Review Aspects of allergy in rheumatology D. Spoerl1, K. Scherer1, A. Tyndall2

1Allergy Unit, Department of Dermatology ABSTRACT reactions (type III), and T-cell mediat- University Hospital Basel, Basel, This review focuses on several basic ed delayed type hypersensitivity (type Switzerland; mechanisms of allergy and when a IV) (Table I) (3). 2Department of Rheumatology, University rheumatologist should consider an ex- The term “allergy” should only be used of Basel, Felix Platter Spital, Basel, Switzerland. ternal agent as being responsible for when an immunologic reaction has seemingly “rheumatic” manifestations. been proven (4). Adverse drug reac- David Spoerl, MD Kathrin Scherer, MD Typical allergic diseases are discussed tion (ADR) on the other side is a wide Alan De Vere Tyndall, MD in order to help the physician to recog- definition including toxic, and both Please address correspondence nise them. In addition, allergic aspects immunologic (including hypersensitiv- and reprint requests to: and adverse drug reactions of anti- ity reactions) and as yet not fully un- David Spoerl, MD, rheumatic drugs and biopharmaceuti- derstood undesired drug effects. ADR Allergy Unit, Department of Dermatology, cal agent therapies will be discussed. on xenobiotics are usually classified University Hospital Basel, in six groups (Table II) (5, 6). Most Petersgraben 4, Introduction reactions are caused by the pharma- 4031 Basel, Switzerland. E-mail: [email protected] Allergies, from the greek αλλεργία, cological or toxicological activities of reaction against “other”, are unde- the drug and are generally predictable Received on August 23, 2010; accepted in revised form on December 15, 2010. sired reactions against something that (Type A). However, non-predictable, does not belong to “self”. Allergy is a idiosyncratic (Type B) reactions count Clin Exp Rheumatol 2011; 29: 560-566. hypersensitivity reaction initiated by for approximately 15% of all reported © Copyright CLINICAL AND immunologic mechanisms to harmless ADR. Whenever a drug-induced hy- EXPERIMENTAL RHEUMATOLOGY 2011. foreign substances called allergens. persensitivity reaction is supposed but Key words: Hypersensitivity, drug Atopy is an individual and/or familial not established, physicians should ei- hypersensitivity, immune complex tendency, which usually manifests in ther describe the clinical picture and diseases, antirheumatic agents, childhood or adolescence, to become the time-course, e.g. “macular exanthe- urticarial vasculitis sensitised and produce immunoglobu- ma 2 days after the start of penicillin lin E (IgE) in response to ordinary ex- administration” or use the term ADR. posures to allergens, usually proteins. Recently, the diagnosis of drug allergy/ The term atopy can not be used until hypersensitivity has been standardised an IgE mediated sensitisation has been by the European Network for Drug documented by IgE antibodies in se- Allergy (ENDA) under the aegis of the rum or by a positive skin prick test (1). European Academy of Allergology and The readiness to react to allergens is Clinical (EAACI) and moreover greatly determined by many standard operating procedures have other concomitant factors which influ- been published (7). ence the immune system during expo- The often encountered term “infusion sure. The concomitant or sequential reaction” (IR) and “injection site re- exposure to a combination of allergens, action” (ISR) describes a subgroup of infection, physical exercise, psycho- ADR against infused or injected (es- logical stress, alcohol, menstruation pecially monoclonal antibodies) drugs. and/or concomitant medication may be The classification of ADR to biophar- necessary to provoke a reaction (2). maceuticals is different from that of xe- nobiotics due to the particular effects Definitions and classifications of those drugs on the immune system. in allergic disease To distinguish it from the classifica- The Coombs and Gell classification tion of side-effects to chemicals/drugs, divides hypersensitivity reactions into the Greek alphabet is used for the five four pathophysiological types, namely types (Table III) (8). This classification IgE-mediated anaphylaxis (type I), is a first attempt to bring some order antibody-mediated cytotoxic reactions in the increasing number of reports of Competing interests: none declared. (type II), immune complex-mediated ADR to biopharmaceuticals. Most of

560 Aspects of allergy in rheumatology / D. Spoerl et al. REVIEW

Table I. Coombs and Gell’s classification.

Type Description Clinical Example Skin manifestations

Type I: IgE-mediated Takes 2-30 mins up to several hours to develop. Systemic anaphylaxis, allergic Urticaria, , hypersensitivity; immediate Ag induces cross-linking of IgE bound to mast cells rhinoconjunctivits, early bronchial flush, hypersensitivity; anaphylaxis. and basophils with release of vasoactive mediators. response in extrinsic asthma, allergic conjunctivitis. urticaria.

Type II: Antibody-mediated, Takes 1-8 hrs to develop. Blood transfusion reactions, Non palpable purpura, cell bound hypersensitivity. Antibody directed against cell-surface antigens autoimmune haemolytic anemia, bullae, urticaria. mediates cell destruction or alters signaling. autoimmune urticaria, pemphigus vulgaris, ITP.

Type III: Immune-complex Takes 2-16 hrs to develop. Arthus reaction, serum sickness, exogen Palpable purpura, mediated hypersensitivity. Antigen-antibody complexes deposited at various allergic alveolitis, urticarial vasculitis. urticarial vasculitis, sites induce inflammation with complement activation. livedo racemosa.

Type IV: Cell-mediated Takes 4-72 hrs to develop. Contact dermatitis, Mantoux test, Eczema, hypersensitivity; Delayed (usually T-) cell-mediated inflammation. late bronchial response in asthma. maculopapular type hypersensitivity. exanthema.

Table II. Classification of adverse drug reaction.

