‘11e21, 65¢ PM hitpsslemedicine.medscape.convartce/332032-print ‘emedicine.medscape.com Medscape Serum Sickness Updated: Nov 02, 2020 ‘Author: Hassan M Alissa, MD; Chief Editor: Herbert S Diamond, MD Overview Practice Essentials ‘Serum sickness is a type Ill hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum Reactions to nonprotein drugs are clinically similar to serum sickness reactions. Historically, the term serum sickness connotes a self-limited syndrome caused by deposition of immune complexes resulting from exposure to foreign proteins or haptens. Von Pirquet and Schick first described the syndrome in 1905, reporting fever, skin ‘eruptions (mainly consisting of urticaria), joint pain, and lymphadenopathy in regions draining the site of injection after patients were given antitoxin in the form of horse serum.(1] Later, physicians reported a similar clinical picture after the injection of other ‘equine-based antitoxins and antivenins {2} Certain medications (eg, penicillin, nonsteroidal antiinflammatory drugs [NSA\Ds}) have also been associated with serum sickness-lke reactions. These reactions typically occur 1 to 3 weeks afler exposure to the drug, but may occur as early as 1 to 24 hours afterward. Accelerated reactions are T-cell mediated, although an IgE mechanism cannot always be ruled out.[3] Identifying serum sickness was a landmark observation in understanding immune complex diseases. Withdrawal of the offending agent is the mainstay of treatment in serum sickness. Ant-inflammatory drugs and antihistamines provide symptomatic relief. Severe cases (multisystem involvement with significant symptoms|4] ) may warrant a brief course of corticosteroids. In some cases, plasmapheresis can attenuate serum sickness.[5] Emedicine Pathophysiology ‘Serum sickness is an example of the type Ill, or immune complex-mediated, hypersensitivity disease. The molecular size, charge, structure, amount, and valence of the antigen involved influence the type of immune complexes formed. [2] After the initial exposure to a foreign antigen in the absence of a preexisting antibody, serum sickness can develop within 1-2 weeks. Upon subsequent exposure, however, serum sickness develops sooner. The disease appears as the antibody formation begins, and the pathogenesis of serum sickness is related to protracted interaction between antigen and antibody in the Circulation, with antigen-antibody complex formation in an environment of antigen excess, ‘The immunologic interactions observed in serum sickness occur when antigens capable of remaining in the circulation for long periods incite antibody formation (6) Typically, serum protein molecules are removed from the circulation by nonimmune processes that are nat yet completely understood, Immune complex formation is a common event and does not typically cause symptoms {7] Small complexes usually circulate without triggering inflammation, and large complexes are cleared by the reticuloendothelial system, However, intermediate-sized ‘complexes that develop in the context of slight antigen excess may deposit in blood vessel walls and tissues, where they induce vascular and tissue damage resulting from activation of complement and granulocytes.[8] Endothelial cells increase the expression of adhesion molecules, and monocytes and macrophages release proinflammatory cytokines. Subsequently, additional inflammatory cells are recruited, and necrosis of the small vessels develops. Complement activation promotes chemotaxis and adherence of neutrophils to the site of immune complex deposition. This may be facilitated by increased vascular permeability due to release of vasoactive amines from tissue mast calls (8) At this point, complement levels fall to half their levels prior to the antibody response {6} This clinicopathological syndrome usually develops within 1-2 weeks of antigen injection. hitpsilemecicine.medscape.comvartcle/332092-prnt wm‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print Free antigen continues to clear from the blood, leading to antibody excess and the formation of large immune complexes, which are quickly removed by circulating macrophages. Finally, the antigen is no longer detectable, and the level of circulating antibodies continues to rise. Clinical recovery is usually apparent after 7-28 days, as intermediate-sized immune complexes are cleared by the reticuloendothelial system. ‘Secondary serum sickness is the result of antigen recognition by presensitized cells of the immune system. It is characterized by a shorter latent period, exaggerated symptoms, and a brief clinical course. Why immune complex disease occurs under certain circumstances is not known. Possible factors may include high levels of immune complexes and a relative deficiency of some complement components leading to a decreased ability to eliminate immune complexes.