To review the reported evidence on the therapeutic management of IgG4-related disease (IgG4-RD) in clinical practice.A systematic search of the literature was conducted. The primary outcome measured was the rate of efficacy of first-line therapeutic approaches. Secondary outcomes measured included the rate of disease relapse, the outcome of untreated patients, the rate of patients without drug therapy at the end of follow-up, the rate of side effects, and mortality. The MOOSE, AHRQ, STROBE, and GRACE recommendations/statements were followed.The results of the systematic search strategy yielded 62 studies that included a total of 3034 patients. Complete information about first-line therapeutic regimens was detailed in 1952 patients, including glucocorticoid-based regimens in 1437 (74%), drug-free regimens in 213 (11%), and other therapies in 38 (2%). No therapy (wait and see management) was reported in 264 (13%) patients. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses treated with glucocorticoids, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases. Wide heterogeneity was observed with respect to the first-line therapeutic approaches used for the different organ-specific disease subsets, including significant differences in the mean dose of glucocorticoids used.Nearly 70% of reported IgG4-RD patients are treated with oral glucocorticoids in monotherapy. However, the therapeutic management is heavily influenced by geographical, epidemiological, and clinical factors, especially with respect to the predominant organ affected. The frequency of glucocorticoid failure to induce sustained remissions both during and after treatment and the assessment of glucocorticoid toxicity in IgG4-RD require further study.