Type Description Example

Type A (Augmented) Reactions which can be predicted from the known Bleeding with anticoagulants, bradycardia with beta blockers, pharmacology of the drug. headache with nitrates, postural hypotension with prazosin. Dose-dependent, can be alleviated by a dose reduction.

Type B (Bizarre) Immune system involved. Anticonvulsant hypersensitivity. Maculo-papular eruptions on Not dose-dependent, host-dependent factors important penicillin. in pre-disposition.

Type C (Chronic) Dose-related and time-related. Hypothalamic-pituitary-adrenal axis suppression by glucocorticoids.

Type D (Delayed) Occur after many years of treatment. Can be due to Secondary tumors after treatment with chemotherapy, analgesic accumulation. nephropathy.

Type E (End of treatment) Occur on withdrawal especially when drug is stopped Withdrawal seizures on stopping phenytoin, adrenocortical abruptly. insufficiency on withdrawal of glucocorticoids.

Type F (Failure) Failure of therapy or insufficient effect. Hypertension on antihypertensive therapy.

Table III. Classification of adverse drug reaction to biopharmaceuticals. (?) means that the mechanism is yet unclear.

Type Description Example

Type α: High cytokine and Side-effects might be connected to the systematic Flu-like symptoms following Interferon alfa. Cytokine release cytokine release syndrome. application of cytokines in relatively high doses or syndrome following anti-thymocyte globulin (?). to high concentrations of cytokines released into the circulation.

Type β: Hypersensitivity. Basically two forms of reactions can be differentiated: Anaphylactic shock following OKT3 infusion. immediate and delayed. Infusion reaction (?). Local reaction to etanercept (?).

Type γ: Immune or cytokine Partly explicable by the effect of the drug. Can be Uncontrolled infection under TNF inhibitors, i.e. tuberculosis imbalance syndromes. further subdivided flare. • immunodeficiency Induction of (?). • autoimmunity Development of atopic dermatitis in patients undergoing • loss of tolerance infliximab therapy (?).

Type δ: Cross-reactivity. Antibodies generated to an antigen expressed on Acneiforme eruptions in the frame of anti-EGFR treatment. tumour cells might also crossreact with normal cells, which express this structure as well, albeit to a lower degree.

Type ε: Non-immunological Not directly related to the immune system, sometimes Cardiac failure in TNF-α inhibitor treatment (?). side-effects. revealing unknown functions of the biopharmaceutical agents.

561 REVIEW Aspects of allergy in rheumatology / D. Spoerl et al.

Table IV. Differentiation between urticarial vasculitis and acute common urticaria.

Urticarial vasculitis Common urticaria

Synonyms Hypersensitivity vasculitis; drug-induced vasculitis; leukocytoclastic ; nettle rash. vasculitis; cutaneous vasculitis; serum sickness or serum sickness-like reactions; allergic vasculitis.

Clinical features of Painful, burning sensation; persistence over 24-72h; eventually purpuric; Pruritic; heals within 24h leaving no a single lesion postinflammatory hyperpigmentation. residual changes.

Associated conditions HIV-, HBV- and HCV-Infections; Sjögren’s syndrome; SLE; HUVS; Angioedema; anaphylactic reactions; Schnitzler’s syndrome; Cogan’s syndrome; Muckle-Wells syndrome; infections; physical and psychological stimuli. haematologic disease; amyloidosis; ; malignancy.

Initial work-up Search for physical signs of systemic disease, preceding infections and Search for eliciting allergen (food, preceding drug ingestion, , complement studies including C1q hymenoptera, drugs) or physical stimuli; Antibodies, complete blood count with differential, urinalysis, serum signs of infection; tryptase in serum. creatinine and liver enzymes, hepatitis B and C serologies, ANA, serum protein electrophoresis. them are only suppositions, showing for an allergic cause (12). It is further with systemic that there still is the need to elucidate classified into spontaneous urticaria (SLE), 38% in Hepatitis C virus (HCV) many mechanisms in immunology. (acute and chronic forms), physical ur- infected individuals, 20% of rheuma- ticaria (cold, pressure, heat, solar, de- toid (RA) patients and in 15% Urticaria: a dermatological mographic and vibratory urticaria) and in patients with scleroderma, Sjögren’s manifestation of hypersensitivity urticaria due to other disorders (aqua- syndrome or mixed connective tissue or of rheumatic disease genic, cholinergic, contact and exercise disease (MCTD) (16). In fact, in about The skin delineates the organism from induced urticaria) (12). Acute urticaria half of cases where hypocomplemen- the outer world and is therefore the pre- is often due to common viral infections temia is present in urticarial vasculitis, disposed organ where hypersensitivity and a specific antigen trigger can rarely diagnostic criteria of SLE are fulfilled reactions against exogenous allergens be found. The concept of autoimmune (17). If not, hypocomplementemic urti- may take place. urticaria is increasingly being rec- carial vasculitis syndrome (HUVS) has This paragraph will focus on urticaria ognised but has still to be defined. A to be considered. Urticarial vasculitis, if as one possible dermatological mani- positive autologous serum skin test and a cause can be found, may be a manifes- festation of hypersensitivity (Coombs autoimmune thyroiditis are frequent tation of a hypersensitivity reaction to Type I) or of rheumatic disease. In associated findings (13). drugs (cimetidine, diltiazem, potassium the first case, a trigger may be found Urticarial vasculitis can present in a iodide, fluoxetine, non-steroidal anti- through a thorough history while the variety of ways, from a mild cutane- rheumatic drugs (NSAR) drugs and re- latter will be accompanied by a flare ous form to a lupus-like disease with cently glatiramer acetate have been re- of the underlying rheumatic disease. severe cardiopulmonary involvement. ported in the literature) and infections, Other dermatological manifestations of Urticarial vasculitis requires a biopsy in particular hepatitis B virus (HBV), rheumatic disease have been reviewed to confirm the diagnosis. Histologically HCV, Human immunodeficiency virus elsewhere (9, 10). there are signs of leukocytoclastic vas- (HIV) and different bacterial patho- Urticaria (hives; nettle rash) is a mor- culitis (14). In this disease, immune gens (18). Urticarial vasculitis has been phological term describing an itchy complex deposition leads to activation otherwise associated with many other weal on the skin. Hives can be seen in of the classic complement pathway, diseases: Schnitzler’s syndrome (typi- two clinical forms depending on the generating C3a and C5a. Those factors cally with monoclonal gammopathy), underlying disease: common urticaria induce mast cell degranulation (with Cogan syndrome (non syphilitic kerati- and urticarial vasculitis. To differenti- consequent urticaria) and tis and vestibuloauditory dysfunction), ate between them might be difficult chemotaxis (causing the typical pic- Henoch-Schönlein purpura, Muckle (Table IV). Urticaria is frequent and ture of leukocytoclastic vasculitis) (11). Wells syndrome (together with deaf- is, in the acute setting, a hallmark of Urticarial vasculitis is an overlap dis- ness and renal amyloidosis) and more anaphylaxis. It occurs in 40% with ease where urticaria and leukocytoclas- commonly, Sjögren syndrome (15, 19). angioedema, which is thought to be tic vasculitis merge into another. It can prevalently due to bradykinin (11). The further be subdivided in normo- and hy- Is it allergy? When should a incidence in the population is 15% and pocomplementemic. Low complement rheumatologist think of an external it does not require further investiga- levels and positive anti-C1q antibod- cause for the symptoms? tion if not chronic, that is by definition ies are markers of more severe disease Patients with rheumatic disease often lasting more than 6 weeks, and the pa- (15), but are not specific. Anti-C1q anti- present with and/or myalgia tient history is not strongly suggestive bodies can be found in 61% of patients which, although common in the gen-

