• adverse side effects;
  • biological agents;
  • fusion proteins;
  • monoclonal antibodies;
  • subclassification


  1. Top of page
  2. Abstract
  3. Biological agents
  4. General principle of adverse effects of biological agents
  5. Conclusion
  6. Acknowledgments
  7. References

Biological agents-like cytokines, monoclonal antibodies and fusion proteins are widely used in anti-inflammatory and tumour therapy. They are highly efficient in certain diseases, but can cause a great variety of adverse side-effects. Based on the peculiar features of biological agents a new classification of these adverse side-effects of biological agents is proposed – related but clearly distinct from the classification of side-effects observed with chemicals and drugs. This classification differentiates five distinct types, namely clinical reactions because of high cytokine levels (type α), hypersensitivity because of an immune reaction against the biological agent (β), immune or cytokine imbalance syndromes (γ), symptoms because of cross-reactivity (δ) and symptoms not directly affecting the immune system (ɛ). This classification could help to better deal with the clinical features of these side-effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine.

During the last decade many new biological immune modulators (‘biological agents’) entered the market as new therapeutic principles. They comprise proteins such as cytokines, monoclonal antibodies and fusion proteins (solubilized receptors). Many of these biological agents have proven to be valuable tools in various inflammatory diseases and tumours as their direct and focused effect makes them superior to immunosuppressive or cytotoxic drugs, whose use is often limited by severe generalized and unwanted side-effects. The progress in this field was based on a better understanding of the immunological basis of many diseases, the identification of relevant molecules in inflammation as well as on tumour cells and the application of biotechnological techniques, which allowed to produce recombinant proteins like cytokines as well as humanized antibodies at a large-scale (1).

The wide use of biological agents in modern medicine is a challenge for doctors, as it is an example of how fast new therapeutical principles based on novel knowledge and modern techniques can enter clinical practice, and that constant learning is required. Their use often requires a special knowledge and familiarity with the disease to be treated. Moreover, not only the function of these compounds has to be understood, but also the underlying immunology – which is often rather complex. Last but not least, these biological agents are expensive medicines and force the treating doctors to consider economic aspects as well.

In addition, some concern regards the side-effects of these biological agents, which are proteins used like drugs (2). Adverse side-effects to drugs are clinically very heterogeneous. One approach was to subclassify them according to their action: so-called type A reactions correspond to the pharmacological activity of the drug, and are thus predictable (3; Table 1). About 16% of side-effects after drug treatment are type B reactions (4), which are not related to the pharmacological activity of the drug and are nonpredictable. The majority of type B reactions are immune-mediated side-effects like hypersensitivity reactions. Clinically, these immune-mediated side-effects are very heterogeneous and can be subdivided according to different pathomechanisms (5, 6).

Table 1.   Classification of adverse drug reactions
  1. Source: Naisbitt et al. (3).

  2. *Type C and D are rarely used.

Type A (augmented) reactions: predicted from the known pharmacology of the drug. These reactions are dose-dependent: examples are bleeding with anticoagulants
Type B (bizarre) reactions: reactions are not predicted from the known pharmacology of the drug. They appear (but actually are not) relatively dose-independent, as very small doses might already elicit symptoms. They include immune-mediated side-effects like maculopapular exanthema, but also other hypersensitivity reactions, like aspirin-induced asthma
Type C (chemical) reactions*: which are related to the chemical structure and its metabolism, e.g. paracetamol hepatotoxicity
Type D (delayed) reactions*: which appear after many years of treatment, e.g. bladder carcinoma after treatment with cyclophosphamide
Type E (end of treatment) reactions*: occur after drug withdrawal, e.g. seizures after stopping phenytoin

Biological agents differ from most drugs as they are not small chemical compounds (xenobiotics) but are proteins produced in a way to make them as similar to human proteins as possible (Table 2). They are not metabolised like drugs but are processed like other proteins, and therefore need to be applied parentally, to avoid digestion in the GI tract. Quite a few of them are actually naturally occurring proteins (e.g. cytokines) or humanized antibodies able to neutralize natural proteins. Thus, adverse reactions to biological agents might differ from those elicited by drugs.

Table 2.   Biological agents and drugs: important differences related to adverse side-effects
Biological agentDrug
Structurally similar to autologous proteinsSynthesized chemicals (xenobiotics)
Are digested and processed, but not metabolizedMetabolized, reactive intermediates with potential immunogenicity (haptens)
Parental application requiredOral or parental
Immune-mediated effects are inherent in their activity, but hypersensitivities are rare and mainly due to immunoglobulins (IgE, IgG)Immune-mediated side-effects are unexpected, differ from the normal action of the drug and are often T cell-mediated
 Drug interactions, organ toxicity

The enormous opportunity seen in these molecules and their success in many diseases lead to the generation of many dozens of biological agents in the last years and many more will follow. As these are quite heterogeneous molecules directed to many different structures, it is impossible to cover all adverse side-effects in detail. The clear difference of xenobiotics and biological agents with regard to mode of action, chemistry, metabolism and immunogenicity suggest that a somewhat different approach to their side-effects is needed (Table 2). Here, some general aspects of these adverse side-effects are outlined and a new classification for adverse effects of biological agents, which is based on mechanistic considerations, is proposed. This subclassification might help to better understand and treat the patient who experiences them. Moreover, it might provide some help to avoid them in the future by defining risk factors and give directions for future research in this novel area.

