Case Presentation: 54-year-old male patient diabetes mellitus type II presented with pain and swelling involving small joints of bilateral hands with wrists. Synovitis involving bilateral interphalangeal, metacarpo-phalangeal were noted.Labs revealed leukocytosis to 15.7K/microL. Hemoglobin was 7.7 g/dL. Anemia work up revealed low serum iron level of 23 µg/dL, low TIBC at 167ug/dL with saturation of 13.8%. Serum ferritin was extremely elevated at 10000. Inflammatory markers were also elevated with ESR >140 and CRP at 167. Radiological studies revealed multifocal joint erosions with loss of joint spaces.A chronic inflammatory condition due to polyarthritis was suspected. A negative rheumatoid factor and extremely elevated serum ferritin with levels > 10,000 ng/ml were suggestive of Adult Onset Stills Disease. Patient responded well to oral prednisone which was then tapered. Subsequent office visit showed recurrence of symptoms with worsening of inflammatory markers. Steroids could not be restarted due to uncontrolled diabetes. Tocilizumab(TCZ) was initiated at 8 mg/kg every 4 weeks. In the next few months, excellent clinical response was achieved with the complete resolution of the synovitis. ESR trended down to 4 and CRP to 1. Ferritin normalized at 338.
Discussion: Pathophysiology of AOSD is poorly understood. Studies have demonstrated significant increase in inflammatory cytokines like interleukin (IL) -1, IL-6, IL-18, tumor necrosis factor-α (TNF-α) indicating their role in the pathogenesis [3].Steroids are the first line of therapy in AOSD. DMARDs have some benefit. Biological agents targeting the cytokines have been used for rescue to achieve remission[6-10]. TCZ is a IL-6 receptor monoclonal antibody. A systemic review done by de Boysson et al, found that 30 of 35 patients (86%) achieved a prompt articular improvement and disappearance of systemic symptoms was seen in 27/28 (96 %) with the use of TCZ[1]. A small pilot study in 2017 by Li involving sample of 8 patients found TCZ alleviated clinical symptoms of refractory AOSD rapidly and efficiently[3]. The only randomized double blind placebo controlled study by Kaneko et al involving 27 patients found Tocilizumab is effective in improving patient’s symptoms at 4 weeks. 61.5% of the patients in the Tocilizumab group and 30.8% in the placebo group achieved response with ACR50 at 4 weeks. However p value was not significant at 0.24[2]. Another observational study by Wang et al involved patients with AOSD who have been refractory to steroids and other additional agent. 28 patients reported improvement in clinical symptoms and inflammatory markers when TCZ was given in addition to methotrexate[7].In all these studies, TCZ is generally well tolerated. Apart from infusion reactions, macrophage activation syndrome (manifested by coagulation abnormalities and hepatic deterioration) and Cytomegalovirus reactivation have been reported and need vigilance.
Conclusions: Tocilizumab has continued to show benefits in the use of AOSD refractory to traditional therapies. Our case demonstrates its use in patients who cannot tolerate steroids and can be used as steroid-sparing agent. However, not many randomized clinical trials exist to validate these results statistically. In May 2019, the drug Actemra (brand name for TCZ) was granted approval in Japan for its use in patients with AOSD. Its use in the United States is currently off-label. Randomized control trials may be difficult due to the rarity of the disease and heterogeneous nature of disease patterns.