562 Aspects of allergy in rheumatology / D. Spoerl et al. REVIEW eral population, are very uncommon and fluid of patients with RA and es- posed in a consensus paper from the symptoms in allergic disease. pecially at sites of cartilage erosion ENDA and the EAACI interest group Myalgia: Myalgia has been reported (25). Therefore, theoretically an “al- on drug hypersensitivity (29). Drug de- among others as a “systemic symp- lergic arthritis” should be conceivable. sensitisation is defined as the induction tom” in DRESS syndrome, the acro- Tumor necrosis factor alfa (TNF-α) of a temporary state of tolerance of a nym for Drug Rash and Eosinophilia production by synovial mast cells of compound responsible for a hypersen- with Systemic Symptoms. The DRESS RA patients has recently been shown in sitivity reaction. Only for some drugs syndrome is an idiosyncratic reaction vitro, but the contribution of those cells (about 100), true desensitisation proto- characterised by febrile maculopapular in the inflammatory process in vivo is cols can be found in literature. exanthema, occurring depending on the unknown (26). eliciting drug 3 weeks to months after Mast cells probably take part in the in- Glucocorticoids the beginning of the treatment, accom- flammatory process, but are unable to Most ADR to glucocorticoids are non panied by systemic symptoms, blood initiate it on their own and therefore, type B (30). Allergic reactions to sys- abnormalities (eosinophilia in 90% of true arthritis due to a hypersensitivity temic glucocorticoids are rare, but are cases, or atypical lym- reaction has not been reported so far. becoming more commonly recognised phocytosis, cytopenias) and interesting- The question in the title of a paper, pub- by clinicians. Glucocorticoids can de- ly a sequential reactivation of herpes vi- lished in 1990 asking “is there an al- velop hypersensitivity reactions of ruses (20). It has a mortality of 10–20% lergic synovitis?” remains unanswered Coombs type I, III or IV (31, 32). There and a protracted course in the remain- (27). are more than 100 published reports of ing cases despite stop of the offend- immediate hypersensitivity reactions ing drug. The paradoxical worsening Allergological aspects of selected (Coombs type I) occurring after oral and of clinical symptoms including febrile disease modifying anti-rheumatic parenteral administration of corticoster- illness after withdrawal of the causa- drugs (DMARDs) oids. Type IV reactions are much more tive drug may lead to prescription of an Drug hypersensitivity reactions (Type frequent with an estimated incidence of empirical antibiotic treatment, which B ADR) are a common clinical prob- up to 4% for cutaneous reactions. increases the risk of developing addi- lem which may affect a considerable Excipients and preservatives in drugs tional drug rashes. It has to be consid- number of the treated patient popula- are often implicated in type IV hyper- ered synonym to Drug Hypersensitivity tion. Between 10 and 15% of patients sensitivity reactions, but many cases Syndrome (DHS) and Drug Induced may suffer from an ADR, 2–5% of of sensitisation to the pharmacological Hypersensitivity Syndrome (DIHS) these have to be hospitalised, and in principle have been reported as well (21). Anticonvulsants, sulfonamides, 1–3% of hospitalised patients mortal- (33). In this case and in particular for dapsone, allopurinol, minocycline and ity may result. A maculopapular ex- topical glucocorticoids, the classifica- antiviral drugs are among the most fre- anthema is the most commonly noted tion of glucocorticoids of Coopman quent culprit drugs. cutaneous adverse reaction pattern to and Goossens may be helpful to predict Myalgia is otherwise commonly report- all drugs, ranging between 51% and crossreactivity (34, 35). Desensitisation ed by patients with multiple chemical 95% of cases in various series (28). For is one treatment option in patients for sensitivity, an exclusion diagnosis in most suspected drug reactions, there whom are essential and which psychiatric advice may be use- is no commercially available test to in whom cross-reactivity precludes the ful (22, 23). verify their tolerance and allergologi- use of alternative steroid preparations Arthralgia: Arthralgia is typical in cal work-up includes skin and in vitro (30) and successful desensitisation has Coombs Type III hypersensitivity reac- tests eventually followed by provoca- been reported using oral and intrave- tions. Urticarial vasculitis, hypersensi- tion with the suspected drug or with an nously hydrocortisone (36, 37). tivity vasculitis, drug-induced vasculi- alternative drug if this appears too dan- tis, serum sickness-like reactions and gerous. As outlined above, not any rash Methotrexate allergic vasculitis all probably describe appeared concomitantly to a new drug Methotrexate may produce an acute the same entity. It is now known that ar- regimen is caused by a hypersensitiv- granulomatous pneumonia mimicking thralgia appears in approximately two- ity reaction. Most patients often draw an infection which must be ruled out thirds of patients and that the joint in- this conclusion resting their opinion by appropriate techniques (38). Criteria volvement tends to occur after the rash merely on a chronological association for defining methotrexate pneumonitis has started, and resolves before the rash and ask for desensitisation protocols. have been published (39). Anaphylaxis has vanished. A case of arthralgia due Many desensitisation protocols found to methotrexate has been reported, but to a type IV hypersensitivity to pros- in literature are rather graded re-admin- the authors could not identify specific thetic joints made from alloys to which istrations since no allergological work IgE and tryptase was negative so that the patient was sensitised has been re- up has been previously performed and this supposition was based merely on ported (24). no induction of tolerance can be dem- skin test (40-42). Most anaphylactoid Arthritis: Increased numbers of mast onstrated. A general algorithm for drug reaction have been reported after high cells are found in the synovial tissue desensitisation has recently been pro- dose methotrexate as a cancer treatment,