Biological agents

  1. Top of page
  2. Abstract
  3. Biological agents
  4. General principle of adverse effects of biological agents
  5. Conclusion
  6. Acknowledgments
  7. References

The biological agents on the market or in clinical trials are mainly tools to affect inflammatory processes and malignancies. They can be subdivided into the following classes (Table 3).

Table 3.   Types of biologicals (examples)
  1. *Not a fusion protein, but acting in a similar way.

  2. EGFR, epidermal growth factor receptor; IFN, interferon; IL, interleukin; TNF, tumour necrosis factor; IgE, immunoglobulin E.

 IFN-α, IFN-β, IL-2, etc.
 To soluble proteins like cytokines: anti-TNF-α (infliximab or adalimumab), anti-IL-2 (daclizumab)
 To cell surface molecules: anti-CD20 (rituximab); anti-IL-2 receptor (basiliximab), anti-LFA-1 (efalizumab)
 To IgE (omalizumab)
 To tumour antigens (e.g. EGFR, cetuximab, anti-HER2, trastuzumab)
Fusion proteins (soluble receptors for cytokines or soluble cellular ligands)
 TNF-αRII (etanercept), a soluble TNF-α receptor
 CTLA4-Ig (abatacept) blocking CD28–CD80/CD86 interaction
 IL-1 receptor antagonist (anakinra)*


Cytokines, like for example interferon (IFN)-α, IFN-β, interleukin (IL)-2, etc. are widely used biological agents. Some of these cytokines have been modified to prolong their in vivo half-life (containing polyethylene glycol, which reduces degradation, e.g. peg-IFNs). Their amino acid sequence is identical to human proteins but their glycosylation might differ.


Xenogeneic antibodies (e.g. from horse) were already in use at the beginning of the last century and were ominous for causing severe hypersensitivity reactions like anaphylaxis and serum sickness after repeated injections. The development of monoclonal antibody by in vitro technology lead to a revolution in this field as it allowed a simplified generation of antibodies directed against a specific surface molecule, a soluble molecule, a cytokine, etc. (7). While the original monoclonal antibodies used for therapeutic purposes were of mouse origin, the progress of molecular biological techniques allowed to modify these and thus the majority of antibodies in use are in the meantime chimaeric, humanized or fully human antibodies. The chimaeric antibodies like infliximab are characterized by ‘ximab’, while humanized antibodies like daclizumab or omalizumab carry a ‘zumab’ and fully human antibodies like adalimumab a ‘mumab’.

  • Anticytokines antibodies consist of antibodies, directed to cytokines, like for example anti-IL-5 or anti-TNF-α antibodies.
  • Antibodies blocking cell-bound molecules like adhesion molecules like, e.g. efalizumab, an anti-LFA-1 antibody, or an anti-IL-2 receptor antibody (basilximab or daclizumab).
  • Antibodies with the ability to deplete or inactivate certain cells: examples would be anti-CD20 antibodies (rituximab) or some antibodies directed against tumour antigens. Some activity might be due to downregulating the target structure on the cell, thus inactivating it (8). Others might even transiently activate the target cell (anti-CD3 antibodies, muromonab).

Fusion proteins

Natural receptors have often a very high affinity for their ligands and are thus as potent as high affinity antibodies. To solubilize and increase the half-life of these normally cell-bound molecules, they are fused with the Fc part (CH2, CH3) of human immunoglobulin (Ig)G1. A special case is the naturally occurring soluble IL-1 receptor antagonists (anakinra; 9).

Soluble cytokine receptors are named using the ending -cept, like in etanercept [the p55, soluble tumour necrosis factor-α receptor II (TNF-αRII)]. Soluble cell ligands interfere with the cell-to-cell communication. To block this interaction either antibodies to the ligand or a soluble form of the ligand itself can be used to interfere. Thereby co-stimulation of cells or their migration can be blocked. An example would be the interaction of CD28 or CTLA4 (on T cells) with CD80/CD86 on antigen-presenting cells (Table 3). This interaction can be blocked by CTLA4-Ig (abatacept), which is a fusion protein between CTLA4 (expressed on activated T cells) and IgG1-Fc: CTLA4 has a 10-fold higher affinity for CD80/CD86 than CD28 and is thus able to block the interaction of CD80/CD86 with CD28 on T cells (1).

