Serum IgG4 concentration is not as important as originally believed for diagnosing IgG4-related disease (IgG4-RD), as almost half of patients with biopsy-proven IgG4-RD have normal serum levels. However, elevated serum IgG4 may identify a subtype of IgG4-related disease that is more “inflammatory” compared with patients with normal serum IgG4, say investigators from Massachusetts General Hospital and Harvard Medical School, Boston.
IgG4-related disease is a unique immune-mediated condition that links multiple fibro-inflammatory disorders that were previously considered to be separate disorders.
Writing online in Arthritis and Rheumatology, the authors report a detailed analysis of the clinical features of the first 125 patients diagnosed with IgG4-RD by strict clinicopathologic correlation at their center.
Of the 125 patients, 61% were men and their average age at evaluation was 50.3 years. At their initial visit, 86% of patients had active disease, 69% were on no treatment, and 31% were receiving immunosuppression (mostly glucocorticoids) for IgG4-RD.
The study included 23 patients with retroperitoneal fibrosis (RPF), representing 18% of the overall cohort, 85% of whom had normal serum IgG4 concentrations.
The mean IgG4-RD Responder Index (RI) was 5.7 at baseline. The RI correlated strongly with serum concentrations of IgG4 (r=0.5), total IgG (r=0.3) and IgG1 (r=0.2), IgG2 (r=0.3), and IgG3 (r=0.2)
A mean of 2.3 organs were involved, with a range of one to seven. The most commonly involved organs were the submandibular glands (28% of cases), lymph nodes (27%), orbits (22%), pancreas (19%), and retroperitoneum (18%).
Organ damage was sustained by 58% of patients at the time of their initial evaluation.
Organs particularly susceptible were the pancreas, lungs, kidneys, and major salivary glands.
Forty percent of the patients had undergone surgery before their diagnosis of IgG4-RD was established, mostly for the purpose of diagnosis or an erroneous diagnosis of cancer.
“Broader education and greater awareness of IgG4-RD as a mimicker of malignancy may obviate the need for many surgical procedures,” the authors believe.
Prior to evaluation, 51.2% of patients were receiving glucocorticoids, 86% of whom had disease improvement but 77% did not achieve stable remission following discontinuation of glucocorticoids. Twenty-eight patients received glucocorticoid-sparing agents, most often methotrexate (5.6%) and rituximab (5.6%). All patients treated with steroid-sparing agents other than rituximab had discontinued them due to lack of efficacy in controlling disease. Sixteen patients (12.8%) received ureteral or biliary tract stents for complications related to IgG4-RD.
“Although glucocorticoids are regarded as the initial treatment of choice, our data highlight the need for studies investigating steroid-sparing agents as maintenance therapy in IgG4-RD,” the authors wrote.
Of the patients with active disease at evaluation, median serum IgG4 concentration was not significantly different between those on treatment and those not on treatment (123 mg/dL versus 155 mg/dL, P=0.66).
Among the 103 patients with active disease and serum IgG4 measured at the time of evaluation, only 51.4% had elevated serum IgG4. “Patients with active disease and elevated serum IgG4 concentrations were older, had a higher RI score, a greater number of organs involved, lower complement levels, a higher absolute eosinophil count, and higher IgE levels compared with those with active disease but normal serum IgG4 levels (P<0.01 for all comparisons),” the authors reported. These features suggest a subtype of IgG4-RD that is more inflammatory compared with patients with normal serum IgG4.
Patients had elevated levels of circulating plasmablasts independent of serum IgG4 concentrations. Levels of circulating plasmablasts, particularly IgG4+ plasmablasts, correlated well with disease activity as assessed by the IgG4-RD RI.
Certain patterns of laboratory abnormalities were detected according to the types of organs involved, with patients with renal disease, lymphadenopathy, and retroperitoneal fibrosis comprising distinctive disease subsets. Seven of 10 patients with active IgG4-related kidney disease were hypocomplementemic at baseline, compared with none of the 13 patients with active, untreated RPF (P<0.001).
“Our observation of disease phenotypes distinguished by specific patterns of organ involvement, serum IgG4 concentrations, and hypocomplementemia deserves further investigation,” the authors state.
In addition, differences in disease pathogenesis and mechanisms of damage may explain some of the observed phenotypic differences. “Future studies might explore this hypothesis by studying gene expression in biopsy samples representative of distinct disease phenotypes,” they add. “Moreover, optimal treatment strategies may differ by disease phenotype and future clinical trials might consider stratifying patients accordingly.”
Because the study evaluated patients from a center within a rheumatology unit, the patient population potentially skewed toward those with multi-organ disease, the authors note. Patients with pancreatic and other gastrointestinal manifestations of IgG4-RD may have been under-represented because they are often managed primarily by gastroenterologists.
reference;Normal Serum IgG4 Seen Often in IgG4-Related Disease