(7] In an epidemiological study of 37 cases of rituximab-induced serum sickness, Bayer and colleagues reported that 54% of cases, ‘occurred after the first injection, mainly in individuals treated for an autoimmune disease (78%), particularly systemic lupus erythematosus (SLE). The investigators concluded this may be due to B~ell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, particulary in patients with elevated autoantibodies (9) Not all substances that are recognized as foreign by the immune system elicit an immune response. The antigen must be of characteristic size or have specific antigenic determinants and physiological properties to be an effective stimulator of the immune system. ‘After an appropriate antigen is introduced, an individual's immune system responds by synthesizing antibodies after 4-10 days. ‘The antibody reacts with the antigen, forming soluble circulating immune complexes that may diffuse into the vascular walls, where they may initiate fixation and activation of complement. ‘Complement-containing immune complexes generate an influx of polymorphonuciear leukocytes into the vessel wall, where proteolytic enzymes that can mediate tissue damage are released. Immune complex deposition and the subsequent inflammatory response are responsible for the widespread vascultc lesions seen in serum sickness. me Etiology ine ‘Currently, the most common cause of serum sickness and serum sickness—ike is hypersensitivity reaction to drugs {5] Drugs containing proteins of other species include the following + Antitoxins + Antivenins {'2) ‘+ Hormones from other species + Streptokinase + Vaccines Polyclonal and monoclonal antibodies prepared from horse, rabbit, or mouse serum (eg, antithymocyte globulin, OKT-3) have also been found to cause serum sickness.|11] Antibiotics and other antimicrobials that can cause serum sickness include the following: ‘+ Cephalosporins + Ciprofloxacin + Griseofulvin + Lincomycin + Metronidazole ‘+ Paraaminosalicylic acid + Penicilins + Streptomycin + Sulfonamides + Tetracyclines (Other drugs associated with serum sickness include the following: + Allopurinal Barbiturates © Bupropion [12.131 + Captopril Carbamazepine hitpsilemecicine.medscape.comvartcle/332032-prnt am‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print Fluoxetine Gold salts Halothane Hydantoins (eg, phenytoin) Hydralazine Indomethacin lodides Iron dextran Methimazole Methyldopa Mirabegron (4) Penicilamine Procainamide Procarbazine Propranolol Thiouracit Monoclonal antibodies have been reported to cause serum sickness-like syndrome. These include infliximab, which is used to treat Crohn disease and rheumatoid arthrits{15, 16] ; omalizumab, which is used to treat allergy-related asthma[17, 18, 19, 20) and rituximab, which is used to treat various diseases, including rheumatolagic disorders, mixed cryoglobulinemia, and lymphoma,(18, 21, 22, 23] ‘Stings from insects in the order Hymenoptera (eg, bees, wasps), mosquitoes, and tick bites may cause serum sickness.[24] Infectious diseases involving circulating immune complexes (eg, hepatitis B, infective endocarditis) may cause serum sickness— like reactions. These conditions are often associated with circulating cryoglobulins. medicine Epidemiology ‘The annual incidence of serum sickness is decreasing as the administration of foreign antigens in medical therapeutics is refined [4] The likelinood of developing serum sickness is dose-related. In one study, 10% of patients who received 10 mL. of tetanus antitoxin developed serum sickness; the administration of 80 mL or more produced the disease in almost all patients [4] ‘The likelihood also varies by antigen type. Antirabies serum is associated with a higher likelihood (16.3%) of serum sickness than tetanus antitoxin (2.5%.5%) 4] The reported rate of serum sickness-lke reaction per course of cefacor in United States children is 0.2% (25) In a clinical tral conducted to evaluate the efficacy and safety of recombinant murine monoctonal antibody to human tumor necrosis factor alpha in patients with sepsis, serum sickness reactions were noted in 15 (2.3%) of 645 patients in the treatment group (26) In one study, serum sickness was more common in patients older than 15 years who were given antirables serum {27] Antibiotic- associated serum sickness-like disease, however, is more frequently described in children younger than 5 years, Ina prospective cohort study of 109 patients who received snake antivenom in Australia, serum sickness occurred in 29% of the patients.