563 REVIEW Aspects of allergy in rheumatology / D. Spoerl et al. and desensitisation protocols have only interaction with other drugs increases TNF-α antagonist seem not be at risk for been proposed for this indication (43, the amount of its active metabolite. another ADR when they are switched to 44). Reassuringly, it seems that the com- Rifampicin is a known example, induc- another TNF-α antagonist (64). bination of etanercept and methotrexate ing the cytochrome (CYP) P450 2C9 The formation of antibodies against the does not lead to new unexpected safety enzyme. For those cutaneous adverse drug depends on cofactors such as the issues over 52 weeks of therapy (45). reactions no desensitisation protocol frequency of administration (scheduled Moreover, concomitant methotrexate exists and because of their severity, re- vs. episodic, the latter being worst from seems to protect from appearance of au- administration of the culprit drug is not this point of view) and the simultane- toantibody and antibodies against biop- recommended. ous administration of immunosuppres- harmaceuticals (46-48). sants (47, 65, 66). The latter may delay Biopharmaceuticals or reduce antibody formation and ADR Antimalarials Initially, TNF-α antagonists were stud- frequency (67). Measurement of HACA The ADR of synthetic antimalarials are ied in the setting of acute sepsis in the and infliximab concentration has been known, although not frequent, and they intensive care units, but were aban- shown to be useful because increasing can involve the ocular, haematopoietic, doned due to unsatisfactory results (54, the dose in patients who have HACAs gastrointestinal, cardiovascular and 55). ADR to TNF-α antagonists are not is ineffective, whereas in patients with central nervous systems. Among ad- rare. Data comparing those drugs indi- subtherapeutic infliximab concentra- verse cutaneous reactions, dark discol- cate that ADR are more common with tions this strategy may be a good alter- oration is most often encountered, while mouse antibodies, followed by chi- native to changing to another anti-TNF- bleaching of the hair, lichenoid reac- meric antibodies (75% human: i.e. in- α agent (68). Most reported cases of tions, maculopapular eruptions, psoria- fliximab), humanised antibodies (90% antibody mediated hypersensitivity re- sis exacerbation and porphyria cutanea human, i.e. omalizumab) and rarest actions have been associated with IgG, tarda are less common. Exanthematous with human antibodies (i.e. adalimu- showing serum sickness like patterns. pustulosis, allergic contact dermatitis mab). The term ADR encompasses IR Recently, a serum sickness like reaction and photosensitivity are rare (49). (for infused drugs) and ISR (for subcu- was reported for infliximab (69) and Acute generalised exanthematous taneous injected drugs), and does not rituximab (70). Type I hypersensitivity pustulosis (AGEP) has been reported tell anything about the pathogenetic response (Type β ADR) was reported as an ADR of hydroxychloroquine mechanisms. IR usually occurs during with convincing evidence for injection (50). AGEP is an uncommon Type B, or within a short time after infusion and site reactions to adalimumab (71). Coombs type IVd ADR to a variety of ISR might take longer to develop, but Cytokine release syndrome (Type α drugs. The reaction results in formation this is not a rule. Whether these mani- ADR) is a common complication oc- of numerous sterile pustules on an ex- festations have to be considered type β curring with the use of anti-T and B tensive erythema associated with , or type γ reactions is still a matter of de- cell antibody infusions (72). Severe neutrophilia and/or eosinophilia. bate (56). Zeltser et al. compared recall cases are known as cytokine storms and A desensitisation protocol has been re- ISR to fixed drug eruptions, known to present with a clinical pattern of a sys- cently published using an orally admin- be T-cell-dependent allergic reactions temic inflammatory response syndrome istered hydroxychloroquine solution in (57). This, together with the fact that (SIRS). Another ADR is the phenome- a patient with SLE after anaphylaxis IR rate depends on the degree of hu- non of development of anti-DNA-anti- (51). manisation and that the presence of an- bodies and antinuclear antibody (ANA) tibodies against the drug (e.g. antibod- with prolonged TNF-α blockade, the Leflunomide ies toward infliximab (ATI) or Human clinical significance of which remains Leflunomide inhibits tyrosine kinases Anti-Chimeric Antibodies (HACA) in unclear. Fortunately the associated drug and thus suppresses the production case of infliximab) correlates with the induced lupus erythematosus (DILE) of proinflammatory cytokines such as risk of IR, speaks in favour of a type seems to be reversible after discon- TNF-α. Suppression of a TNF-α in- β reaction (58). ATI of the IgE isotype tinuation of the suspected drug and the duced cellular response may be one could be detected so far only in a few presence of those antibodies do not put of the mechanisms of leflunomide ef- patients after IR and support this hy- the patient at risk for other ADR such ficacy in RA which could explain the pothesis (59, 60). On the other hand, the as IR or loss of efficacy. TNF-α antago- induction of subacute cutaneous lupus fact that IR often occur at the first dose nist induced lupus erythematosus cases erythematosus in a recently published supports the hypothesis that IR are type had a higher prevalence of antibodies case (52). The recent cases of lupus- γ ADR. Consistent with this hypothesis to double-stranded DNA, rash, and hy- like syndrome induced by anti- TNF-α was the finding that tryptase was nega- pocomplementemia than DILE due to treatment favour this hypothesis (53). tive in 11 patients with Crohn’s disease other drugs. Fever is common in both Other severe adverse cutaneous reac- who had an IR to infliximab and that it types of DILE. Renal disease, which is tions are Stevens-Johnson syndrome was possible to re-treat patients using rare in classic DILE, has been reported (SJS) and toxic epidermal necrolysis specific protocols (61-63). In addition, in cases of TNF-α antagonist induced (TEN), occurring in particular if the fortunately patients who reacted to one DILE (73). The onset of chronic inflam-

