Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta-analysis

Abstract

Objective To assess the safety and efficacy of glucocorticoids (GCs), immunosuppressive agents (IM) and rituximab (RTX), alone or in combination, for the treatment of IgG4-RD. Methods Relevant articles published were searched in the databases with relevant key words. Network meta-analysis was conducted, with various outcomes including relapse rate, remission rate and adverse events. Data were calculated with odds ratio (ORs) and 95% CI. P-score was used to rank the treatments. Results A total of 15 studies involving 1169 patients were included. Network meta-analysis indicated that RTX maintenance therapy had the lowest relapse rate of all treatments (OR = 0.10, 95% CI [0.01, 1.63]), whereas GCs + IM was associated with a lower relapse rate compared with GCs alone (OR = 0.39, 95% CI [0.20, 0.80]). Further, patients treated with GCs + IM had a higher remission rate than those given GCs (OR= 3.36, 95% CI [1.44, 7.83]), IM (OR= 55.31, 95% CI [13.73, 222.73]) monotherapies or RTX induction therapy only (OR= 7.38, 95% CI [1.56, 34.94]). The rate of adverse events was comparable among the different treatment groups. Conclusion Treatment of IgG4-RD patients with GCs and IM was associated with higher remission rates and lower relapse rates, as well as comparable safety profiles compared with GC, IM and RTX induction therapy. RTX maintenance therapy had a larger reduction in the relapse rate compared with GC and IM. The current evidence should be carefully scrutinized as the included studies were observational in design. Larger randomized controlled trials are needed to confirm.

Advances in the diagnosis and management of IgG4 related disease

“…These findings were further confirmed by a meta-analysis of 15 studies involving 1169 patients, whereby combination therapy with glucocorticoid and immunosuppressive drugs was associated with a lower relapse rate compared with glucocorticoids alone (odds ratio 0.39, 0.20 to 0.80) 120. Other scant reports, mostly focused on AIP, described positive experiences with tacrolimus, azathioprine, methotrexate, or leflunomide in preventing relapse of IgG4-RD, but these studies remain small, retrospective, and uncontrolled 120124125151…”

“…Conversely, two prospective Chinese clinical trials showed a reduced relapse rate at one year when either mycophenolate mofetil (1-1.5 g/day) or oral cyclophosphamide (50-100 mg/day) was added to low dose corticosteroids, compared with steroid treatment alone (21% v 40% and 12% v 39%, respectively) 122123. These findings were further confirmed by a meta-analysis of 15 studies involving 1169 patients, whereby combination therapy with glucocorticoid and immunosuppressive drugs was associated with a lower relapse rate compared with glucocorticoids alone (odds ratio 0.39, 0.20 to 0.80) 120. Other scant reports, mostly focused on AIP, described positive experiences with tacrolimus, azathioprine, methotrexate, or leflunomide in preventing relapse of IgG4-RD, but these studies remain small, retrospective, and uncontrolled 120124125151…”

“…Mycophenolate mofetil (1-1.5 g/day), cyclophosphamide, and iguratimod seemed to be particularly effective in this regard, although the latter has been used only in localized sialadenitis without internal organ involvement 122123129. A meta-analysis of 15 observational, uncontrolled, non-randomized clinical trials involving 1169 patients confirmed these findings and reported that patients treated with combination therapy had a higher remission rate than those given only glucocorticoid (odds ratio 3.36, 95% confidence interval 1.44 to 7.83) or DMARD (55.31, 13.73 to 222.73) monotherapy 120…”

“…When predictors of relapse—such as multi-organ involvement, elevation of serum IgG4 and IgE at baseline, and peripheral blood eosinophilia—are present, disease modifying anti-rheumatic drugs (DMARDs) can be added to first line steroid therapy to improve the likelihood of obtaining disease remission. Azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, ciclosporin A, iguratimod, and cyclophosphamide have been all used in combination with glucocorticoids, but little evidence exists for the additional efficacy of these drugs and most data derive from retrospective studies 120121122123124125126127128129130. In the only four prospective studies that we are aware of (all uncontrolled and only one randomized), DMARDs combined with steroid therapy led to a higher remission rate (93%) compared with glucocorticoids alone (79%) at six months 131.…”

“…According to available retrospective studies and to a single meta-analysis, rituximab performs better than DMARD therapies in reducing the rate of relapses (odds ratio 0.10, 0.01 to 1.63), but the interval between rituximab doses and the protocols of administration largely differ from patient to patient 120148. Maintenance treatment with rituximab was performed either with two 1 g infusions 15 days apart or with four weekly 375 mg/m 2 infusions, typically when evidence of disease flare existed rather than at predetermined time intervals.…”