General principle of adverse effects of biological agents

  1. Top of page
  2. Abstract
  3. Biological agents
  4. General principle of adverse effects of biological agents
  5. Conclusion
  6. Acknowledgments
  7. References

In a recent review of adverse reactions of biological agents, Lee and Kavanaugh differentiated between target-related or agent-related adverse side-effects (10). Indeed, target-related side-effects are common with biological agents, as e.g. a biological agent may alter the composition and functional integrity of the normal immune response, and thereby predispose the patient to certain side-effects, while the agent itself is rather ‘harmless’. Consequently, to understand the great variety of adverse side-effects of biological agents, one has to be aware not only of the activity of the biological agent for the particular disease, but also its influence on the normal immune balance.

  • Many biological agents have a well defined range of physiological actions (11), some of which may already explain some adverse ‘side’ effects. For example, it is expectable that high concentrations of a proinflammatory cytokine like IFN-α can cause symptoms which are also observed during an immune reaction with high IFN-α levels (e.g. flu-like syndrome).
  • Biological agents often affect T and B cells or their products, as well as the different effector cells leading to various forms of inflammation. Side-effects of biological agents affecting the immune response are to a certain degree predictable and consequently cannot be classified as unpredictable ‘type B’ reactions (3). In the same line, can a hypersensitivity reaction to an injected protein which contains parts of a foreign protein, be classified as an unpredictable type B reaction, or is not it actually a predictable reaction, even if it does not occur in each individual?
  • Immunological reactions during therapy with small molecular compounds (drugs) are mainly classified as hypersensitivity reactions (5, 6). Hypersensitivity reactions are immune responses against the substance applied, which surely is not explaining many of the side-effects seen with these biological agents.

The many distinct functions of these biological agents make it impossible to subclassify their adverse side-effects based on clinical symptoms. More appropriate is a subclassification based on mechanism of action and structure, as illustrated in Fig. 1. To distinguish it from the classification of side-effects to chemicals/drugs (Table 1), the Greek alphabet is used for the five types (type α, β, γ, δ and ɛ, Fig. 1).


Figure 1.  Type of adverse effects of biological agents.

Download figure to PowerPoint

  • Type α (high cytokine and cytokine release syndrome): Side-effects might be connected to the systematic application of cytokines in relatively high doses or to high concentrations of cytokines released into the circulation (12).
  • Type β (hypersensitivity): The second group of reactions can be termed as ‘hypersensitivity’. Thereby basically three forms of allergies can be differentiated: IgE-, IgG- and T cell-mediated reactions.
  • Type γ [immune (cytokine) imbalance syndromes]: A major group of side-effects have immunological features, but cannot be explained by high cytokine levels or typical hypersensitivity reactions. As illustrated in Fig. 1, these reactions can be further subdivided in, impaired functions, and unmasking or causing an immune imbalance leading to autoimmune, autoinflammatory or allergic reactions.
  • Type δ (cross-reactivity): Another cause for side-effects might be that antibodies generated to an antigen expressed on tumour cells might also cross-react with normal cells, which express this structure as well, albeit to a lower degree (13).
  • Type ɛ (nonimmunological side-effects): Quite a few of the biological agents may elicit symptoms not directly related to the immune system, sometimes revealing unknown functions of the biological agents given or targeted.

This classification considers the well accepted classification of side-effects to drugs (Table 1), as the first two types are similar (type A/α are both dose-dependent and related to the function of the drug or biological agent, type B/β comprises hypersensitivity). One has, however, to emphasize that it is not a clinical classification based on similarity of symptoms, but an attempt to classify the side-effects according to mechanism.

Type α– high cytokine and cytokine release syndrome

Most cytokines (as well as chemokines) are produced locally and have a predominant local activity: their action is directed to the neighbouring cell (paracrine) or has even an autocrine function (1). Some cytokines like TNF-α or IL-5 have also a systemic activity, which comes into play if the immune reaction is strong and a systemic reaction of the immune system required (1). Thus, for most cytokines only the local concentration is relatively high, while the systemic concentrations are rather low and affect often bone marrow-derived progenitor cells. If the cytokine is applied therapeutically, the situation is inverse: comparatively high systemic concentrations are applied to achieve a sufficiently high concentration locally. Such high systemic concentrations can cause sometimes severe, not tolerable side-effects, limiting the use of cytokines (fever, myalgia, headache,…).

Alternatively, one of the first monoclonal antibodies on the market was directed against CD3 (muromunab), which is the signal transmitting complex associated with the specific T-cell receptor for antigen. Cross-linking these T-cell receptor-associated molecules leads to activation of T cells and release of different cytokines into the circulation with generalized symptoms like flash, arthralgia, capillary leak syndrome with pulmonary oedema, encephalopathy, aseptic meningitis, pyrexia, gastrointestinal (GI) symptoms like severe vomiting or diarrhoea, called cytokine release syndrome (12).

