimmune diseases not only had high levels of IgG, but also lower white blood cell counts and decreases in hemoglobin, hematocrit, and complement, and normal C-reactive protein (CRP).

In addition to female sex, multivariate analysis confirmed the independent association of these risk factors for autoimmune/autoinflammatory disease:

• WBC <5 x 10³/mcL, OR 3.9 (95% CI 1.9-8, P<0.001)
• CRP <0.5 mg/dL, OR 2.3 (95% CI 1.4-3.8, P=0.002)
• HgB <10 mg/dL, OR 2.1 (95% CI 1.2-3.8, P=0.015)

When these factors were combined in a predictive algorithm, the presence of normal CRP, anemia, and leukopenia had a 95% probability of autoimmunity, the researchers reported.

They pointed out that potential bias was an important limitation to the study, however.

“Rheumatologists and immunologists are more likely to check immunoglobulin levels than other specialists, and thus patients with rheumatologic and immunologic disorders are probably over-represented in our cohort,” they noted.

They also stressed that because of this potential bias, their predictive algorithm needs to be tested prospectively.

Nonetheless, they concluded, “There should be a high index of suspicion for underlying autoimmune disease in pediatric patients with high IgG levels and no clear infectious or malignant process.”