Current Understanding and Unknown Aspects of the Treatment of Granulomatosis with Polyangiitis (Wegener's Granulomatosis): Opportunities for Future Studies.

Granulomatosis with polyangiitis (GPA) is a rare and systemic autoimmune disease, causing necrotizing vasculitis of small arteries and veins. The majority of diagnosed patients with GPA have circulating anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3). Here, we have reviewed the last findings and uncertainties regarding the treatment of GPA. Between the available treatments, in addition to corticosteroids, cyclophosphamide (CYP) is effective for remission-induction, while it is associated with some serious side effects, such as infertility and increased risk of malignancies. On the other side, rituximab (RTX) seems a safer alternative option and as effective as CYP. It could be used as both remission-induction and maintenance therapy in GPA patients, especially in women of childbearing age. Pregnant patients, who must not be exposed to the CYP and RTX could be well-managed with intravenous immunoglobulin (IVIg). Co-trimoxazole, which is widely used to treat certain bacterial infections or as prophylaxis in immunosuppressed patients, could be effective in preventing disease relapse. In the meantime, 15- deoxyspergualin, plasma exchange are other therapeutic options with a low level of evidence. Regarding potential treatments, ofatumumab, ocrelizumab, belimumab, atacicept, tabalumab, abatacept (CTLA4-Ig), and Janus kinase inhibitors seem to be effective. Renal involvement, older age, the presence of baseline organ damage, delayed-diagnosis of disease, rising in creatinine level, and higher neutrophil/lymphocyte ratio is associated with poor outcomes. Optimum doses of medications, prediction of treatment response and disease relapse, explaining lack of response in some patients, treating children with GPA, and management of GPA during the pregnancy are controversial issues, which need further studies.

Toward cure chronic hepatitis B infection and hepatocellular carcinoma prevention: Lessons learned from nucleos(t)ide analogues therapy.

Nucleos(t)ide analogues (NAs) could successfully suppress hepatitis B virus (HBV) replication in patients with chronic hepatitis B (CHB). However, due to probable development of drug resistance or low/delayed response, these treatments may not be satisfactory. In addition to the HBV DNA polymerase inhibiting activity, these drugs could lead to changes in cytokines profiles. It is important to monitor these changes so that they could be used as target of treatment. Evaluating the previously reported immune responses due to NAs treatments, it was concluded that interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), and IL-12 increase after the treatment. This will be followed by the improved capacity of immune cells for eliminating HBV. In contrast, regulatory responses including IL-10 and transforming growth factor-beta (TGF-ß) significantly decreased as the result of NAs therapy. Unexpectedly, T helper (Th) 17-associated cytokines also decreased significantly. These results could be used to employ the new strategies to suppress viral replication, minimize HBV DNA levels, inducing hepatitis B e antigen (HBeAg) seroconversion or even hepatitis B surface antigen (HBsAg) seroclearance. In order to accomplish these goals, extended treatment with high dose of both IL-12 and IFN in combination with high barrier to resistance NA might significantly improve the HBsAg seroclearance rate. Considering the danger of emerging aberrant immune responses, determining the optimum dosage as well as close monitoring of patients during the treatment is strongly advised. In order to make HBV immunotherapy practical, further studies are needed to confirm these results.