The Arthus reaction is a localized inflammatory response caused by a type III hypersensitivity reaction. It involves the formation of antigen-antibody complexes in small blood vessel walls, leading to activation of the complement system and recruitment of neutrophils. This causes localized tissue damage, edema, and hemorrhage at the site of antigen injection. Symptoms develop rapidly and resolve within a week without long term effects.

1. Arthus Reaction
Serum Sickness
Serum Sickness-Like Reaction
Natthiya Pholmoo, MD
7/2021

2. Arthus Reaction

3. Definition
• The Arthus reaction is a localized inflammatory response, belonging
to a typical local subacute type III hypersensitivity reaction.

4. Backgrounds
The Arthus reaction was discovered by Nicolas Maurice Arthus in 1903.
Arthus subcutaneously injected 5 cc. of horse serum into rabbits per 6 d.
• After the third injection, the slight infiltration was observed at the injection
site, persisting 2 or 3 d.
• After the fourth injection, he noted that a local oedematous reaction
occurred and the absorption of serum became slow.
• After the fifth injection, the infiltration became more severe, and
edematous did not disappear until after 5 or 6 d.
• After the sixth injection a white (not containing pus and absolutely sterile),
solid, compact and thick mass was produced in the subcutaneous cellular
tissue, lasting for several weeks.
• After the seventh injection the skin became rapidly red, then blanched and
dried, and even leading to a gangrenous plaque.
Background

5. Background
• The cutaneous inflammation is caused by a local vasculitis of the
small blood vessels of the skin.
• Vasculitis follows the formation of antigen-antibody complexes in the
region of the vessel walls, their binding to cells with Fc receptors, and
the subsequent activation of a variety of mediators of inflammation.

6. • The antigen will diffuse into the walls of local
blood vessels.
• The immune complexes which are comprised of
antigen, antibody, and complement in vessels
precipitating close to the injection site.
• The C3a, C4a, and C5a complements are activated
by the immune complexes.
• The activation of FcγRIII (Binding immune
complexes) on the localized mast-cells induces
their degranulation with an increase in local
vascular permeability.
• C3a, C5a, and C5b67 attract large numbers of
neutrophils to immune-complexes followed by
lytic enzymes release, which can lead to the injury
of vessel walls with the development of
hemorrhage, edema, thrombi, local ischemia, and
necrosis.
http://www.sivabio.50webs.com/hyper.htm

7. https://healthjade.net/arthus-reaction

8. Arthus Reaction
• The series actions can lead to localized tissue and vascular damage,
which are characterized by redness, swelling, pain, erythema, central
blanching, induration, petechiae, and occasionally by tissue necrosis.
• These signs and symptoms usually begin 2–12 h after exposure to the
antigen, develop gradually in the next few hours and most of them
resolve within one week without sequelae.

9. • Active Arthus reactions reach peak intensity between 4 and 10 hours. If sufficient
antigen and antibody are available, there is pronounced hemorrhage and edema
in the site of the reaction, followed by necrosis 8 to 24 hours after injection.
• The most common clinical manifestations of Arthus reaction are local tissue
hardening, accompanied by obvious redness, swelling, and pain, diameter less
than 5.0 cm at or around the site following the injection in mild cases, but in
some severe cases the diameter of the redness or swelling can spread to the
entire upper arm or extend to the injected upper arm from shoulder to elbow.
• Those clinical manifestations usually can persist for one week, or even persisting
for few months, without scar left after healing.
• The mild necrosis at the injection site, sclerosis in the deep tissue, and even
severe necrosis and ulceration in local tissues, skin, and muscles can be found in
severe cases.
Baozhen Peng, Mingwei Wei, Feng-Cai Zhu & Jing-Xin Li (2019) The vaccines-associated
Arthus reaction, Human Vaccines & Immunotherapeutics, 15:11, 2769-2777
Arthus Reaction

10. • https://www.flickr.com/photos/27488107@N03/2563304368
• https://www.jem-journal.com/article/S0736-4679(18)31240-
X/fulltext
• https://www.youtube.com/watch?v=GZyvu9l04LU

11. Histopathologic studies
• PMNs rapidly marginate, binding to the
walls of small blood vessels, penetrate
the walls, and accumulate in the
surrounding tissue.
• Intravascular clumping of platelets also
occurs.
• The PMNs undergo leukocytoclasis, the
walls of the blood vessels become
swollen, and the endothelial cells are
damaged.
• As the reaction progresses, hemorrhage
from the damaged cutaneous vessels
may become prominent.
• Immunofluorescent studies have shown
that the earliest event is the deposition
of antigen-antibody complexes and
complement in and around blood vessel
walls.
M. M. Frank and C. G. Hester, “Immune complex–mediated diseases,” in Middleton’s Allergy Principles and Practice, 9th edition, 2019.