[10] met Prognosis ine ‘Serum sickness is typically selfJimited and resalves within days.(5] The prognosis of serum sickness in patients without intornal ‘organ involvement is good.{7] Although occasional reports show mortality resulting from progressive glomerulonephrits or severe neurological complications. Complications of serum sickness may include the following Vasculitis Neuropathy ‘Acute kidney injury Glomerulonephritis (rare) Anaphylaxis hitpsilemecicine.medscape.comvartcle/332032-prnt amt‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print + Shock medicine Presentation History ‘Serum sickness develops 1-3 weeks after intial administration of the causative agent (in many cases a medication) but can ‘occur within 12-36 hours in individuals who have been previously sensitized through an antecedent exposure.[5] ‘Symptoms described in serum sickness include the following{S] Feverimalaise - ~100% Cutaneous eruptions - 93% Arthralgias - 77% Gastrointestinal (GI) complaints - 67% Headaches - 57% Myalgias - 37% Blurred vision - 37% Dyspnealwheezing - 20% Lymphadenopathy - 17% ‘Specific GI symptoms may include abdominal pain, nausea, vomiting, or diarrhea {2 Chest pain or breathlessness due to pleuritis, pericarditis, or myocarditis is possible but rare. @medicine Physical Examination Fever develops in almost all patients with serum sickness, preceding skin rash in 10-20% of cases. The fever is characterized by high spikes that normalize within the same day, (8) Most rashes associated with serum sickness are urticarial (32%) and/or serpiginous.[2] They typically start on the anterior lower trunk or the periumbilical or axillary regions and spread to the back, upper trunk, and extremities [8] In the extremities, eruptions ‘occur at the junction of the palmar or plantar skin with the dorsolateral surface of the hands, feet, fingers, and toes. Morbiliform or scaflatiniform rash, palpable purpura, erythema simplex, or erythema multiforme are less common, Pruritus and ‘erythema are possible at injection sites. Edema can be limited to site of injection but can also be observed in the face [2] Lymphadenopathy (10-20%) may be generalized or may involve tenderness in the nodes that drain the injection site. ‘Splenomegaly may occur. Arthritis (10%-50%) is usually in the metacarpophalangeal and knee joints and usually symmetrical [4] Occasionally, smal joins, Joints of the spine, and the temporomandibular joint may be inflamed, Myalgias or myositis also may occur. Edema may occur, particularly about the face and neck Kidney manifestations include proteinuria, microscopic hematuria, and oliguria; however, significant disease usually does not result. Cardiovascular findings may include myocardial and pericardial inflammation. Generalized vasculitis occurs rarely. Neurologic manifestations include the followingl2, 4] Peripheral neuropathy Brachial plexus neuritis Optic neuritis Cranial nerve palsies Guillain-Barré syndrome Encephalomyelits (rare) Pulmonary manifestations, such as pleurisy, are rare. However, dyspnea and cyanosis are not uncommon. hitpsilemecicine.medscape.comvartcle/332032-prnt ants1e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print @medicine DDx gnostic Considerations Problems to be considered in the differential diagnosis of serum sickness include the following: Dermatitis herpetiformis: Henoch-Schonlein purpura (IgA vascullts) Microscopic polyangiitis, Shunt nephritis Stil disease ferent | Diagnoses + Cryoglobulinemia + Immediate Hypersensitivity Reactions ‘+ Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono) + Infective Endocarditis + Kawasaki Disease + Leukocytoclastic Vasculitis + Poststreptococcal Glomerulonephritis + Sickle Cell Anemia + Systemic Lupus Erythematosus (SLE) + Viral Hepatitis medicine Workup Workup Approach Considerations Laboratory studies are not helpful in establishing a diagnosis of serum sickness. However, certain laboratory findings have been reported, including the following: + Loukopenia or mild leukocytosis, with or without eosinophilia + Plasma cells on peripheral blood smear [2] + Erythrocyte sedimentation