Herein, we report on a 67-year-old Caucasian originating from Portugal admitted to the hospital for fever of unknown origin and asthenia. His medical history was relevant for hypertension, insulin-dependent type two diabetes, and vitiligo and was on aspirin cardio, lisinopril, torasemid, omeprazole, and insulin therapy. On clinical examination, we noticed anasarca with pleural effusion, ascites, and edema of the lower limbs. Laboratory tests revealed microcytic anemia (hemoglobin 100 g/l, MCV 75 fl) with thrombocytopenia (73 G/l), marked elevation of C-reactive protein (204 mg/l), renal insufficiency (creatinine 463 micromol/l), and cholestasis (alkaline phosphatase 300 U/l, gamma-GT 56 U/l), with normal transaminases. Urinalysis showed severe proteinuria (5.29 g/l) and glomerular microhematuria. Immunological evaluation revealed normal IgG, IgM, IgA, and complement (C3, C4) levels, anti-nuclear antibodies (1/640 speckled), anti-SSA, anti-actine, and anti-parietal cell antibodies were positive. The infectious work-up was negative (HIV, hepatitis B/C, CMV, TB spot, and blood culture) except for EBV that was slightly positive by PCR (3,560 copies/ml). A thoraco-abdominal CT scan detected multiple mediastinal, axillary and retroperitoneal adenopathies, pleural and pericardial effusions, hepatosplenomegaly, and ascites. There was no sign of peripheral hemolysis (absence of schsitocytes). Finally, a cytokine profile showed elevation of IL-6, VEGF, soluble IL-2 receptor, and TNF-alpha, whereas IL-8 was normal.
The etiology remained unclear and the patient underwent several supplementary investigations. An axillary lymph node was surgically removed and showed atreic secondary lymphoid follicles with hyalinized/vascular GCs. Interfollicular areas showed a marked vascular proliferation and contained a small number of CD138-positive plasma cells (Figures 1A-D). Immunohistochemistry for HHV-8 with latency-associated nuclear antigen-1 was negative. The histopathological findings were consistent with the newly defined diagnostic criteria for iMCD. The blood smear and the flow cytometry in the blood were normal without evidence for lymphoproliferative disease. A bone marrow trephine biopsy revealed megakaryocytic hyperplasia and mild reticulin myelofibrosis without abnormal lymphocytic infiltration (Figures 1E,F).
Renal biopsy showed (1) thickening of the peripheral basement membrane and the intern lamina rara, (2) mesangial proliferation without glomerular deposition of immunoglobulin, and (3) a band-like pattern of interstitial fibrosis associated with lymphohistiocytic inflammatory cell infiltrates. Malignancies were also actively searched for. Colon biopsies showed a collagenous colitis rich in eosinophils (Figure 2A). Gastric biopsies revealed chronic inflammation and glandular atrophia with intestinal metaplasia of the fundus suggestive of an atrophic gastritis (Figure 2B). Prostatic biopsies showed mild chronic inflammation without neoplasia (Figure 2C). Liver biopsy showed mild sinusoidal distension, unspecific portal and lobular inflammation, and rare epithelioid granulomas without necrosis (Figures 2D,E). Finally, the patient underwent a bronchial biopsy showing unspecific chronic inflammation without granuloma, which was not suspicious for sarcoidosis (Figure 2F).
Together, these clinicopathological findings are compatible with a diagnosis of iMCD and TAFRO syndrome.
The best management of iMCD disease remains poorly defined with only one randomized clinical trial published in 2014 on siltuximab compared to best supportive care. Thus, this case required multidisciplinary discussion and consensus in 2011 when the diagnosed was made and judgment was based on available data with tocilizumab and rituximab for the treatment of HHV-8-associated MCD. Thus, treatment was initiated with high dose methylprednisolone (1 g/day for 3 days) transitioned to prednisone 1 mg/kg for several weeks, one single infusion of tocilizumab (8 mg/kg), and 1 week later rituximab 375 mg/m2 (total 4 weekly doses) (Figure 3A). The rational to use methylprednisolone and tocilizumab was to rapidly stop IL-6-mediated inflammation as induction regimen, whereas rituximab was used as maintenance treatment. We observed resolution of the inflammatory syndrome and slow clinical improvement over the course of 3 weeks, thrombocyte values normalized (>100 G/l) after 5 weeks and cholestasis parameters several months later. Corticosteroids were rapidly weaned off because of poor control of the diabetes, and the patient was hemodialyzed for end-stage renal disease. In the following 5 years, the patient relapsed twice, each time about 1 year after rituximab was discontinued (Figure 3A). The first relapse was successfully treated with rituximab alone and the second with methylprednisolone/tocilizumab (2 doses)/rituximab (4 weekly doses 375 mg/m2). Five years after the diagnosis was made (before the second relapse), the PET-CT showed reduction of the lymphadenopathies (Figures 3B,C). Auto-antibodies disappeared over the years and hypogammaglobulinemia developed, probably due to repeated rituximab treatments. Follow-up bone marrow biopsies were not performed in this case.