564 Aspects of allergy in rheumatology / D. Spoerl et al. REVIEW matory skin disease is the most frequent 4. PRZYBILLA B, ABERER W, BIRCHER AJ et 23. SALVAGGIO JE, TERR AI: Multiple chemical cutaneous ADR of TNF-α antagonist in al.: Allergological approach to drug hyper- sensitivity multiorgan dysesthesia, multiple sensitivity reactions. J Dtsch Dermatol Ges symptom complex, and multiple confusion: the skin, followed by infectious skin 2008, 6: 240-3. problems in diagnosing the patient present- disease (74). Infliximab, etanercept and 5. BIRCHER A: Arzneimittelallergie. In Manuale ing with unexplained multisystemic symp- adalimumab can induce psoriasis, espe- Allergologicum. Dustri Verlag 2008; 1-37. toms. Crit Rev Toxicol 1996; 26: 617-31. 6. HUNZIKER T, BRUPPACHER R, KUENZI UP 24. THOMSSEN H, HOFFMANN B, SCHANK M et cially the palmoplantar pustulosis form. et al.: Classification of ADRs: a proposal al.: Cobalt-specific T lymphocytes in synovi- The prevalence of this adverse effect for harmonization and differentiation based al tissue after an allergic reaction to a cobalt has been estimated at 1.5-5% of patients on the experience of the Comprehensive alloy joint prosthesis. J Rheumatol 2001; 28: taking TNF-α antagonists (75). In a mi- Hospital Drug Monitoring Bern/St. Gallen, 1121-8. 1974-1993. Pharmacoepidemiol Drug Saf 25. WOOLLEY DE, TETLOW LC: Mast cell activa- nority of patients, this ADR persisted 2002; 11: 159-63. tion and its relation to proinflammatory cy- upon discontinuation of the drug. Re- 7. BOUSQUET PJ, DEMOLY P, ROMANO A et al.: tokine production in the rheumatoid lesion. mission of psoriasis was similar when- Pharmacovigilance of drug allergy and hy- Arthritis Res 2000; 2: 65-74. ever TNF-α antagonist were continued persensitivity using the ENDA-DAHD data- 26. SANDLER C, LINDSTEDT KA, JOUTSINIEMI base and the GALEN platform. The Galenda S et al.: Selective activation of mast cells or stopped. The underlying paradoxi- project. Allergy 2009; 64: 194-203. in rheumatoid synovial tissue results in pro- cal pathomechanisms of induction of 8. PICHLER WJ: Adverse side-effects to biologi- duction of TNF-alpha, IL-1beta and IL-1Ra. psoriasis or psoriasiform exanthematic cal agents. Allergy 2006; 61: 912-20. Inflamm Res 2007; 56: 230-9. 9. RASHTAK S, PITTELKOW MR: Skin involve- 27. GOLDING DN: Is there an allergic synovitis? disease by TNF-α inhibitors remain ment in systemic autoimmune diseases. Curr J R Soc Med 1990; 83: 312-4. elusive (76). Because no validated di- Dir Autoimmun 2008; 10: 344-58. 28. SONTHEIMER RD: Desensitization to hy- agnostic tools exists to detect immuno- 10. ALBRECHT J, ATZENI F, BALDINI C et al.: droxychloroquine: alternative interpreta- logically mediated and clinical relevant Skin involvement and outcome measures tions. J Rheumatol 2007; 34: 253-5. in systemic autoimmune diseases. Clin Exp 29. CERNADAS JR, BROCKOW K, ROMANO A et hypersensitivity to biopharmaceuticals, Rheumatol 2006; 24: S52-9. al.: General considerations on rapid desensi- desensitisation protocols found in lit- 11. DEACOCK SJ: An approach to the patient tization for drug hypersensitivity - a consen- erature must be considered with caution with urticaria. Clin Exp Immunol 2008; 153: sus statement. Allergy 2010; 65: 1357-66. 151-61. 30. CHEAM H, BUTANI L: Immunoglobulin E- (77-80). A protocol for adalimumab de- 12. ZUBERBIER T, ASERO R, BINDSLEV-JEN- mediated reactions to corticosteroids. Curr sensitisation has been proposed (81). SEN C et al.: EAACI/GA(2)LEN/EDF/WAO Allergy Asthma Rep 2005; 5: 22-7. guideline: definition, classification and diag- 31. VENTURINI M, LOBERA T, DEL POZO MD, Conclusions nosis of urticaria. Allergy 2009; 64: 1417-26. GONZALEZ I, BLASCO A: Immediate hy- 13. KONSTANTINOU GN, ASERO R, MAURER M, persensitivity to corticosteroids. J Investig Knowledge of allergic disease is in- SABROE RA, SCHMID-GRENDELMEIER P, Allergol Clin Immunol 2006; 16: 51-6. creasingly required in the clinical GRATTAN CE: EAACI/GA(2)LEN task force 32. KAMM GL, HAGMEYER KO: Allergic-type re- setting, both to exclude possible dif- consensus report: the autologous serum skin actions to corticosteroids. Ann Pharmacother ferential diagnosis, and to understand test in urticaria. Allergy 2009; 64: 1256-68. 