Cumulative defined daily doses enable objective assessment of treatment intensity and outcome prediction in immunoglobulin G4-related disease and its subtypes.

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibroinflammatory disorder with heterogeneous clinical behaviour. Although glucocorticoids remain the mainstay of treatment, relapse and fibrosis are common. This study investigated predictors of relapse and mortality, integrating disease subtype and cumulative drug exposure using the defined daily dose (DDD) framework. Eighty-five patients fulfilling the 2020 revised comprehensive diagnostic criteria for IgG4-RD were retrospectively analysed. Clinical features, laboratory data and cumulative DDD (cDDD) of corticosteroids and immunosuppressants were compared between proliferative or fibrotic subtypes. Multivariate Cox regression identified predictors of relapse and mortality, and forest plots were used for overall and subgroup analysis. Azathioprine cDDD and hydroxychloroquine cDDD showed a weak positive correlation with alanine aminotransferase (ALT) levels, which reflects hepatic involvement of IgG4-RD. Elevated ALT, higher serum IgG and greater steroid exposure (>1225 cDDD) independently predicted relapse, while anaemia (Hb <10.9 g/dl) predicted both relapse and mortality. Lower IgG levels (<1600 mg/dl), low steroid exposure (<1225 cDDD), or classified as non-responders were less likely to experience flare. Early hydroxychloroquine use and lower initial steroid exposure were linked to improved survival. The fibrotic subtype was associated with older age, renal impairment, and lower flare risk, but higher hydroxychloroquine dosage and anaemia increased risk of flare. Proliferative disease exhibited greater responsiveness to immunosuppressive therapy but has shorter median time to first relapse. Distinct proliferative and fibrotic phenotypes exhibit divergent risks and treatment responses. Quantitative cDDD assessment enables objective evaluation of therapeutic intensity and outcome prediction, supporting a stage-tailored, precision approach to IgG4-RD management.