Japanese Journal of Clinical Immunology Vol. 40(2017) No. 2

  Recent introduction of immune checkpoint inhibitors represented by anti-PD-1 antibodies such as nivolumab and pembrolizumab, and anti-CTLA-4 antibody such as ipilimumab had a great impact on cancer immunotherapy especially for melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma. On the other hand, immune checkpoint inhibitors have their own distinctive adverse events, which are collectively named as “immune-related adverse events”. Although immune-related adverse events may occur at any part of the body, interstitial pneumonia, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis are representative. The onset of these immune-related adverse events varies. As for ipilimumab, cutaneous and mucous complications appear relatively early, and subsequently digestive symptoms emerge. As for nivolumab, most immune-related adverse events start around a few months after its administration. These immune-related adverse events are basically managed according to the algorism. Prompt consultation to the experts are of great importance and the grade of immune-related adverse events and patients' disease conditions need to be carefully evaluated to decide the optimal measures. As immune-related adverse events could affect various organs, cooperation with many experts from various fields is critical and it is important to organize a cooperative system within a hospital.

  Immune checkpoint inhibitors, used for cancer immunotherapy, show anti-tumor effects through T cell activations. Monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death (PD)-1, or PD-ligand 1 which is a ligand of PD-1 have been shown to be effective in the treatments of advanced cancers including malignant melanoma, non-small cell lung cancer, and renal cell carcinoma. However, these drugs also have immune-related adverse events (irAEs). The irAEs, which have unique characteristics different from those seen in conventional cytotoxic anti-tumor medicines, are observed in the several tissues such as skin, gastrointestinal tract, liver, lung, muscle, nerve and endocrine systems. To safely use immune checkpoint inhibitors, it is quite important to understand the characteristics of irAEs and to manage them in clinical practice. In this review, we focus on clinical characteristics and pathogenesis of adverse events in the pituitary gland.

  Nivolumab is a standard recombinant antibody treatment for patients with malignant melanoma (MM), which functions as an immune checkpoint inhibitor by blocking the programmed cell death-1 (PD-1) pathway in T cells. However, it leads to various immune-related adverse events (irAEs), and also exacerbates underlying autoimmune diseases. Herein we report cases of MM with irAE. Case 1: A 69-year-old woman with MM developed destructive thyroiditis resulting in hypothyroidism after 3 doses of nivolumab, and had been treated with thyroid gland auxiliary therapy. Case 2: A 80-year-old man with MM developed an acute onset of hyperthyroidism after 4 doses of nivolumab. Case 3: A 85-year-old woman with MM developed polyradiculoneuropathy resulting in somatosensory disorder and muscle weakness after 2 doses of nivolumab, and had been treated with intravenous immunoglobulin and oral predonisolone (40 mg/day). Case 4: A 77-year-old man with MM developed psoriasiform dermatitis after local injections of IFN-β and 11 doses of nivolumab. Case 5: Case 2 also developed psoriasiform dermatitis. We analyzed serum levels of inflammatory cytokines in MM patients before/after treatments with nivolumab. All six patients who developed psoriasiform dermatitis with/without anamnesis of psoriasis after treatment with nivolumab, and all seven patients with other irAE exhibited increased serum IL-6 levels after nivolumab treatment, while decreased serum levels of IL-6 were observed in 5 of 7 non-afflicted MM patients. In addition, MM patients who achieved good responses to nivolumab significantly exhibited decreased serum TNF-α levels after nivolumab treatment compared to progressive MM patients.

  Development and application of anti-CTLA-4 antibody and anti-PD-1 antibody to cancer immunotherapy brought great survival benefits to advanced cancer patients. They have been applied to various cancers such as melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's disease, and head and neck cancers, and there is no doubt that immunotherapy is becoming a standard therapy as well as surgery, chemotherapy, and radiotherapy. On the other hand, immune-related adverse events (irAEs) have been increasingly reported. Nevertheless, mechanisms of the immune-mediated toxicities are still unclear. There has been a growing interest in the elucidation of the mechanisms. This review describes the general characteristics of irAEs induced by immune checkpoint inhibitors, especially 1. Heterogeneity, 2. Multiplicity, 3. Durability, and 4. Correlativity.