12. Serum Sickness

13. • Serum sickness is a systemic, immune complex–mediated
hypersensitivity vasculitis classically attributed to the therapeutic
administration of foreign serum proteins or other medications.
Anna Nowak-Węgrzyn, Scott H. Sicherer “Serum sickness,” in Nelson Textbook
of Pediatrics, Kliegman, Ed., Elsevier, Amsterdam, Netherlands, 21st edition
Definition

14. Background
• Serum sickness was first described in 1905 by two pediatricians von
Pirquet and Schick when they introduced a horse serum derived
antitoxin against diphtheria and scarlet fever. They observed a
reaction to the antitoxin in the form of fever, skin eruption, joint
involvement, and lymphadenopathy.
• Serum sickness is a type III hypersensitivity reaction mediated by
immune complex accumulation followed by complement activation,
small vessel vasculitis, and tissue inflammation.
Clin Rheumatol (2018) 37:1389–1394

15. Serum Sickness
• The most common cause of serum sickness today is hypersensitivity
reaction to drugs.
• Generally, serum sickness occurs 1 to 3 weeks after the start of
administration of the medication, although it can occur within 12 to 36
hours in individuals thought to have been sensitized during a previous
exposure.
• Medications frequently implicated in drug-induced serum sickness
include penicillin, sulfonamides, hydantoins, phenylbutazone, and
thiazides, as well as cefaclor in children.
• Some monoclonal antibodies, blood products, and even allergens
used in immunotherapy are also capable of producing serum
sickness.
M. M. Frank and C. G. Hester, “Immune complex–mediated diseases,” in
Middleton’s Allergy Principles and Practice, 9th edition, 2019.

16. Proteins and Medications That Cause Serum Sickness
Proteins From Other Species
• Antibotulinum globulin
• Antithymocyte globulin
• Antitetanus toxoid
• Antivenin (Crotalidae)
polyvalent (horse serum
based)
• Crotalidae polyvalent
immune Fab (ovine serum
based)
• Antirabies globulin Anna Nowak-Węgrzyn, Scott H. Sicherer “Serum sickness,” in Nelson Textbook
of Pediatrics, Kliegman, Ed., Elsevier, Amsterdam, Netherlands, 21st edition
• Infliximab
• Rituximab
• Etanercept
• Anti-HIV antibodies ([PE]HRG214)
• Hymenoptera stings
• Streptokinase
• H1N1 influenza vaccine

17. Drugs : Antibiotics
• Cefaclor
• Penicillins
• Trimethoprim sulfate
• Minocycline
• Meropenem
Anna Nowak-Węgrzyn, Scott H. Sicherer “Serum sickness,” in Nelson Textbook
of Pediatrics, Kliegman, Ed., Elsevier, Amsterdam, Netherlands, 21st edition
Proteins and Medications That Cause Serum Sickness

18. Drugs : Neurologic
• Bupropion
• Carbamazepine
• Phenytoin
• Sulfonamides
• Barbiturates
Anna Nowak-Węgrzyn, Scott H. Sicherer “Serum sickness,” in Nelson Textbook
of Pediatrics, Kliegman, Ed., Elsevier, Amsterdam, Netherlands, 21st edition
Proteins and Medications That Cause Serum Sickness

19. Etiology
• Immune complexes involving heterologous (animal) serum proteins
and complement activation are important pathogenic mechanisms in
serum sickness.
• Rabbit-generated ATGs, which target human T cells, continue to be
widely used as immunosuppressive agents during treatment of kidney
allograft recipients; serum sickness is associated with a late graft loss
in kidney transplant recipients.

20. Pathogenesis
• Serum sickness is a classic example of a type III hypersensitivity
reaction caused by antigen-antibody complexes.
• As free antigen concentration falls and antibody production increases
over days, antigen-antibody complexes of various sizes develop in a
manner analogous to a precipitin curve.
• Small complexes usually circulate harmlessly.
• Large complexes are cleared by the reticuloendothelial system.
• Intermediate-sized complexes that develop at the point of slight
antigen excess may deposit in blood vessel walls and tissues.