Type β– hypersensitivity reactions to biological agents

Different factors determine the immunogenicity of the biological agent, and the type of clinical symptoms because of real hypersensitivity.

Degree of humanization.  Allergic reactions to biological agents are directed against the protein itself. The frequency of such reactions depends on the degree of humanization of the applied protein, which is often an antibody. The allergic immune response can be directed to the constant or the variable part. While, e.g. mouse antibodies (almost not used any more) as well as chimaeric antibodies have at least some xenogenic determinants on its constant part, which can elicit quite rapidly an immune response, humanized or fully human antibodies have a low immunogenicity as immunological tolerance exists to the constant part of the immunoglobulin. Nevertheless, the antigen-binding site of the monoclonal antibody can still elicit an immune response (anti-idiotypic; 14).

Cofactors.  Another important aspect for the immunogenicity of a biological agent is its content of adjuvants. For the cases of pure red cell aplasia observed in 2000 and 2001 outside the USA and related to erythropoietin injections, differences in rubber stoppers used for the vials containing the erythropoietin is thought to have contributed to the immunogenicity, as certain stoppers allowed the diffusion of some organic compounds with adjuvant activity inside the vial, which was enough to cause immunogenicity of the erythropoietin (15). The way of application (s.c. vs i.v.), the IgG isotype of the biological agent, and in particular the amount of immunosuppressive co-treatment may also have an influence. For example, the sensitisation and antibody formation to infliximab, a chimaeric anti-TNF-α antibody, can be reduced by the co-medication with methotrexat (16, 17).

Type of allergic reaction.  The IgE-mediated reactions can cause a local wheal and flare reaction at the injection site, if applied s.c. but may also cause urticaria and anaphylaxis. Such a reaction appears rather rapidly, which means within 20 min after the injections. One has to differentiate it from an unspecific irritation induced by the solvent, which might also lead to local redness and a typical wheal. Irritative responses are often diminished at subsequent applications – but this is not a strict criterion to differentiate it from real allergy, as tolerance might develop in IgE-mediated reactions. The majority of these allergic reactions are mild, but severe IgE-mediated anaphylaxis has also been described (18).

Acute infusion reactions are mostly not IgE-mediated. They occur in 3–5% of patients treated with chimaeric antibodies, often already during the infusion and can be reduced by slowing the infusion rate (19). Their pathomechanism is unclear, but may be related to activation of cells (by Fc-IgG receptors) or of the complement system via immune complexes, as they appear more frequently when antibodies are detectable (16, 19, 20). Symptoms are chills, nausea, dyspnoea, headache and fever (19).

Delayed reactions appear >6 h after the application. They can be subdivided in immunoglobulin- and T cell-mediated reactions. The normal physiological immune response to a foreign, soluble protein is immunoglobulin-mediated. Thus, the development of IgG antibodies directed to the biological agent is by far the most frequent reaction. Formation of IgG antibodies against the biological agent may occur rather frequently, if the biological agent is immunogenic and if no immunsuppression-like methotrexate accompanies the treatment (16). In a study with infliximab, up to 68% of the treated patients developed antibodies to this chimaeric antibody (16, 17). These antibodies are not necessarily associated with symptoms. The most frequent effect is inactivation of the biological agent. The half-time of an injected cytokine or antibody is reduced and the patient needs more of the biological agent or an alternative to achieve the same effect. However, if the substance injected is unique for a certain function, the inactivation may have severe consequences. This has been shown for antierythropoietin antibodies, which lead to pure red cell aplasia (15).

Formation of antibodies to the biological agent may also result in activation of the complement cascade via immune complex formation as well as by Fc-IgG receptor-mediated activation of the neutrophils and may thus cause immune complex diseases like serum sickness, vasculitis and nephritis. Some symptoms appear after 3–12 days, and are classified as delayed infusion reactions, characterized by myalgia, arthralgia, fever, ‘rash’, pruritus, facial and lip oedema, dysphagia and urticaria (19). Another immunoglobulin-associated side-effect may be thrombocytopenia, if immune complexes are formed that bind to Fc-IgG receptors on thrombocytes, which are then removed from the circulation by the phagocytic system in liver and spleen (20).

In these immunoglobulin-dependent reactions T cells are probably also involved, but mainly as regulators of the humoral immune response. In contrast to hypersensitivity reactions to small molecular weight compounds (chemicals/drugs), where T cell-mediated reactions cause different forms of exanthems or hepatitis, etc. (6), biological agents seem to elicit such reactions quite rarely. However, immunohistological examinations of delayed appearing and persisting injection site reactions to etanercept (soluble TNF-αR) revealed infiltration of T cells (21), suggesting that T-cell reactions themselves may cause clinical symptoms.