1999; 33: 451-60. 14. VENZOR J, LEE WL, HUSTON DP: Urticarial 33. VENTURA MT, MURATORE L, CALOGIURI GF adverse effects of immune modulating vasculitis. Clin Rev Allergy Immunol 2002; et al.: Allergic and pseudoallergic reactions drugs used in rheumatology. Because 23: 201-16. induced by glucocorticoids: a review. Curr of limited experience with biopharma- 15. BROWN NA, CARTER JD: Urticarial vasculi- Pharm Des 2003; 9: 1956-64. tis. Curr Rheumatol Rep 2007; 9: 312-9. 34. COOPMAN S, DEGREEF H, DOOMS-GOOS- ceuticals, the risk-benefit evaluation for 16. LIENESCH DW, SHERMAN KE, METZGER A, SENS A: Identification of cross-reaction pat- a given patient is often difficult (82). In SHEN GQ: Anti-Clq antibodies in patients terns in allergic contact dermatitis from topi- the next years, it will be essential to de- with chronic hepatitis C infection. Clin Exp cal . Br J Dermatol 1989; 121: velop adequate screening tools to eval- Rheumatol 2006; 24: 183-5. 27-34. 17. DAVIS MD, BREWER JD: Urticarial vasculitis 35. MATURA M, GOOSSENS A: Contact allergy uate the immunogenicity of therapeutic and hypocomplementemic urticarial vascu- to corticosteroids. Allergy 2000; 55: 698-704. proteins (83). Only good understanding litis syndrome. Immunol Allergy Clin North 36. CLEE MD, FERGUSON J, BROWNING MC, of the immune system will allow the Am 2004; 24: 183-213. JUNG RT, CLARK RA: Glucocorticoid hyper- identification of other application areas, 18. CICEK D, KANDI B, OGUZ S, COBANOGLU sensitivity in an asthmatic patient: presenta- B, BULUT S, SARAL Y: An urticarial vascu- tion and treatment. Thorax 1985; 40. 477-8. i.e. in transplantation medicine and al- litis case induced by glatiramer acetate. J 37. LEE-WONG M, MCCLELLAND S, CHONG K, lergic immune response, and to recog- Dermatolog Treat 2008; 1-3. FERNANDEZ-PEREZ ER: A case of hydrocor- nise and maybe forecast ADR (84, 85). 19. CARLSON JA, NG BT, CHEN KR: Cutaneous tisone desensitization in a patient with radio- vasculitis update: diagnostic criteria, clas- contrast-induced anaphylactoid reaction and sification, epidemiology, etiology, patho- corticosteroid allergy. Allergy Asthma Proc References genesis, evaluation and prognosis. Am J 2006; 27: 265-8. 1. JOHANSSON SG, BIEBER T, DAHL R et Dermatopathol 2005; 27: 504-28. 38. CAMUS P, FANTON A, BONNIAUD P, CAMUS al.: Revised nomenclature for allergy for 20. SHIOHARA T, KANO Y: A complex interac- C, FOUCHER P: Interstitial lung disease in- global use: Report of the Nomenclature tion between drug allergy and viral infection. duced by drugs and radiation. Respiration Review Committee of the World Allergy Clin Rev Allergy Immunol 2007; 33: 124-33. 2004; 71: 301-26. Organization, October 2003. J Allergy Clin 21. VALEYRIE-ALLANORE L, ROUJEAU JC: 39. CLEARKIN R, CORRIS PA, THOMAS SH: Immunol 2004; 113: 832-6. Denominations and classification of severe Methotrexate pneumonitis in a patient with 2. SCHERER K, BALLMER-WEBER BK, BIR- cutaneous adverse reactions to drugs: split- rheumatoid arthritis. Postgrad Med J 1997; CHER AJ: Highlights in nonhymenoptera an- ters versus mergers. Eur J Dermatol 2007; 73: 603-4. aphylaxis. Curr Opin Allergy Clin Immunol 17: 359-60. 40. HOUTMAN PM, JANSEN TL, BLANKEN R: 2008; 8: 348-53. 22. SAITO M, KUMANO H, YOSHIUCHI K et al.: Anaphylactic reaction in a patient with rheu- 3. DESCOTES J, CHOQUET-KASTYLEVSKY G: Symptom profile of multiple chemical sen- matoid arthritis: a rare side effect of meth- Gell and Coombs’s classification: is it still sitivity in actual life. Psychosom Med 2005; otrexate with etanercept as a provoking fac- valid? Toxicology 2001; 158: 43-9. 67: 318-25. tor? J Clin Rheumatol 2006; 12: 321-2.