  Chronic mucocutaneous candidiasis (CMC) is an infectious phenotype which is characterized by recurrent or persistent infections affecting the nails, skin, and oral and genital mucosae caused by Candida species. Th17 cells produce interleukin-17 (IL-17) and play an important role in host mucosal immunity to Candida. Recent studies revealed that an impairment of IL-17 immunity underlies development of CMC. CMC disease (CMCD) is a primary immunodeficiency disease which is defined as CMC in patients in the absence of other prominent clinical signs. However, this definition is not strict. Thus, CMCD is currently used to refer to patients presenting with CMC as the main clinical phenotype. As well as CMCD, CMC is a major infectious phenotype in syndromic CMC. However, patients with syndromic CMC also present other clinical and infectious manifestations in addition to CMC. The genetic defects which affect development and/or proliferation of Th17 cells have been identified in patients with syndromic CMC. In contrast, germline mutations in the genes which directly involved in IL-17 signaling have been identified in patients with CMCD. Here, we review current knowledge of IL-17-signaling defects and the genetic etiologies of CMCD and syndromic CMC.

  In systemic lupus erythematosus (SLE), lupus nephritis (LN) is an important complication as an intractable condition and considered to be a prognostic factor. Based on the past reports that explain immunological functions of OPN and its relationship with autoimmune diseases such as LN or IgA nephropathy, we measured OPN full and OPN N-half in serum and urine of SLE patients and examined the possibility as a disease biomarker. OPN N-half is known as a more physiologically active form than OPN full. As a result, OPN N-half in urine was higher in LN than in healthy control, and also higher than in diabetic nephropathy that is a non-inflammatory nephropathy. In addition, OPN N-half in urine decreased after the treatment of LN, suggesting that OPN N-half in urine could be a biomarker for evaluating disease activity of LN.

  Neonatal lupus (NL), a passively-acquired autoimmune disease associated with maternal anti-SSA antibody, presents both cardiac manifestations such as cardiac NL and non-cardiac manifestations including rashes, cytopenia, and hepatic abnormalities. Cardiac NL, occurring in 1-2% of anti-SS-A antibody-positive mothers, is a life-threatening complication with a mortality rate of 20% and a pacemaker implantation rate of 70%. In contrast, cutaneous NL, which is more common than cardiac NL, usually resolves in six months. Since half of NL cases occur in asymptomatic mothers, if an infant presents characteristic cutaneous or cardiac manifestations of NL, the mother should be tested for anti-SS-A antibody. In mothers positive for anti-SS-A antibody, the risk of having a child with cardiac NL increases ten-fold and five-fold for a previous child with cardiac NL and cutaneous NL, respectively. A joint American, British, and French retrospective study of NL registries showed that hydroxychloroquine (HCQ) reduced the cardiac NL risk in subsequent pregnancies in mothers who previously had a child with cardiac NL. A prospective open-label study to confirm this effect is being undertaken in the USA. A similar prospective multi-center study will be undertaken in Japan. Establishing a Japanese registry of children with NL and subsequent pregnancies of their mothers will help promote clinical research in NL in Japan.

  We experienced a 6-year-old girl diagnosed with mevalonate kinase deficiency (MKD) who had cholestasis, anemia, and elevated inflammatory markers in neonatal period. She was admitted to our hospital because of fever and elevated inflammatory markers at 5 years 11months of age. Without using antibiotics, the fever and the inflammatory markers were spontaneously resolved. MKD was suspected from elevated serum IgD level and the recurrent febrile attacks. The genetic test revealed heterozygous mutation of p.Leu51Phe known as causative gene of MKD and p.Met 282Thr which is the novel mutation. In addition, urinary mevalonate levels increased both in afebrile and febrile periods, and mevalonate kinase activity level was very low. Prednisolone was administered on each attack, and her febrile attack has been controlled well since she was diagnosed with MKD. Fetal edema, cholestasis, anemia, elevation of inflammatory markers in her neonatal period are considered to be complications of MKD. Recurrent fever attacks compromise quality of life in patients with MKD. Children with unexplained cholestasis and anemia in neonatal period, or recurrent fever attacks with elevated inflammatory markers should be examined for MKD.