rate elevation 2 + Polyclonal gammopathy or a transient monoclonal immunoglobulin G (\gG) spike (4 + Mild proteinuria or hematuria + Transient elevation of serum creatinine levels + Decreased complement levels (C3, C4) (2 ‘+ Cryoglobulinemia, often of the mixed (IgM-IgG) type medicine Histologic Findings hitpsilemecicine.medscape.comvartcle/332032-prnt sit‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print Numerous histological changes may be found in serum sickness, depending on the organ involved and, possibly, the nature of the antigen. The tissues most commonly involved include those of the heart, arteries, joints, and kidneys. Arteritic lesions are focal, necrotizing, and inflammatory processes that usually involve all layers of the artery. ‘Acute inflammatory exudate, necrosis of the arterial wall, fibrinoid material, or primarily a mononuclear reaction may be ‘observed. Joints may have focal mononuclear infiltrates with edema and fibrinoid formation in the synovial tissues. Kidneys develop endothelial proliferation of the glomerular capillaries with slight basement membrane thickenings (6) medicine Treatment Approach Considerations Withdrawal of the offending agent is the mainstay of treatment in serum sickness. Nonsteroidal anti-inflammatory drugs and antihistamines provide symptomatic roe. ‘Severe cases (multisystem involvement with significant symptoms{4] ) may warrant a brief course of corticosteroids. In some cases, plasmapheresis can attenuate serum sickness.[5] Hospitalize the patient if any significant comorbidities are present (eg, advanced or very young age, immunocompromise), if any severe symptoms or hemodynamic instabilityMhypotension is present, or if the diagnosis is unclear. ‘The presenting features of fever, rash, and joint pain may be observed in numerous infectious and autoimmune diseases. Consider a consultation with an allergist or a rheumatologist. Emer Deterrence, Prevention, and Long-Term Monitoring ine Avoidance of the offending agent is the best way to prevent serum sickness. However possible. in some circumstances, avoidance is not ‘Skin tests are indicated before antiserum administration, particularly in patients with a history of allergy to horse dander or in those who have previously received the substance, Skin tests reveal the presence of immunoglobulin E antibodies and, thus, help to identify individuals at risk of anaphylaxis. However, these tests are not reliable inthe identification of individuals with an increased risk for serum sickness. Ifrapid administration of antiserum is necessary, establish intravenous access in each arm (one site for the infusion of antiserum and the other for the treatment of complications) and premedicate the patient with 50-100 mg of diphenhydramine. Ifa reaction ‘occurs, temporarily discontinue the infusion, and administer epinephrine and other necessary medications. Once the adverse reaction is halted, resume slow infusion. Premedication with steroids is not protective. Desensitization Fajt and Petrov reported the frst case of successful drug desensiization in a patient with rituximab-induced serum sickness. ‘hough drug desensitization has traditionally been used to treat typeI IgE-mediated hypersensitivity reactions, a rapid 12-step intravenous rituximab desensitization protocol allowed resumption of treatment in a 37-year-old worman who had developed serum sickness 72 hours following tuximab infusion fora gastric mucosa-associated lymphoid issue lymphoma (MALToma). (28) ‘The patient's MALToma, which had progressed after stopping rituximab, went into remission after the completion of four rtuximab desenstizatons. She received 25 maintenance rtuximab doses using ths desensitization protocol quarterly without complications.[28] Dilley etal report on the successful use of a new patient weighl-based protocol in two children who had experienced hypersensitivity reactions to rituximab. The authors conclude that desensitization to rituximab isa safe and effectve procedure in the pediatric population [29] Long-term monitoring hitpsilemecicine.medscape.comvartcle/332032-prnt en‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print Reconsider the diagnosis of serum sickness if symptoms persist beyond 3-4 weeks, Symptoms may reappear in severe cases if steroids are tapered too quickly; this recurrence is usually responsive to another course of treatment, After identifying the ‘causative agent, inform the patient and advise that future exposure may cause a