21. • The immune microprecipitates induce vascular (leukocytoclastic
vasculitis with immune complex deposition) and tissue damage
through activation of complement and granulocytes.
• Complement activation (C3a, C5a) promotes chemotaxis and
adherence of neutrophils to the site of immune complex deposition.
• The processes of immune complex deposition and of neutrophil
accumulation may be facilitated by increased vascular permeability,
because of the release of vasoactive amines from tissue mast cells.
• Mast cells may be activated by binding of antigen to IgE or through
contact with anaphylatoxins (C3a).
Pathogenesis

26. Clinical Manifestations
• The symptoms of serum sickness generally begin 7-12 days after injection
of the foreign material, but may appear as late as 3 wk afterward.
• A few days before the onset of generalized symptoms, the site of injection
may become edematous and erythematous.
• Symptoms usually include fever, malaise, and rashes.
• Urticaria and morbilliform rashes are the predominant types of skin
eruptions.
• It began as a thin, serpiginous band of erythema along the sides of the
hands, fingers, feet, and toes at the junction of the palmar or plantar skin
with the skin of the dorsolateral surface.

27. • In most patients the band of erythema was replaced by petechiae or
purpura, presumably because of low platelet counts or local damage
to small blood vessels
• Additional symptoms include edema, myalgia, lymphadenopathy,
symmetric arthralgia or arthritis involving multiple joints, and
gastrointestinal complaints, including pain, nausea, diarrhea, and
melena.
• Symptoms typically resolve within 2 wk of removal of the offending
agent, although in unusual cases, symptoms can persist for as long as
2-3 mo.
Clinical Manifestations

28. LAELEY et al, “serum sickness in human beings”, The New England Journal of Medicine. 2010

29. https://www.pinterest.com/pin/82331499418000270

30. Diagnosis
• Characteristic pattern of acute or subacute onset of a rash, fever, and
severe arthralgia and myalgia disproportionate to the degree of
swelling.

31. Symptoms triad
1. Fever
2. Rash
3. Joint involvement
(arthralgia and arthritis)
• Usually occurring 7–14 days
(occasionally as late as three
weeks) after exposure to the
offending agent.
Saja alhawal, Manar Aldarwish, Zainab Almoosa, "Serum Sickness
following Tetanus Toxoid Injection", Case Reports in Pediatrics, vol. 2021
Less common symptoms
• Lymphadenopathy
• Nonspecific headache
• Gastrointestinal complaints
• Blurred vision
• Myalgia

32. Differential Diagnosis
• Viral illnesses with exanthems
• Hypersensitivity vasculitis
• Kawasaki disease
• Acute rheumatic fever
• Acute meningococcal or gonococcal infection
• Endocarditis
• Systemic-onset juvenile idiopathic arthritis (Still disease)
• Lyme disease
• Hepatitis
• Other types of drug reactions

33. Laboratory tests
• There is no definitive diagnostic test for serum sickness.
• CBC : Leucocytosis, Thrombocytopenia is often present.
• Erythrocyte sedimentation rate (ESR) / C-reactive protein
: usually elevated
• Urinalysis
• Proteinuria
• Hemoglobinuria
• Microscopic hematuria
• BUN, Cr
• LFT

34. • Complement studies
• CH50
• C3
• C4
• Serum complement levels (C3 and C4) are generally decreased and
reach a nadir at about day 10.
• Circulating immune complex-C1q (CIC-C1q) test
Laboratory tests

35. • Patients who developed
serum sickness developed
high levels of circulating
immune complexes, as
measured by the 125I-C1q
binding assay and reached
a peak at day 10 ± 1,
coincident with peak
clinical disease activity.
M. M. Frank and C. G. Hester, “Immune complex–mediated diseases,” in
Middleton’s Allergy Principles and Practice, 9th edition, 2019.

36. • Patients with serum
sickness also had
pronounced decreases in
serum C3 and C4 levels
coincident with disease
onset.
• The lowest levels of C3 and
C4 were closely correlated
with the peak immune
complex values, and when
circulating immune
complexes were cleared
they returned to baseline.
M. M. Frank and C. G. Hester, “Immune complex–mediated diseases,” in
Middleton’s Allergy Principles and Practice, 9th edition, 2019.

37. Skin biopsies
• Skin biopsies are not usually necessary for confirming the diagnosis
because the findings are variable and not specific for serum sickness.
• Direct immunofluorescence studies of skin lesions often reveal
immune deposits of IgM, IgA, IgE, or C3.

