Infections in the era of immunobiologicals.

Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios.

Commentary on: "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial." Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA, Electronic address: kwon.eugene@mayo.edu; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; Institut Gustave Roussy, University of Paris-Sud, Villejuif, France; Institut Gustave Roussy, Villejuif, France; VU University Medical Centre, Amsterdam, Netherlands; Vienna General Hospital, Medical University Vienna, Vienna, Austria; Institut Bergonié, Bordeaux, France; CHU Caremeau, Nimes, France; Centro Médico Austral, Buenos Aires, Argentina; Centre Jean Perrin, Clermont-Ferrand, France; St John of God Hospital, Subiaco, WA, Australia; University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Hospital de Caridade de Ijuí, Ijuí, Brazil; Nottingham University Hospital, Nottingham, UK; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Británico de Buenos Aires, Buenos Aires, Argentina; Herlev Hospital, Herlev, Denmark; Odense University Hospital, Odense, Denmark; University of Texas MD Anderson Cancer Center, Houston,

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8Gy in one fraction) followed by either ipilimumab 10mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11.2 months (95% CI: 9.5-12.7) with ipilimumab and 10.0 months (8.3-11.0) with placebo (hazard ratio [HR] = 0.85, 0.72-1.00; P = 0.053). However, the assessment of the proportional hazards assumption showed that it was violated (P = 0.0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1.46 (95% CI: 1.10-1.95), for 5-12 months was 0.65 (0.50-0.85), and beyond 12 months was 0.60 (0.43-0.86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb.

Infliximab: efficacy in psoriasis.

Moderate to severe psoriasis often needs to be addressed with standard disease modifying therapies such as methotrexate, cyclosporine, acitretin or ultraviolet radiation, which have their potential benefits and limitations. The tumor necrosis factor-alpha (TNF-α) is elevated in psoriatic plaques compared to non lesional skin as well as in the plasma of patients with moderate to severe psoriasis. Infliximab, a TNF-α blocker, has been recommended for the treatment of moderate to severe plaque psoriasis in adults who have failed to respond to these therapies or who cannot tolerate them. Its specific action on the bound and membrane forms of the pro-inflammatory cytokine TNF-α has made it the molecule of choice for obtaining quicker and longer remission in recalcitrant cases. However, the widespread use of infliximab in the Indian subcontinent is limited by its cost. This article reviews the international guidelines for use of infliximab, its dosage patterns, and efficacy in chronic plaque psoriasis, nail psoriasis, erythrodermic psoriasis, and pustular psoriasis as well as Indian experience.

Secondary leprosy infection in a patient with psoriasis during treatment with infliximab.

Tumor necrosis factor α antagonists are proven to be effective for the treatment of chronic inflammatory conditions, such as psoriasis. A major concern for patients is the risk of acquiring granulomatous infectious diseases caused by the immunosuppressive effects of the drugs. We report a 60-year-old man with psoriasis who underwent infliximab treatment for 2 years and developed secondary leprosy, presenting extensive erythematous and infiltrated plaques on the trunk and limbs with loss of sensitivity (thermal, pain and tactile). The skin lesion biopsy showed perivascular epithelioid granulomas, nodular dermal aggregates of foamy macrophages and bundles of acid-fast bacilli. The clinical picture associated with histopathologic evaluation suggested borderline lepromatous leprosy. Before infliximab treatment, the patient had a positive tuberculin skin test and underwent chemoprophylaxis treatment for latent tuberculosis. Although the tuberculin reactivity suggests a strong correlation with a latent Mycobacterium tuberculosis infection, the possibility of infections by other mycobacteria, such as Mycobacterium leprae, should not be discarded.

Golimumab and certolizumab: the two new anti-tumor necrosis factor kids on the block.

Anti-tumor necrosis factor (anti-TNF) agents have revolutionized treatment of psoriasis and many other inflammatory diseases of autoimmune origin. They have considerable advantages over the existing immunomodulators. Anti-TNF agents are designed to target a very specific component of the immune-mediated inflammatory cascades. Thus, they have lower risks of systemic side-effects. In a brief period of 10 years, a growing number of biological therapies are entering the clinical arena while many more biologicals remain on the horizon. With time, the long-term side-effects and efficacies of these individual agents will become clearer and help to determine which ones are the most suitable for long-term care. Golimumab (a human monoclonal anti-TNF-α antibody) and Certolizumab (a PEGylated Fab fragment of humanized monoclonal TNF-α antibody) are the two latest additions to the anti-TNF regimen. Here, we are providing a brief description about these two drugs and their uses.

Development of leprosy in a patient with ankylosing spondylitis during the infliximab treatment: reactivation of a latent infection?

The use of tumor necrosis factor alpha as a treatment for chronic inflammatory conditions has been shown to be associated with an increased risk of developing infections, especially Mycobacterium tuberculosis, atypical mycobacteria, and other microorganisms. We report the case of a 58-year-old man with ankylosing spondylitis, receiving infliximab treatment, who presented with multiple plaques on the face, chest, and extremities, a thickened, tender ulnar nerve, and severe neuritis of the feet. The results of a biopsy of these lesions revealed histopathological features of lepromatous Hansen disease. The use of anti-tumor necrosis factor biologic agent on this patient may have resulted in either a new infection or reactivation of a latent infection of Mycobacterium leprae.