similar or more severe response. medicine Medication Medication Summary ‘The goal of therapy is to treat the clinical syndrome resulting from the effects of soluble circulating immune complexes that form under conditions of antigen excess. These immune complexes can originate from the administration of either heterologous antisera or drugs known to cause serum sickness. medicine Nonsteroidal anti-inflammatory drugs Class Summary ‘These agents have analgesic, ant-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions. Ibuprofen (Motrin, Ibuprin, Advil, Caldolor, Addaprin, Ultraprin) Ibuprofen decreases inflammation by blocking prostaglandin synthesis and reduces fever by acting on the hypothalamic temperature-regulating center. Its usually administered for mild symptoms of arthralgia, myalgia, or fever. Naproxen (Anaprox, Aleve, Naprosyn, Naprelan) Naproxen is indicated for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis. Ketoprofen Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response. medicine Antihistamines Class Summary ‘Antihistamines act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arthythmias. Diphenhydramine HCL (Benadryl, Aler-Cap, Aler-Dryl, Anti-Hist) Diphenhydramine blocks histamine H1 receptors on the target tissue. It used for urticarial rash, hitpsilemecicine.medscape.comvartcle/332032-prnt mms1e21, 65¢ PM hitpsslemedicne.medscape.convatcle/332082-print @medicine Corticosteroids Class Summary ‘These agents have antiinflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimull Prednisone Prednisone acts by altering the number and availability of leukocytes, reducing vascular permeability, and suppressing cytokines, This agent is the mainstay of treatment in severe cases; tis usually administered in moderate doses for 1-2 weeks, Prednisone, or other oral corticosteroids (eg, prednisolone), is useful in managing mild-to-moderate serum sickness treated in an outpatient setting medicine Questions & Answers Overview What is serum sickness? What is the pathophysiology of serum sickness? What is the role of endothelial cells in the pathophysiology of serum sickness? What is the role of the immune system in the pathophysiology of serum sickness? Which drugs can cause serum sickness? What is the role of monaclonal antibodies in the etiology of serum sickness? What is the prevalence of serum sickness? What is the prognosis of serum sickness? Presentation What are the signs and symptoms of serum sickness? Which physical findings are characteristic of serum sickness? What are neurologic manifestations of serum sickness? Dx Which disorders should be included in the differential diagnosis for serum sickness? What are the differential diagnoses for Serum Sickness? Workup What is the role of lab studies in the workup of serum sickness? Which histologic findings are characteristic of serum sickness? Treatment What are the treatment options for serum sickness? When is inpatient care indicated for the treatment of serum sickness? hitpsilemecicine.medscape.comvarticle/332032-prnt ant‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print Which specialist consultations are beneficial for the diagnosis of serum sickness? How i serum sickness prevented? Whats the role of desensitization inthe treatment of serum sickness? What is included in long-term monitoring of patients with serum sickness? Medications Whats the goal of therapy for serum sickness? Which medications inthe drug class Corticosteroids are used inthe treatment of Serum Sickness? Which medications inthe drug class Antihistamines are used in he eatment of Serum Sickness? Which medications inthe drug class Nonsteroidal ant-inlammatorycrugs are used inthe treatment of Serum Sickness? medicine Contributor Information and Disclosures Author Hassan M Alissa, MD Rheumatologst, Mulispecialy Group, San Marcos, Texas Hassan M Alissa, MD is a member ofthe following medical societies: American College of Rheumatology Disclosure: Nothing to disclose Coauthors) Susan M Chen, MD Clinical Assistant Professor, Department of Emergency Medicine, University of Pennsylvania Health ‘System, Penn Presbyterian Medical Center ‘Susan M Chen, MD is a member of the following medical societies: American Academy of Emergency Medicine Disclosure: Nothing to disclose. Francis Counselman, MD, FACEP Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical Schoo! Francis Counselman, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Norfolk Academy of Medicine, Association of Academic Chairs