38. • Lesional skin biopsy
specimens were obtained
during clinical serum sickness,
deposits of IgM and C3 were
found in the blood vessel
walls.
• IgE and IgA deposits were also
frequently present.
• These data clearly support
the concept that serum
sickness in humans, as in the
rabbit model, is an immune
complex–mediated disease.
M. M. Frank and C. G. Hester, “Immune complex–mediated diseases,” in
Middleton’s Allergy Principles and Practice, 9th edition, 2019.

39. Complications
• Carditis
• Glomerulonephritis
• Guillain-Barré syndrome
• Peripheral neuritis

40. Treatment
• There are no evidence-based guidelines or controlled trials on which
to base therapy recommendations.
• Primarily supportive
• Discontinuation of the offending agent
• Antihistamines for pruritus
• Nonsteroidal antiinflammatory drugs and analgesics for low-grade
fever and mild arthralgia

41. When the symptoms are especially severe
• Fever > 38.5°C
• Severe arthralgia or myalgia
• Renal dysfunction
>> Systemic corticosteroids can be used
>> Prednisolone (1-2 mg/kg/day; maximum 60 mg/day) for 1-2 wk is
usually sufficient.
Treatment

42. • Once the offending agent is discontinued and depending on its half-
life, symptoms resolve spontaneously in 1-4 wk.
• Symptoms lasting longer suggest another diagnosis.
Treatment

43. Prevention
• The primary mode of prevention of serum sickness is to seek
alternative therapies.
• Serum sickness is not prevented by desensitization or by
pretreatment with corticosteroids.

44. Serum sickness-like reaction

45. Serum sickness-like reaction
• Serum sickness-like reaction (SSLR) is an immunological condition
characterised by skin rash and arthralgia, with or without fever
• It is seen more often in children.
• Prevalence is unknown.
• SSLR is mainly triggered by drugs, mostly β-lactam antibiotics.
• Vaccines and infectious agents have also been implicated in SSLR
development.
• A great variety of other drugs have been reported to trigger SSLR:
sulfonamide drugs, anticancer agents, anticonvulsants, anti-inflammatory
agents, griseofulvin, metronidazole, bupropion, and more recently,
biological agents such as rituximab, infliximab, and efalizumab, among
others.
Blanca R. Del Pozzo-Magaña,1 Alejandro Lazo-Langner, “SERUM SICKNESS-LIKE REACTION
IN CHILDREN: REVIEW OF THE LITERATURE”, EMJ Dermatol. 2019;7[1]:106-111.

46. • SSLR is usually unrecognised or easily mistaken by other cutaneous
entities such as urticaria, urticaria multiforme, erythema multiforme,
infectious rashes, or other drug reactions.
• SSLR is usually less severe with low grade fever or no fever
• Other difference is that the causing agents (e.g., antibiotics,
infections, and antiepileptic medications), and the underlying
pathogenesis is not fully understood as serum sickness.
Serum sickness-like reaction

47. Pathophysiology
• SSLR is not associated with antigen-antibody complex formation and
the blood levels of complement are usually normal.
• Some theories consider the possibility that drugs, or their
metabolites, may act similarly to haptens that bind plasma proteins
and subsequently induce an abnormal immunologic response.
• Other studies have suggested that drug metabolites by themselves
have a direct toxic effect on the lymphocyte affected patients.
• More recently, Zhang et al. reported that in children, antibiotics such
as Cefaclor may increase the intestinal mucosal permeability by
damaging its integrity, which leads to the passing of antigens to the
blood circulation favouring the development of SSLR.

48. Clinical Features
• Initial reports of patients with SSLR described presentation of skin rash associated
with joint inflammation or arthralgia with or without a fever.
• The development of skin rash and arthralgia in children with SSLR can present
several days after exposure of the trigger, ranging from a couple of days up to
several weeks.
• In the case of SSLR induced by antibiotics, the clinical features typically appear
after the course has been completed (approximately 7–10 days).
• The morphology of the skin rashes reported in the literature varies widely
including morbilliform rash, urticarial and annular plaques with central clearing,
or erythema multiformelike lesions (erythematous annular converging plaques
with purplish/dusky centre)
• Unlike acute urticaria, skin lesions in SSLR are not migratory, but are fixed.
• Once skin lesions develop, they stay in the same area until they resolve, and
occasionally leave a bruise-like postinflammatory hyperpigmentation behind that
may last for several days.

