Discussion:
This case report presents the management of a 43-year-old female with Still’s Disease who developed severe hepatitis as a complication. Despite initial responsiveness to Tocilizumab and steroid therapy, subsequent treatment challenges arose, including steroid dependency and anaphylaxis to Rituximab. This case underscores the complexities in managing Still’s Disease and highlights the need for alternative therapeutic strategies.
The diagnosis of AOSD relies heavily on clinical evaluation, patient history, identification of characteristic symptoms, and exclusion of other diseases. Patients typically present with high spiking fevers, maculopapular rashes, arthralgia or arthritis, pharyngitis, and elevated levels of acute-phase reactants like ESR, CRP, and serum ferritin. [3] AOSD is often diagnosed through exclusion during an investigation for fever of unknown origin (FUO). Studies show that 10-20% of patients evaluated for FUO are diagnosed with AOSD. [3] Bilgin et al. proposed an algorithm differentiating AOSD from other FUO causes, emphasizing arthralgia, hyper-ferritinemia, sore throat, and neutrophilia as strong indicators of AOSD. [4]
Commonly used classification criteria include the Yamaguchi and Fautrel criteria. The Yamaguchi criteria, with a sensitivity of 96.2%, require a combination of major and minor criteria, excluding other conditions. The Fautrel criteria involve major criteria like spiking fever, arthralgia, transient erythema, pharyngitis, and polymorphonuclear cells, along with minor criteria. Biomarkers like glycosylated ferritin and heme-oxygenase-1 (HO-1) have shown potential in diagnosing AOSD. Elevated serum cytokines such as IL-1, IL-6, IL-18, and IL-37 also play roles in diagnosis and management. Despite advancements, the diagnostic process for AOSD remains challenging due to its non-specific symptoms and lack of a specific diagnostic test. Diagnosis delays are common, often due to the overlap of AOSD symptoms with other diseases and the absence of specific biomarkers. Median diagnostic delays range from 1 to 4.1 months across studies. [3]
Tirotta et al. compiled a comprehensive literature review focusing on cases of AOSD with acute hepatitis reported in the past ten years [16]. Data were collected on patient demographics, comorbidities, clinical manifestations, liver tests, inflammatory indices, autoimmunity tests, infectious etiology tests, liver biopsy results, treatment, and prognosis. Out of 79 cases reviewed, only six met the criteria for inclusion due to the presence of liver biopsy data and acute hepatitis [4-11]. These cases were categorized into four main types of acute hepatitis in AOSD: autoimmune hepatitis (AIH), drug-induced liver injury (DILI), hepatitis due to AOSD, and hepatitis associated with hemophagocytic lymphohistiocytosis (HLH).
AIH can occur concurrently with AOSD or emerge as a complication. Histological examination of liver biopsies in AOSD patients often shows periportal mononuclear infiltration, Kupffer cell hyperplasia, lobular inflammation, and sub-massive hepatic necrosis, features that overlap with AIH and DILI [5, 11]. Differentiating AIH from AOSD is critical for treatment decisions, particularly regarding corticosteroid use. AIH in AOSD patients can exacerbate despite immunosuppressive treatment, and drugs like tocilizumab may trigger AIH-like responses [5].
Steroids and tocilizumab are notable causes of DILI in AOSD patients. The exact mechanism of corticosteroid-induced liver injury is unclear, though it may involve cytochrome P450 3A4 metabolism aberrations [7]. Tocilizumab-related hepatitis is rare but severe, potentially disrupting IL-6-mediated liver regeneration [13]. Early identification and management, including possible steroid withdrawal and N-acetyl-cysteine therapy, are crucial.
Liver dysfunction in AOSD can coincide with disease onset or occur during steroid tapering, sometimes years after remission. Elevated IL-18 levels and macrophage activation within the liver may mediate hepatotoxic effects [14]. Markedly high serum ferritin levels often indicate active AOSD and potential liver involvement, emphasizing the need for regular monitoring of ferritin and liver enzymes in AOSD patients [15].
HLH, a severe hyper-inflammatory condition, can be a life-threatening complication of AOSD, presenting with acute liver failure. Diagnosis involves clinical criteria and histological evidence of hemophagocytosis in bone marrow or liver biopsies [11]. Treatment typically includes immunosuppressive therapies, and in severe cases, liver transplantation may be necessary.
Acute hepatitis in AOSD encompasses a spectrum of conditions, including AIH, DILI, direct liver involvement due to AOSD, and HLH-induced hepatitis. Accurate diagnosis, guided by clinical, biochemical, and histological data, is essential for appropriate treatment and improved patient outcomes.
In this case, initial treatment with Tocilizumab aligned with findings from Article 1, showing efficacy in controlling systemic inflammation and reducing flare frequency. However, steroid dependence and diminished response after multiple doses necessitated a switch to Rituximab, as suggested by Article 2. The abrupt discontinuation of Rituximab due to anaphylaxis underscores the importance of monitoring for adverse reactions despite its potential benefit in refractory cases. With our patient, we had no option but to resume steroid therapy, as there is no data on any other forms of treatment. The patient will also be given a new trial of rituximab since other treatment options are very limited.
In conclusion, severe hepatitis as a complication of Still’s Disease presents significant therapeutic challenges. This case highlights the complexities in managing recurrent flare-ups and underscores the need for alternative therapies in patients refractory to initial treatments. Further research is warranted to explore novel therapeutic strategies and improve outcomes in such cases.
Figure 1 Legend: Images of the patient’s diffuse salmon-colored rash upon presentation
Figure 2 Legend: Patients Labs upon latest Presentation, fourth flare up