If a hypersensitivity reaction is suspected, one can confirm it by skin tests (prick, i.d.) with the biological agent. If specific IgE to the biological agent is present a local wheal and flare reaction might appear; if T cells are involved, induration and vesicle formation can be seen after 24–72 h. Alternatively, enzyme-linked immunosorbent assay (ELISA) detecting newly formed antibodies to the biological agent (human antichimaeric or antimouse-immunoglobulin antibodies, etc.) can confirm the presence of antibodies.

Type γ– immune/cytokine imbalance syndromes

Quite a few side-effects to biological agents cannot be explained by high concentrations or by an immune response directed to the biological agent and are thus not hypersensitivities. Tests to detect hypersensitivities, like skin tests with the biological agent as well as in vitro determinations of antibodies to the substrate are negative. Some side-effects might be explained by the potent and unique activity of the biological agent in certain types of the normal immune response or by the elimination of certain cytokine activity by an injected antibody. Other effects are often not explainable as easily. They may reveal a new or hitherto neglected activity of the biological agent given or eliminated. Thereby, the broader the physiological role of the biological agent, the more heterogeneous effects can be seen. For example, recombinant erythropoietin or omalizumab, an antibody directed against IgE, have a limited pattern of adverse side-effects, as it replaces or reduces a certain effector molecule with a limited function in the immune system. In contrast, essential, broadly active cytokines like IFN-α or TNF-α are associated with a wide variety of quite different side-effects, due to the very broad activity of these cytokines (Table 4; 2, 22–24).

Table 4.   Subclassifying side-effects of IFN-α and anti-TNF-α
 IFN-αAnti-TNF-α (infliximab)
  1. IFN, interferon; TNF, tumour necrosis factor; IgA, immunoglobulin A; SLE, systemic lupus erythematodes; (?), unknown.

Type α: High doseFlu-like symptoms  Myalgia  Arthralgia  Fever
Type β: HypersensitivityLocal and generalized urticaria Local dermatitisLocal and systemic urticaria, erythema, serum sickness Loss of efficiency Acute and delayed infusion reactions, local dermatitis
Type γ: Cytokine or immune imbalance syndromes
 ImmunodeficiencyTuberculosis, listeriosis, other granulomatous infectious diseases
 Autoimmune/autoinflammatory disordersThrombocytopenia, haemolytic anaemia, IgA nephropathy, dermatitis herpetiformis, SLE, vasculitis, thyroid disease, pernicious anaemia sarkoidosis, psoriasis, vitiligoInterstitial pneumopathy, acute fibrosis, systemic sclerosis, SLE, demyelinating diseases, pancytopenia, lichenoid skin reaction, psoriasis
 Atopic–allergicAtopic dermatitis
Type δ: Cross-reactivity– (?)
Type ɛ: Nonimmunological side-effectsNeurological symptoms-like Bell's palsy, hearing loss, depression, dystonia, restless legsHeart insufficiency

Impaired function (immunodeficiency).  Quite a few of the biological agents are actually used in inflammatory disorders or transplantation and one aim of the treatment was to dim the inflammation or immune response to the transplanted organ (14, 25). The best understood and to a certain extent expected adverse side-effect of certain biological agents is impaired function of the immune system resulting in a certain immunodeficiency. Actually, one could classify impaired function also as predictable, type α reactions. However, type A/α reactions are mainly due to a high dose, which may or may not lead to immunodeficiency and therefore impaired function is classified within imbalance syndromes.

Typical examples would be efalizumab, an antibody to LFA-1 (CD11a), the ligand for CD18 on neutrophils and T cells. It inhibits the migration of these cells into the affected tissue (25). While this may be beneficial, for example in psoriasis, it may be contra-productive for the optimal and rapid control of infections. TNF-α is another example. One main obstacle in the use of anti-TNF-α therapy is the danger that an underlying disease like tuberculosis or listeriosis escape the control of the immune response and disseminate, as TNF-α is essential for the control of these intracellular infections by stimulating macrophage function (2, 26).

Unmasking a pre-existing imbalance or causing an imbalance.  The immune system is well balanced, and central and peripheral tolerance mechanism, regulatory T cells, certain cytokines like transforming growth factor (TGF)-β and IL-10, as well as the Th1/Th2 balance are involved (11, 22, 24). A disturbance of this balance can occur by eliminating or injecting certain cytokines, which have an immunoregulatory function. It can result in autoimmunity (e.g. systemic lupus erythematodes) and autoinflammatory responses (e.g. eosinophilic or neutrophilic inflammations without autoantibodies, e.g. psoriasis) – if the immunological tolerance to autoantigens is altered. Or it might lead to the appearance of other immunological reactions, which are normally suppressed, like e.g. an immune response to a harmless exogenous antigen (allergic and atopic disorders). All three patterns have been described for anti-TNF-α, IFN-α, anti-CTLA4 antibodies and others (22, 23, 27–30; Table 4).

