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DSB: EULAR 2015 Safety Reports

Jun 17, 2015 11:55 am

Biologic Use Curtails Sepsis Events. An analysis of the German biologics register, RABBIT, examined the effect of current biologic therapy on future risk of sepsis (#OP0161). In their very large database of DMARD and TNFi treated RA patients they sought to see if a serious infectious event (SIE) was followed by subsequent sepsis (within 30 days) or death after SI without sepsis (within 90 days) or no complication at all. SIE occurred in 859 patients, sepsis in 135 patients, and 53 died within 90d after SI without sepsis. The adjusted risk of sepsis increased with age and chronic renal disease. The risk was significantly lower in TNFi exposed (OR 0.55; 95%CI 0.36–0.83) and those on other biologics (OR 0.42; 95CI 0.23–0.76) at the time of SIE. TNFi and bDMARDs also lowered the risk of death after SIE, unrelated to sepsis. Risk factors of death after SIE were higher age, use of high GC dose and heart failure. Interestingly, patients on conventional DMARDs who discontinued biologic therapy before their SIE, had a 2 fold higher risk of sepsis compared to those with continuous biologic exposure. (Editor’s note: these data are surprising and enlightening knowing that the TNF inhibitors were initially developed for use in sepsis. While they did not help such patients, the data is equivocal for their benefit or harm in patients with sepsis. This report from RABBIT seems to imply that optimal control of inflammation may be important in avoiding subsequent complications after serious infection. These researchers did not examine the effects of continued TNFi or bDMARD exposure after the SIE.)

Biologic Registries Show Continued Safety. Analyses of the French biologic registries for rituximab (AIR), abatacept (ORA) and tocilizumab (REGATE) looked at the risk of SIE, TB and cancers with biologic exposure in the community (#OP0035). SIE event rates for AIR, ORA and REGATE were with the expected range (4.5, 3.5, 5.2 per 100 patient-years). No cases of TB were seen with tocilizumab and low rates were observed with rituximab (0.04/100PY) and abatacept (0.07/100PY). Cancer rates were similar across all 3 registries for solid tumors, hematologic malignancies and nonmelanomatous skin cancers.

Conventional DMARD Use Has Higher Rates of Serious Infection. Adult RA patients in the Swedish National Register were studied for the risk of serious infectious events (SIE) when exposed to non-biologic DMARDS (nbDMARDs) and compared to the general population (#FRI0064). The SIE risk within 1 year in nbDMARD-exposed RA was 5.9% compared to 2.2% in the general population. The risk of SIE did not vary over time, or with switching nbDMARDs. nbDMARD exposed RA patients have a 3 fold higher risk of SIE compared to the general population. (Editor’s note: these data are important as we often compare biologic SIE rates relative to those exposed to methotrexate or nbDMARDs. What is not known from this data is whether initial or switching nbDMARD users had well controlled disease activity, as this too would greatly influence the infection risk rate.)

Psoriasis, Biologics and Malignancies. PSOLAR is a multicenter, longitudinal, observational database that evaluates the long-term safety and clinical outcomes of biologic use in psoriasis patients (#SAT0559). This data set was used to search for malignancies (excluding nonmelanomatous skin cancers). This fully enrolled registry has 12,095 patients and 31818 total pt-years of follow up. Cumulative, overall malignancy rates were 0.68 events/100 pt-years of observation (95%CI: 0.59, 0.77). Individual drug related malignancy rates were similar – ustekinumab was 0.51/100PY (95% CI: 0.37, 0.68); infliximab was 0.64/100PY (95%CI: 0.42, 0.93); other TNF inhibitors (mainly etanercept and adalimumab) was 0.74/100PY (95% CI: 0.60, 0.91), and rates for nonbiologic therapies was 0.81/100PY (95% CI: 0.59, 1.08). While age and history of prior malignancy were predictive of new malignancy, biologics and immunomodulators were not associated with an increased risk of malignancy.

The Safety of JAK Inhibitors. Winthrop and co-workers analysed the frequency of H.zoster (HZ) infections from the tofacitinib database that includes phase’s I-III and long-term studies (##SAT0229). They found that among 6192 treated patients (16 839 patient-yrs. of exposure), 636 HZ infections. HZ infections were lowest in Eastern and Western Europe and highest in Japan and Korea. Moreover, they showed that HZ rates were lowest in those on tofacitinib monotherapy and higher when tofacitinib as used in combination with nonbiologic DMARD therapy or corticosteroids. Among the two baricitinib studies presented at EULAR, no surprising or standout safety signals were seen. In the RA-Beacon study serious AE rates were for baricitinib 2 or 4 mg or PBO (4%, 10%, and 7%, respectively) including serious infections (2%, 3%, and 3%, respectively). There were no opportunistic infections, TB, orGI perforations. Two non-melanoma skin cancers and 2 major adverse cardiovascular events, including 1 death (stroke), were seen with baricitinib 4 mg group. AE leading to discontinuation were infrequent (#OP0029).

Safety of Biologics in the Elderly. In a retrospective, single center study, Marta et al followed 216 established RA patients after starting infliximab, abatacept or tocilizumab and determined the safety of these agents based on discontinuation for adverse events (AE). When the analyzed patient groups according to age (young 75rs), similar rates of AE discontinuation over time were seen, although the rate was lowest in the young group (#FRI0158).

The Safety of Arthrocentesis in Gout. As part of the recently published SUGAR study (, arthrocentesis was performed in 910 patients and 887 of these patients (97.5%) were evaluated for AE by telephone survey after the procedure (#AB1095). Adverse events were seen in 12 patients (1.4%); with the more common being pain (5 events). Other non-serious AE reported were bruising (2 events), and joint swelling (4 events). There was 1 case (0.1%) of septic arthritis subsequent to the arthrocentesis who required hospitalization and antibiotics. Based on these data the frequency of arthrocentesis is estimated to be between 0 and 3.4 per 1000 patient-procedures.

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