565 REVIEW Aspects of allergy in rheumatology / D. Spoerl et al.

41. LLUCH-BERNAL M, CUESTA-HERRANZ J, DE DEMOLY P: Hypersensitivity reactions to Immediate type I hypersensitivity response LAS HERAS M et al.: Anaphylactic reaction to biological agents with special emphasis on implicated in worsening injection site reac- methotrexate. Allergy 1997; 52: 1150-1. tumor necrosis factor-alpha antagonists. tions to adalimumab. Arch Dermatol 2008; 42. VEGA A, CABANAS R, CONTRERAS J et al.: Curr Opin Allergy Clin Immunol 2007; 7: 144: 1190-4. Anaphylaxis to methotrexate: a possible 393-403. 72. SUNTHARALINGAM G, PERRY MR, WARD S IgE-mediated mechanism. J Allergy Clin 57. ZELTSER R, VALLE L, TANCK C, HOLYST et al.: Cytokine storm in a phase 1 trial of the Immunol 1994; 94: 268-70. MM, RITCHLIN C, GASPARI AA: Clinical, anti-CD28 monoclonal antibody TGN1412. 43. KOHLI A, FERENCZ TM, CALDERON JG: histological, and immunophenotypic charac- N Engl J Med 2006; 355: 1018-28. Readministration of high-dose methotrexate teristics of injection site reactions associated 73. COSTA MF, SAID NR, ZIMMERMANN B: in a patient with suspected immediate hy- with etanercept: a recombinant tumor necro- Drug-induced lupus due to anti-tumor persensitivity and T-cell acute lymphoblastic sis factor alpha receptor: Fc fusion protein. necrosis factor alpha agents. Semin Arthritis . Allergy Asthma Proc 2004; 25: Arch Dermatol 2001; 137: 893-9. Rheum 2008; 37. 381-7. 249-52. 58. MIELE E, MARKOWITZ JE, MAMULA P, BAL- 74. LEE HH, SONG IH, FRIEDRICH M et al.: 44. DAVIS KA, WILLIAMS P, WALKER JC: DASSANO RN: Human antichimeric antibody Cutaneous side-effects in patients with Successful desensitization to high-dose meth- in children and young adults with inflamma- rheumatic diseases during application of tu- otrexate after systemic anaphylaxis. Ann tory bowel disease receiving infliximab. J mour necrosis factor-alpha antagonists. Br J Allergy Asthma Immunol 2003; 90: 87-9. Pediatr Gastroenterol Nutr 2004; 38: 502-8. Dermatol 2007; 156: 486-91. 45. VAN DER HEIJDE D, BURMESTER G, MELO- 59. CANDON S, MOSCA A, RUEMMELE F, GOU- 75. WENDLING D, BALBLANC JC, BRIANCON GOMES J et al.: The safety and efficacy of LET O, CHATENOUD L, CEZARD JP: Clinical D et al.: Onset or exacerbation of cutaneous adding etanercept to methotrexate or meth- and biological consequences of immuniza- psoriasis during TNFalpha antagonist thera- otrexate to etanercept in moderately active tion to infliximab in pediatric Crohn’s dis- py. Joint Bone Spine 2008; 75: 315-8. rheumatoid arthritis patients previously ease. Clin Immunol 2006; 118: 11-9. 76. WOLLINA U, HANSEL G, KOCH A, SCHON- treated with monotherapy. Ann Rheum Dis 60. VULTAGGIO A, MATUCCI A, NENCINI F et al.: LEBE J, KOSTLER E, HAROSKE G: Tumor 2008; 67. 182-8. Anti-infliximab IgE and non-IgE antibodies necrosis factor-alpha inhibitor-induced pso- 46. SELLAM J, ALLANORE Y, BATTEUX F, and induction of infusion-related severe ana- riasis or psoriasiform exanthemata: first 120 DESLANDRE CJ, WEILL B, KAHAN A: phylactic reactions. Allergy 2010; 65: 657-61. cases from the literature including a series of Autoantibody induction in patients with re- 61. CHEIFETZ A, SMEDLEY M, MARTIN S et al.: six new patients. Am J Clin Dermatol 2008; fractory spondyloarthropathy treated with in- The incidence and management of infusion 9. 1-14. fliximab and methotrexate. Joint Bone Spine reactions to infliximab: a large center experi- 77. LELONG J, DUBURQUE C, FOURNIER C et al.: 2005; 72: 48-52. ence. Am J Gastroenterol 2003; 98. 1315-24. [Desensitisation to infliximab in patients 47. BAERT F, NOMAN M, VERMEIRE S et al.: 62. CHEIFETZ A, MAYER L: Monoclonal antibod- with Crohn’s disease]. Rev Mal Respir 2005; Influence of immunogenicity on the long- ies, immunogenicity, and associated infusion 22: 239-46. term efficacy of infliximab in Crohn’s dis- reactions. Mt Sinai J Med 2005; 72. 250-6. 78. PUCHNER TC, KUGATHASAN S, KELLY KJ, ease. N Engl J Med 2003; 348: 601-8. 63. CASTELLS MC, TENNANT NM, SLOANE DE BINION DG: Successful desensitization and 48. VERMEIRE S, NOMAN M, VAN ASSCHE et al.: Hypersensitivity reactions to chemo- therapeutic use of infliximab in adult and G, BAERT F, D’HAENS G, RUTGEERTS P: therapy: outcomes and safety of rapid de- pediatric Crohn’s disease patients with prior Effectiveness of concomitant immunosup- sensitization in 413 cases. J Allergy Clin anaphylactic reaction. Inflamm Bowel Dis pressive therapy in suppressing the forma- Immunol 2008; 122: 574-80. 