49. • Fever in children with SSLR may not be present.
• Concomitant fever ranges from 30% to 75% in these patients.
Likewise, paediatric SSLR seldom presents with lymphadenopathy or
systemic involvement.
Clinical Features

50. Skin
• The skin lesions usually start as small erythematous papules or plaques on
the trunk and then enlarge and progressively spread to the rest of the
body.
• With regard to facial impact, periorbital or lip swelling may present
resembling angioedema; however, these patients do not develop tongue
swelling or respiratory compromise as seen in other allergic reactions.
• Unlike classical urticaria, itchiness in SSLR is mild or nonexistent; however,
skin soreness or burning sensation may present instead.
• Other health professionals often misdiagnose SSLR with erythema
multiforme because skin lesions in SSLR may present with a violaceous
centre that simulate target lesions. Unlike erythema multiforme, SSLR
lesions do not have three rings (typical target lesion), do not blister, and
have no involvement of mucous membranes.

51. Joint
• The presence of joint involvement, characterised by joint swelling and
arthralgia, is also necessary to make the diagnosis of SSLR.
• Joints are usually affected bilaterally but may present on only one
side. Joints in the hands and feet are the most commonly involved,
followed by knees, and then elbows.
• Purple discolouration and edema may also be seen on the skin
overlaying the joints.
• Children : Parents usually report that children with SSLR avoid walking
or move abnormally.

52. Erythematous papules and annular lesions, some of them with a polycyclic
arrangement, central clearing and purplish discolouration
EMJ Dermatol. 2019;7[1]:106-111.

53. • Painful inflammation of hands and feet
• Notice erythema and edema overlaying the joints
EMJ Dermatol. 2019;7[1]:106-111.

54. Target lesion

55. INVESTIGATIONS
• The diagnosis of SSLR is primarily based on history and clinical
features.
• Laboratory profile is usually nonspecific.

56. Laboratory tests
• Low levels of complement (C3, C4, and CH50)
• High erythrocyte sedimentation rate
• Leukocytosis
• Circulating immune complexes
• Proteinuria
• Haematuria
• Abnormal liver function tests
• Elevated creatinine
• Skin testing and radioallergosorbent test were usually negative because
SSLR does not appear to be an IgE-mediated reaction.

57. Differential diagnoses
• Rheumatic fever
• Urticarial vasculitis
• Systemic lupus erythematosus
• Drug induced lupus
• Still’s disease
• Henoch-Schönlein purpura

58. Histopathology
• Perivascular and mid-dermal inflammatory infiltrate with admixed
neutrophils, eosinophils, and lymphocytes, usually without
leukocytoclastic vasculitis.

59. Succaria, Farah MD; Sahni, Debjani MD; Wolpowitz, Deon MD, PhD
Rituximab-Induced Serum Sickness–Like Reaction, The American Journal
of Dermatopathology: April 2016 - Volume 38 - Issue 4 - p 321-322

60. EMJ Dermatol. 2019;7[1]:106-111.

61. Treatment
• Self-limiting condition with no sequelae
• Complete resolution of the symptoms can take several days and even
weeks.
• Immediate withdrawal of the causal drug
• Antihistamines and nonsteroidal anti-inflammatory drugs are used to
control joint pain and itchiness.
• When symptoms are more severe and prolonged, the use of a short
course of oral corticosteroids such as prednisone (0.5–1.0 mg/kg/d
for 3–5 days) or intravenous methylprednisolone (10.0 mg/kg/d for 3
days) is recommended.

62. Prognosis
• The prognosis of children with SSLR is typically favourable because
they have a mean recovery time of 5–7 days with no evidence of
sequalae, even if they do not receive any treatment.
• Avoidance of the trigger drug is highly recommended to prevent
severe recurrences.
• Classical desensitisation does not appear to have a role in patients
with SSLR because protocols for desensitisation were designed to
treat Type 1 (IgE-mediated) mast cell reactions.

63. QUIZ
The antibody subclass responsible for the pathologic reaction in the
direct Arthus reaction is :
a. Immunoglobulin G (IgG).
b. IgM
c. IgA
d. IgD
e. IgE

64. QUIZ
The most common clinical sign of serum sickness is :
a. Necrosis at the point of injection
b. Lymphadenopathy
c. Urticaria.
d. Nausea and vomiting
e. Arthralgia