Autoimmunity and autoinflammatory disorders.  Tumour necrosis factor-α neutralization leads rather frequently to autoimmune phenomena and rarely even to autoimmune diseases. Antinuclear antibodies can be found in up to 11% of patients treated with etanercept, a soluble TNF-α receptor (31), and in up to 68% in patients treated with infliximab (16, 17). But the development of a clinically lupus is a rather rare event (approximately 0.5%; 2, 29). Also the development of demyelinating diseases have been observed under anti-TNF-α treatment (31) and treatment of patients with multiple sclerosis with lenercept (the soluble, p75 form of the TNF-αRI) had to be stopped, as the disease became more severe (2). The reason for this stimulation of autoimmune reactions by this presumably immunosuppressive treatment is unclear, but deregulated TNF-α production has been associated with autoimmunity (22, 24). Interestingly, the use of an immunostimulatory cytokine like IFN-α treatment may also induce autoimmune and autoinflammatory diseases, as lupus like syndrome, systemic sclerosis, Guillain-Barré syndrome, autoimmune thyroid disease, idiopathic thrombocytopenic purpura, vitiligo and psoriasis have been described (20, 30, 32–35; Table 4). The underlying pathomechanism is not yet understood. It could be due to an immunostimulatory effects of IFN-α leading to the appearance of hidden antigens, the enhanced expression of co-stimulatory molecules or to an enhanced signalling in activated B-cells secreting autoantibodies (36).

Autoinflammatory or allergic diseases may also arise if a shift of the Th1–Th2 balance, which regulate the type of immune response, occurs. Th1 cells booster macrophage function, the production of complement fixing antibodies and cellular immune responses, while Th2 cells enhance the production of IgE/IgG4 and eosinophilic inflammations. Both T cell subsets do also control each other, as e.g. the Th2 cytokine IL-4 downregulates Th1-driven macrophage functions, but boosters IgE responses, while the Th1 cytokine IFN-γ stimulates macrophages but can suppress IgE (1). Biological agents can interfere with this balance, e.g. a Th1-driven autoinflammatory process might be enhanced by IFN-α or be dimmed by reducing the high activity of, e.g. TNF-α. While the suppression of TNF-α may give a rather good result in the control of an autoinflammatory process like rheumatoid arthritis or Crohn's disease, it may uncover an hitherto controlled readiness to generate a Th2 response (28, 37–39).

Atopic/allergic disorders.  The immune response to harmless exogenous antigens is normally suppressed but under certain circumstances these tolerance mechanism fail and atopic/allergic diseases may develop (40). With anti-TNF-α treatments, various skin diseases appeared, and some had the clinical features of an atopic dermatitis. It could reflect a development of a Th2-biased disease due to suppression of TNF-α, whereby it is unknown whether exogenous or autoantigens are driving this reaction (37, 38). Abrogating the suppressive function of activated CTLA4+ T cells, which have immunoregulatory properties, by anti-CTLA4 antibodies (MDX-010) may also lead to skin symptoms like an eosinophilic dermatitis similar to drug hypersensitivity (28).

The immune imbalance syndromes are clinically very heterogeneous, dependent on the effect of eliminating or bolstering a crucial cytokine or function/expansion of a cell. They occur only in a minority, suggesting that either the individual predisposition (e.g. atopy) or an individual co-morbidity may be important in order that the treatment results in a clinical symptom. These immune or cytokine imbalance syndromes are complex diseases and surely need to be better defined for each biological agent, which may reveal interesting, neglected aspects of the target molecule and pave the way to identify individuals at risk.

Type δ– cross-reactivity

Cross-reactivity can be due to expression of the same antigen on different tissue cells or that the antibody reacts with a similar structure. Tumour antigens are often ‘normal’ proteins, which are overexpressed on tumour cells. Antibodies to these antigens may also react with these structures on normal cells. For example, epidermal growth factor receptor (EGFR) is strongly expressed on a variety of carcinomas of different origin and is thought to be partly associated with tumour progression (13). In addition, EGFR plays a major role in the homeostasis of the epidermis and epidermal appendages. Antibodies to these EGFR (e.g. cetuximab) are used in the treatment of various tumours. Interestingly, acneiforme eruptions appear very frequently in the frame of these anti-EGFR treatments – possibly due to cross-reactivity with EGFR on skin cells (13). In addition, it cannot be ruled out that some of the antibodies used do also react with structurally similar proteins – and thus cause unexpected side-effects.

Type ɛ– nonimmunological side-effects

Many molecules, originally detected in the immune system and inflammatory response may also be involved in other physiological functions. Actually, the in vivo use of a biological agent in humans may reveal these ‘new’ functions. Examples are blocking CD40–CD40–ligand interactions (important for immunoglobulin class switch in B cells), where both soluble CD40-Ig or anti CD40L antibodies precipitated the appearance of thrombosis and subsequently the detection of the CD40 and CD40L on thrombocytes (41); or the role of TNF-α in heart failure, where high TNF-α levels were detected, but neutralization of TNF-α lead to aggravation of the disease (42). Also the rather frequent neuropsychiatric adverse effects of IFN-α (acute confusional state, depression), as well as various retinopathies observed during IFN-α treatments may represent such type ɛ reactions (42, 43). Manifestations of such nonimmunological side-effects might actually be quite frequent. Some of these type ɛ reactions may be due to cross-reactivity (type δ reactions), if antibodies are involved. On the other hand, such unexpected side-effects of biological agents provide a chance to detect new functions of molecules, which were originally detected in the immune response, but play a role outside of it as well.

