Table 6.

Biologic Immune Response Modulators Targeting Cytokines and other Immune Mediators

Immune Response Modulator	Agent	Targeted Immune Mediator	Mechanism(s)	Immunologic Effects	Reported Infectious Complications	Treatment Indications
Anti-cytokine therapies	Anakinra	IL-1 receptor	Recombinant human IL-1 receptor antagonist protein, IL-1Ra, competitively binds to IL-1 receptor	Inhibits immune and pro-inflammatory actions of IL-1	Increased risk of serious bacterial infection with doses ≥ 100 mg/day (cellulitis, pneumonia)	-Moderate to severe rheumatoid arthritis - NOMID* - TRAPS**
	Tocilizumab	IL-6 receptor	Competitively blocks interaction of IL-6 with its receptor	Interferes with proliferation and differentiation of T cells and terminal differentiation of B cells	Bacterial pneumonia, cellulitis, sepsis Herpes zoster virus Tuberculous and nontuberculous mycobacteria Pneumocystis jirovecii pneumonia Invasive fungal infections	-Moderate to severe rheumatoid arthritis -- Juvenile rheumatoid and idiopathic arthritis (JIA)
	Infliximab (chimeric human mouse anti-TNFα mAb) Adalimumab (human anti-TNFα mAb) Golimumab (human anti-TNFα mAb) Etanercept (soluble TNFα receptor fusion protein) Certolizumab (pegol-pegylated Fab fragment of human mAb)	TNF	Bind to TNF-α	Impairment of differentiation of monocytes to macrophages, macrophage and phagosome activation, recruitment of neutrophils and macrophages, formation and maintenance of granulomas	Active and latent tuberculosis Bacterial pneumonia Herpes zoster virus Tuberculosis Non-tuberculous mycobacteria Listeria Legionella Nocardia Hepatitis B virus Hepatitis C virus Invasive fungal infections	-Rheumatoid arthritis -Psoriatic arthritis -Seronegative spondyloarthropathies -Inflammatory bowel disease -Sarcoidosis
Inhibitors of leukocyte migration	Natalizumab	Alpha 4 integrin	Blocks integrin association with vascular receptors, limiting adhesion and transmigration of leukocytes from vasculature into tissues	Reduction of specific inflammatory cell populations in target tissues	PML HSV and VZV encephalitis and meningitis	-Multiple sclerosis -Crohn’s disease Chronic moderate to severe plaque psoriasis
	Fingolimod	Sphingosine phosphate 1, 3, 4, and 5 receptors	Fingolimod-phosphate binds to sphingosine phosphate 1, 3, 4, and 5 receptors	Blocks lymphocyte egress from lymph nodes	PML Cryptococcal meningitis	Multiple sclerosis Disseminated primary herpes zoster virus Herpes simplex encephalitis
JAK Inhibitor	Tofacitinib	Janus associated kinase (JAK) inhibitor	Inhibition of JAK prevents the phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs)	-Prevents cytokine and growth factor mediated gene expression and intracellular activity of immune cells -Reduces circulating NK cells and serum immunoglobulin levels	Bacterial pneumonia and cellulitis TB Herpes zoster EBV PTLD (in renal transplant) Cryptococcus PCP CMV BK virus	Moderate to severe RA for patients with inadequate response to or intolerant of methotrexate
Monoclonal antibodies to complement	Eculizumab	C5	Binds complement protein C5, preventing cleavage into C5a and C5b	Inhibits terminal complement activation	Bacteremia/sepsis: Meningococcal infections (Neisseria meningitidis) S. pneumoniae H. influenzae	-Atypical hemolytic uremic syndrome -Paroxysmal nocturnal hemoglobinuria

^*Neonatal Onset Multisystem Inflammatory Disease

^**Tumor necrosis receptor-1 associated periodic syndrome