Multiple capillary hemangiomas: a distinctive lesion of multicentric Castleman's disease and POEMS syndrome.

A diagnosed case of Castleman's disease, proven by biopsy from enlarged inguinal lymph nodes, presented with multiple, asymptomatic, erythematous papules and nodules prevalent since nine years over the trunk and extremities. The lesions had been gradually increasing in number and size. The patient had had plasmacytoma of the lower thoracic vertebra 12 years ago, for which he was adequately treated with chemotherapy and local radiotherapy. Dermatological examination revealed erythematous papules and nodules on the face, trunk, and extremities that were diagnostic of capillary hemangiomas. Histopathology of the erythematous, soft papule was suggestive of capillary hemangioma. Contrast-enhanced computerized tomography of the abdomen and pelvis showed multiple retroperitoneal nodes suggestive of Castleman's disease along with multiple osteolytic lesions in the pelvic girdle and vertebrae. The patient was treated with injection rituximab and is currently under follow-up. We report this case to highlight a rare association between Castleman's disease and POEMS syndrome.

Development of leprosy and type 1 leprosy reactions after treatment with infliximab: a report of 2 cases.

Humanized monoclonal antibodies to tumor necrosis factor- alpha are valuable for the treatment of rheumatologic conditions, but they have been associated with the development of serious infections. We report the first 2 cases of leprosy developing after treatment with infliximab. After discontinuation of infliximab, both patients developed type 1 ("reversal") leprosy reactions.

Chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) in psoriasis.

BACKGROUND: Insights into the pathogenesis of psoriasis have provided opportunities to target key steps in the disease process. Tumor necrosis factor-alpha (TNF- alpha) being crucial to the pathogenesis of psoriasis, monoclonal antibodies against this cytokine have proved useful in its treatment. AIM: To study the efficacy of chimeric monoclonal antibody to TNF- alpha (infliximab) in Indian patients with recalcitrant psoriasis vulgaris. MATERIALS AND METHODS: Three patients with recalcitrant psoriasis vulgaris were studied. Baseline haemogram, biochemical parameters, chest radiograph and Mantoux skin test were performed. A loading dose regimen of 5 mg/kg infliximab was administered at weeks 0, 2 and 6. PASI assessment, adverse drug event monitoring and laboratory assessments were carried out at 2-week intervals until week 10. Patients were followed up until week 22 for relapse. RESULTS: Infliximab was well tolerated. The mean PASI was 25.4 at presentation and declined to 5.5 at 10 weeks. PASI 75 was attained at a mean of 9.6 weeks. Relapse occurred at a mean of 18.6 weeks after the first infusion. CONCLUSIONS: This study on Indian patients brings out the importance of cytokine-based therapies in psoriasis. Indigenous production could make these therapies a viable therapeutic option for psoriasis patients in the near future.

Addiction of anti-CD28 antibodies restores PBMC proliferation and IFN-gamma production in lepromatous leprosy patients.

During antigen recognition, T lymphocytes are primed by a physical interaction with antigen-presenting cells (APC). At least two signals are needed to activate T cells. One is provided by T cell receptor (TCR)/CD3 in the context of the mayor histocompatibility complex (MHC), and another signal is mediated by antigen-independent molecules, that is T cell membrane-bound CD28 and its specific ligand B7-1 (CD80) present in APC. Both signals trigger a series of metabolic events initiating right at the cell membrane and ending with activation and proliferation of T cells as well as specific cytokines synthesis. Our main goal was to determine whether deficiency in interferon-gamma (IFN-gamma) production shown by peripheral blood mononuclear cells (PBMC) from lepromatous leprosy (LL) patients, could be overcome by reconstituting in vitro the appropriate signals (by means of addition of anti-CD28 and anti-CD80 monoclonal antibodies). We also determined the stimulation index (SI) in the same PBMC. Our results demonstrated no significant differences in CD80 expression monocytes and B lymphocytes from LL patients when compared with healthy subjects. Nonetheless, CD28 expression significantly decreased in lymphocytes from LL patients (p < 0.01). Regarding IFN-gamma levels and SI, LL-PBMC failure before mitogenic stimuli could be reversed by further incubation with anti-CD28 antibody, but stimulation by specific antigen of Mycobacterium leprae was not changed. Addition of anti-CD80 antibody significantly increased IFN-gamma levels in phytohemagglutinin (PHA)-stimulated PBMC, although proliferation deficiency persisted. Cells stimulated with specific antigen did not modify either their proliferation or IFN-gamma levels.

The use of monoclonal antibodies for the characterization and production of Mycobacterium leprae antigens

Similar immunizations of mice and hybridoma technology were used by several investigators to raise monoclonal antibodies which identified a limited range of epitopes and antigenic molecules. Further studies would have the scope for revealing yet more novel structures. The existing MABs are agreed standard reagents, avaiable to investigators and valuable for several applications. At least six epitopes specific for M. leprae were defined in molecular terms. Monoclonal antibody based immunoassays proved to be invaluable for the screening of recombinant DNA clones and for the topographic study of individual epitopes. Purification of antigens using affinity chromatography requires further development of techniques whilst serology of leprosy is open for clinical and epidemiological evaluation.