A further aspect to be considered in the evaluation of side-effects is the combined use of biological agents and drugs: an example would be the treatment of hepatitis C infection, where IFN-α is often provided in combination with ribavirine. If an anaemia develops, it might be related to ribavirin, while the development of autoimmunity is likely due to IFN-α itself (44, 45). And in oncology, where many biological agents are in use, attempts are made to increase the efficacy of the treatment by coupling cytotoxic or radioactive compounds to biological agents, which of course can also be responsible for adverse side-effects (46).


  1. Top of page
  2. Abstract
  3. Biological agents
  4. General principle of adverse effects of biological agents
  5. Conclusion
  6. Acknowledgments
  7. References

Biological agents are used like drugs, but they have many features which distinguish them from drugs, and this has important consequences for understanding and classifying adverse side-effects. As biological agents will be used far more in the future, it is essential that the knowledge about these adverse side-effects will be improved. An analysis of the adverse side-effects of different biological agents reveals that many are related to their biological activity and are not due to an immune response against them, as it occurs in hypersensitivity. Based on these observations a new classification of these adverse side-effects of biological agents is proposed – related but still distinct from the classification of side-effects observed with chemicals used as drugs. It is clear that such a classification based on the mechanism of the biological agent needs to be evaluated in the daily care of patients treated with the biological agent and thereby prove its practicability. This will reveal whether it is too complex or fulfils all or at least some of its scopes, namely to help to better understand the clinical features, to direct research in this area and possibly identify individual and general risk factors, which would reduce the incidence of adverse side-effects.


  1. Top of page
  2. Abstract
  3. Biological agents
  4. General principle of adverse effects of biological agents
  5. Conclusion
  6. Acknowledgments
  7. References

The author would like to thank A. Helbling, M. Seitz and N. Yawalkar for helpful comments. This study was supported by SNF 3100AO-101509 of the Swiss National Science Foundation to W.J.P.