of Emergency Medicine, Society for Academic Emergency Medicine Disclosure: Nothing to disclose, Elaine Adams, MD Associate Chief of Staff, Chief of Rheumatology Section, Hines Veterans Affairs Hospital; Professor of Medicine, Loyola University School of Medicine Elaine Adams, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology Disclosure: Nothing to disclose. Rochella Abaygar Ostrowski, MD Assistant Professor, Department of Medicine, Division of Rheumatology, Loyola University Medical Center, Staff Physician, Department of Medicine, Division of Rheumatology, Edward Hines Jr Veterans Affairs Hospital Rochella Abaygar Ostrows! Collage of Rheumatology MD is a member of the following medical societies: American College of Physicians, American Disclosure: Nothing to disclose. Richard Hariman, MD Assistant Professor, Division of Rheumatology, Medical College of Wisconsin Richard Hariman, MD is a member of the following medical societies: American College of Rheumatology hitpsilemecicine.medscape.comvartcle/332032-prnt ont‘11e21, 65¢ PM hitpsslemedicine. medscape.comatce/332032-print Disclosure: Nothing to disclose. Specialty Editor Board Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape. Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Lewis Katz ‘School of Medicine at Temple University Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Collage of Rheumatology Disclosure: Nothing to disclose. Chief Editor Herbert $ Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital Herbert § Diamoné, MD is a memier of the folowing medical societies: Alpha Omega Alpha, American College of Physicians, “American College of Rheumatology, American Medical Association, Phi Beta Kappa Disclosure: Nothing to disclose. Additional Contributors Matthew M Rice, MD, JD, FACEP Senior Vice President, Chief Medical Officer, Northwest Emergency Physicians of ‘TeamHealth; Assistant Clinical Professor of Medicine, University of Washington School of Medicine Pending Approval Matthew M Rice, MD, JD, FACEP is a member of the following medical societies: American College of Emergency Physicians, ‘American Medical Association, National Association of EMS Physicians, Society for Academic Emergency Medicine, Washington State Medical Association Disclosure: Nothing to disclose. References 4. Shulman ST. Clemens von Pirquet: A Remarkable Life and Career. J Pediatric Infect Dis Soc. 2016 Oct 28. [Medline]. 2 Mannik M. Serum sickness and pathophysiology of immune complexes. Rich RR, ed. Clinical Immunology Principles and Practice. St Louis, Mo: Mosby; 1998. 1062-71. 3, Torres MJ, Salas M, Ariza A, Feméndez TD. Understanding the mechanisms in accelerated drug reactions. 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Serum sickness-lke reaction in a pediatric patient using omalizumab for chronic spontaneous urticaria Pediatr Allergy Immunol, 2018 Jun, 29 (4):449-460, [Medline] 21. Karmacharya P, Poudel DR, Pathak R, Donato AA, Ghimire S, Gir S, et al. Rituximab-.induced serum sickness: A systematic review. ‘Semin Arthritis Rheum. 2015 Dec. 45 (3)'334-40. (Medline 22, Khan DA. Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist. Ann Allergy Asthma Immunol. 2016 ‘Aug. 117 (2):115-20. [Medline]. 23, Cheong J, Oo! K. Rituximab-induced serum sickness in the treatment of idiopathic membranous nephropathy. Clin Kidney J. 2018 Feb. 11 (1):51-83. (Medline). [Full Text 24, Lazoglu AH, BogloliLR, Taff ML, Rosenbluth M, Macris NT. Serum sickness reaction following multiple insect stings. Ann Allergy Asthma Immunol. 1995 Dec. 75(6 Pt 522-4. [Medline] 25. King BA, Geelhoed GC. Adverse skin and joint reactions associated with oral antibities in children: the role of cefaclor in serum sickness-lke reactions. J Paediatr Child Health, 2003 Dec. 39(9):677-81. [Medline] 26. Abraham E, Wunderink R, Silverman H, etal. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical tal, TNF-alpha MAb Sepsis Study Group. JAMA. 1995 Mar 22-28, 273(12)'934-41. [Medline] 27, Karliner JS, Belaval GS, Incidence of reactions following administration of antirabies seru’ 193:359-62. [Medline] study of 526 cases, JAMA, 1965 Aug 2, 28. Fajt ML, Petrov AA. Desensitization protocol for rtuximab-induced serum sickness. Curr Drug Saf. 2014. 9(3):240.2. [Medline]. 29. Dilley MA, Lee JP, Platt CD, Broyles AD. Rituximab Desensitization in Pediatric Patients: Results of a Case Series. Pediatr Allergy Immuno! Pulmonol, 2016 Jun 1, 29 (2):91-84, [Medine}. 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