2001; 7: 34-7. tion of antibodies to infliximab in Crohn’s 64. ANG HT, HELFGOTT S: Do the clinical re- 79. BRENNAN PJ, RODRIGUEZ BOUZA T, HSU FI, disease. Gut 2007; 56: 1226-31. sponses and complications following etaner- SLOANE DE, CASTELLS MC: Hypersensitivity 49. LISI P, ASSALVE D, HANSEL K: Phototoxic cept or infliximab therapy predict similar out- reactions to mAbs: 105 desensitizations in and photoallergic dermatitis caused by hy- comes with the other tumor necrosis factor- 23 patients, from evaluation to treatment. droxychloroquine. Contact Dermatitis 2004; alpha antagonists in patients with rheumatoid J Allergy Clin Immunol 2009; 124: 1259-66. 50: 255-6. arthritis? J Rheumatol 2003; 30: 2315-8. 80. LIMSUWAN T, CASTELLS MC: Outcomes and 50. EVANS CC, BERGSTRESSER PR: Acute gener- 65. CASSINOTTI A, TRAVIS S: Incidence and safety of rapid desensitization for chemo- alized exanthematous pustulosis precipitated clinical significance of immunogenicity to therapy hypersensitivity. Expert Opin Drug by hydroxychloroquine. J Am Acad Dermatol infliximab in Crohn’s disease: a critical sys- Saf 9: 39-53. 2004; 50: 650-1. tematic review. Inflamm Bowel Dis 2009; 15: 81. RODRIGUEZ-JIMENEZ B, DOMINGUEZ- 51. DONADO CD, DIEZ EM: Successful desensiti- 1264-75. ORTEGA J, GONZALEZ-HERRADA C, KIN- zation for hydroxychloroquine anaphylaxis. 66. KAPETANOVIC MC, LARSSON L, TRUEDSSON DELAN-RECARTE C, LORIBO-BUENO P, J Rheumatol 2010; 37: 1975-6. L, STURFELT G, SAXNE T, GEBOREK P: GARRIDO-PENO N: Successful adalimumab 52. MARZANO AV, RAMONI S, DEL PAPA N, Predictors of infusion reactions during inf- desensitization after generalized urticaria BARBARESCHI M, ALESSI E: Leflunomide- liximab treatment in patients with arthritis. and rhinitis. J Investig Allergol Clin Immunol induced subacute cutaneous lupus erythema- Arthritis Res Ther 2006; 8: R131. 2009; 19: 246-7. tosus with -like lesions. 67. AUGUSTSSON J, EKSBORG S, ERNESTAM 82. NURMOHAMED MT: Newer biological agents Lupus 2008; 17: 329-31. S, GULLSTROM E, VAN VOLLENHOVEN R: in the treatment of rheumatoid arthritis: do 53. GENSBURGER D, KAWASHIMA M, MAROTTE Low-dose glucocorticoid therapy decreases the benefits outweigh the risks? Drugs 2009; H, KANITAKIS J, MIOSSEC P: Lupus ery- risk for treatment-limiting infusion reaction 69: 2035-43. thematosus with leflunomide: induction or re- to infliximab in patients with rheumatoid ar- 83. NECHANSKY A: HAHA--nothing to laugh activation? Ann Rheum Dis 2005; 64: 153-5. thritis. Ann Rheum Dis 2007; 66. 1462-6. about. Measuring the immunogenicity (hu- 54. ABRAHAM E, ANZUETO A, GUTIERREZ G et 68. AFIF W, LOFTUS EV, JR, FAUBION WA et al.: man anti-human antibody response) induced al.: Double-blind randomised controlled trial Clinical utility of measuring infliximab and by humanized monoclonal antibodies apply- of monoclonal antibody to human tumour human anti-chimeric antibody concentrations ing ELISA and SPR technology. J Pharm necrosis factor in treatment of septic shock. in patients with inflammatory bowel disease. Biomed Anal 2010; 51: 252-4. NORASEPT II Study Group. Lancet 1998; Am J Gastroenterol 2010; 105: 1133-9. 84. TRUONG W, PLESTER JC, HANCOCK WW et 351: 929-33. 69. GAMARRA RM, MCGRAW SD, DRELICHMAN al.: Combined coinhibitory and costimulato- 55. ABRAHAM E, WUNDERINK R, SILVERMAN VS, MAAS LC: Serum sickness-like reactions ry modulation with anti-BTLA and CTLA4Ig H et al.: Efficacy and safety of monoclonal in patients receiving intravenous infliximab. facilitates tolerance in murine islet allografts. antibody to human tumor necrosis factor J Emerg Med 2006; 30. 41-4. Am J Transplant 2007; 7: 2663-74. alpha in patients with sepsis syndrome. A 70. TONELLI AR, LOTTENBERG R, ALLAN RW, 85. LINHART B, BIGENZAHN S, HARTL A et al.: randomized, controlled, double-blind, multi- SRIRAM PS: Rituximab-induced hypersen- Costimulation blockade inhibits allergic center clinical trial. TNF-alpha MAb Sepsis sitivity pneumonitis. Respiration 2009; 78: sensitization but does not affect established Study Group. Jama 1995; 273: 934-41. 225-9. allergy in a murine model of grass pollen al- 56. CAMPI P, BENUCCI M, MANFREDI M, 71. PALTIEL M, GOBER LM, DENG A et al.: lergy. J Immunol 2007; 178: 3924-31.

566