  1. Top of page
  2. Abstract
  3. Biological agents
  4. General principle of adverse effects of biological agents
  5. Conclusion
  6. Acknowledgments
  7. References
  • 1
    Abbas AK, Lichtman AH. Cellular and molecular immunology, 6th edn. Philadelphia, USA: WB Saunders Company, 2005.
  • 2
    Weber RW. Adverse reactions to biological modifiers. Curr Opin Allergy Clin Immunol 2004;4:277283.
  • 3
    Naisbitt DJ, Gordon SF, Pirmohamed M, Park BK. Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment. Drug Saf 2000;23:483507.
  • 4
    Hoigne R, Schlumberger HP, Vervloet D, Zoppi M. Epidemiology of allergic drug reactions. Monogr Allergy 1993;31:147170.
  • 5
    Coombs RR, Gell GP. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: CoombsRR, ed. Clinical aspects of immunology. Oxford, UK: Oxford Univ Press, 1968:575596.
  • 6
    Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139:683693.
  • 7
    Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495497.
  • 8
    Walker C, Herzog C, Rieber P, Riethmuller G, Muller W, Pichler WJ. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: II. Effect of in vivo treatment on in vitro proliferative response of CD4 cells. J Autoimmun 1989;2:643649.
  • 9
    Waugh J, Perry CM. Anakinra: a review of its use in the management of rheumatoid arthritis. BioDrugs 2005;19:189202.
  • 10
    Lee SJ, Kavanaugh A. Adverse reactions to biological agents: focus on autoimmune disease therapies. J Allergy Clin Immunol 2005;116:900905.
  • 11
    Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787793.
  • 12
    Vasquez EM, Fabrega AJ, Pollak R. OKT3-induced cytokine-release syndrome: occurrence beyond the second dose and association with rejection severity. Transplant Proc 1995;27:873874.
  • 13
    Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005;23:52355246.
  • 14
    Chatenoud L. Immunologic monitoring during OKT3 therapy. Clin Transplant 1993;7(4 Pt 2):422430.
  • 15
    Boven K, Knight J, Bader F, Rossert J, Eckardt KU, Casadevall N. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol Dial Transplant 2005;20(Suppl. 3):iii3340.
  • 16
    Baert F, Noman M, Vermeire S, Van Assche G, D’Haens G, Carbonez A et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601608.
  • 17
    Lipsky PE, Van Der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:15941602.
  • 18
    Abramowicz D, Crusiaux A, Goldman M. Anaphylactic shock after retreatment with OKT3 monoclonal antibody. N Engl J Med 1992;327:736.
  • 19
    Han PD, Cohen RD. Managing immunogenic responses to infliximab: treatment implications for patients with Crohn's disease. Drugs 2004;64:17671777.
  • 20
    Arimura K, Arima N, Ohtsubo H, Matsushita K, Kukita T, Ayukawa T et al. Severe autoimmune thrombocytopenic purpura during interferon-alpha therapy for chronic myelogenous leukemia. Acta Haematol 2004;112:217218.
  • 21
    Werth VP, Levinson AI. Etanercept-induced injection site reactions: mechanistic insights from clinical findings and immunohistochemistry. Arch Dermatol 2001;137:953955.
  • 22
    Kassiotis G, Kollias G. TNF and receptors in organ-specific autoimmune disease: multi-layered functioning mirrored in animal models. J Clin Invest 2001;107:15071508.
  • 23
    Vermeire S, Noman M, Van Assche G, Baert F, Van Steen K, Esters N et al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study. Gastroenterology 2003;125:3239.
  • 24
    Banchereau J, Pascual V, Palucka AK. Autoimmunity through cytokine-induced dendritic cell activation. Immunity 2004;20:539550.
  • 25
    Hershberger RE, Starling RC, Eisen HJ, Bergh CH, Kormos RL, Love RB et al. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med 2005;352:27052713.
  • 26
    Wellington K, Perry CM. Efalizumab. Am J Clin Dermatol 2005;6:113118; discussion 119–120.
  • 27
    Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003;48:21222127.
  • 28
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003;100:83728377.
  • 29
    Debandt M, Vittecoq O, Descamps V, Le Loet X, Meyer O. Anti-TNF-alpha-induced systemic lupus syndrome. Clin Rheumatol 2003;22:5661.
  • 30
    Seckin D, Durusoy C, Sahin S. Concomitant vitiligo and psoriasis in a patient treated with interferon alfa-2a for chronic hepatitis B infection. Pediatr Dermatol 2004;21:577579.
  • 31
    Day R. Adverse reactions to TNF-alpha inhibitors in rheumatoid arthritis. Lancet 2002;359:540541.
  • 32
    Solans R, Bosch JA, Esteban I, Vilardell M. Systemic sclerosis developing in association with the use of interferon alpha therapy for chronic viral hepatitis. Clin Exp Rheumatol 2004;22:625628.
  • 33
    Niewold TB, Swedler WI. Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C. Clin Rheumatol 2005;24:178181.
  • 34
    Boz C, Ozmenoglu M, Aktoz G, Velioglu S, Alioglu Z. Guillain-Barre syndrome during treatment with interferon alpha for hepatitis B. J Clin Neurosci 2004;11:523525.
  • 35
    Doi F, Kakizaki S, Takagi H, Murakami M, Sohara N, Otsuka T et al. Long-term outcome of interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C. Liver Int 2005;25:242246.
  • 36
    Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 2005;204:2742.
  • 37
    Devos SA, Van Den Bossche N, De Vos M, Naeyaert JM. Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology 2003;206:388390.
  • 38
    Chan JL, Davis-Reed L, Kimball AB. Counter-regulatory balance: atopic dermatitis in patients undergoing infliximab infusion therapy. J Drugs Dermatol 2004;3:315318.
  • 39
    Menon Y, Cucurull E, Reisin E, Espinoza LR. Interferon-alpha-associated sarcoidosis responsive to infliximab therapy. Am J Med Sci 2004;328:173175.
  • 40
    Taylor A, Verhagen J, Akdis CA, Akdis M. T regulatory cells in allergy and health: a question of allergen specificity and balance. Int Arch Allergy Immunol 2004;135:7382.
  • 41
    Danese S, Fiocchi C. Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Crit Rev Immunol 2005;25:103121.
  • 42
    Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;138:807811.
  • 43
    Kasahara A, Hiraide A, Tomita N, Iwahashi H, Imagawa A, Ohguro N et al. Vogt-Koyanagi-Harada disease occurring during interferon alpha therapy for chronic hepatitis C. J Gastroenterol 2004;39:11061109.
  • 44
    Bagheri H, Fouladi A, Barange K, Lapeyre-Mestre M, Payen JL, Montastruc JL et al. Follow-up of adverse drug reactions from peginterferon alfa-2b-ribavirin therapy. Pharmacotherapy 2004;24:15461553.
  • 45
    Chamberlain AJ, Poon E. Cutaneous reactions to interferon and ribavirin. Intern Med J 2004;34:519.
  • 46
    Panwar P, Iznaga-Escobar N, Mishra P, Srivastava V, Sharma RK, Chandra R et al. Radiolabeling and biological evaluation of DOTA-Ph-Al derivative conjugated to anti-EGFR antibody or egf/r3 for targeted tumor imaging and therapy. Cancer Biol Ther 2005;4:814.