DÄ internationalArchive6/2022Paradoxical Reactions to Biologicals in Chronic Inflammatory Systemic Diseases

Review article

Paradoxical Reactions to Biologicals in Chronic Inflammatory Systemic Diseases

Dtsch Arztebl Int 2022; 119: 88-95. DOI: 10.3238/arztebl.m2022.0067

Kremenevski, I; Sander, O; Sticherling, M; Raithel, M

Background: Biological agents that contain substances affecting the immune system are increasingly being used to treat chronic inflammatory systemic diseases. Aside from the expected adverse effects, they can also induce unexpected paradoxical reactions (PR). A reaction is called paradoxical when a substance that is generally therapeutically effective induces the opposite of what is intended, with the new appearance or exacerbation of inflammatory changes in the skin and other organs.

Methods: The paradoxical reactions that have been described since 1997 are presented here on the basis of the available literature on the main types of chronic inflammatory systemic disease, which was retrieved by a selective search in the PubMed and Google Scholar databases.

Results: Many studies and registers to date contain no mention of paradoxical reactions. Anti–TNF-alpha treatment for patients with ankylosing spondylitis leads to paradoxical reactions in 19 per 1000 patient years, compared to 11 per 1000 patient years with conventional treatment; the corresponding frequency for paradoxical psoriasis in patients with other chronic inflammatory systemic diseases are 1.04–3.68 versus 1.45 per 1000 patient years. Paradoxical reactions tend to be more common with anti–TNF-alpha treatment than, for example, with the administration of ustekinumab, vedolizumab, and other agents. It is unclear whether some drugs have been noted to cause PR more commonly than others because of varying times since their approval, differences in immunogenicity, and differences between their target structures.

Conclusion: Paradoxical reactions induced by biological agents are a problem confronting physicians in multiple specialties. They need to be distinguished from infectious and neoplastic diseases and from autoimmune conditions of other types. The treatment options for paradoxical reactions include local treatment, symptomatic therapy, prednisolone administration, and the discontinuation or switching of the biological agent, although some patients will react with a further paradoxical reaction to a different biological agent that is used instead.

LNSLNS

The treatment of rheumatoid arthritis (RA), spondyloarthritis (SPA), chronic inflammatory bowel disease (IBD), psoriasis (PSO), and other chronic systemic inflammatory diseases has been significantly improved by the use of biological agents (biologics, biologicals). Biologics are genetically engineered, high molecular weight proteins that resemble the body’s own substances. These include anti-tumor necrosis factor (TNF)-alpha monoclonal antibodies, PEGylated Fab’ antibody fragments (certolizumab), TNF receptor Fc fragment fusion proteins (etanercept), cytokine antagonists (for example, interleukin (IL)-12/23 antagonist ustekinumab), receptor and integrin antibodies (for example, vedolizumab), and therapies directly targeting cells (1, 2, 3). Administered parenterally as (glyco)proteins, they can trigger the following reactions (4, 5, 6):

  • non-immunological, dose-dependent immunosuppressive adverse drug reactions (ADRs)
  • allergic and non-allergic hypersensitivity reactions
  • unexpected paradoxical reactions (PR).

Whereas non-immunological, dose-dependent immunosuppressive ADRs of biological agents are recorded in many registers compiled by various disciplines (1, 2, 3, 7, 8, 9, e1, e2, e3, e4), PR are considered rare individual immunological reactions (1, 2, 3, 10).

Definition of paradoxical reactions and clinical problems

Paradoxical reaction is the term used to describe the effect of a drug approved for a specific indication when the use of this otherwise therapeutically active substance induces the opposite of what is intended, the recurrence of non-infectious inflammation, or the exacerbation of a predisposed disease (10, 11, 12, 13, e1, e2, e3, e7, e8, e9). Criteria for PR are met when there is no infection or activation of an occult infection, no biological agent-induced autoimmune reaction, and no malignant transformation, and the new-onset disease manifestation is not due to an increase in disease activity of the underlying condition (10, 11, 12, 13, 14, e2, e5, e6).

Since around 1997, PR became known mainly in connection with anti-TNF-alpha therapies (1, 2, 3, 10, 11, 12, 13, e2, e3, e7). Nowadays, the spectrum is widening to include many other groups of biological agents and needs to be continually updated (13, e7, e10, e11, e12, e13, e14, e15, e16, e17, e18, e19, e20, e21, e22, e23). The main clinical problem of PR is to recognize such reactions at all, because it is not uncommon for the patient to present to a different specialty than that which initially prescribed the biological agent (12, 14, 15, 16, 17, 18, 19, 20, 21). Being able to even consider PR when making a diagnosis requires an accurate medication and family history (predisposition).

The aim of this review article is to present the results of a literature review using the search term “paradoxical reaction to biologicals” in the PubMed and Google Scholar databases up to May 2021 and to differentiate PR from other adverse reactions. It became apparent that PR were not considered a particular problem, even in larger registers, due to their uncommon nature (1, 2, 3, 7, 10, e1, e2, e3, e5, e6, e7, e8). This is also a possible reason for the lack of references to PR in drug approval studies (for example, in the benefit analysis of the German Institute for Quality and Efficiency in Health Care [IQWiG]), even after thorough evaluation (7, e1-e3), and in product information documents.

Results

PR are considered aberrant, immunologically explainable disease reactions. They may present in various organs with few manifestation clusters (for example, psoriasiform skin reactions, arthralgias, or arthritis) and in many other more uncommon manifestations (for example, granulomatous skin and lung lesions, vasculitis, pyoderma gangrenosum). PR during biological therapy show different underlying kinetics than typical adverse drug reactions. They occur after a median latency of 6–12 months of therapy, with individual cases of PSO reported as early as 4 days of treatment (1, 2, 3, 10, e1, e5). Their occurrence is difficult to predict due to the lack of biomarkers with high predictive power and no phenotypic spectrum nor clinical characteristics.

It is typical for the majority of PR that good therapeutic efficacy is usually found in the organ system presenting the inflammatory manifestation for which the therapeutic indication exists. In contrast, a new disease symptomatology is subsequently induced in other, non-involved organ systems due to an immunopathological reaction, or an established disease predisposition is exacerbated (1, 3, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28). Extremely rare exacerbations and changes in disease phenotype in the affected organ system have also been reported (20, 21, 28, e2, e5, e6, e23, e24, e25).

Characteristic features of PR found in the literature and those based on our own experience are listed in the Box. PR are not a class effect of anti-TNF-alpha therapies, because they also occur in association with other biological agents (for example, IL-17 antagonists, ustekinumab, tocilizumab, etc.) (7, 10, 13, 21, 22, 26, 27, 28, 29, e26).

Incidence rates of paradoxical reactions to biological agents

Incidence rates depend on the examined patient population, the biological agent used, duration of treatment, study or observation period, concomitant immunosuppression, and the question of whether the reaction is even recognized as a PR (3, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, e5, e6, e7, e10). Based on literature data, different rates are found among anti-TNF biologics, for example, for how often PSO occurs in RA or in Crohn’s disease and ulcerative colitis, or uveitis and enterocolitis in rheumatic diseases, including juvenile idiopathic arthritis (JIA) (16, 17, 20, e51, e52, e53, e54, e60, e61, e62, e63, e64). The question of whether a PR occurs at all and preferentially in a certain patient population, and in what form or frequency depends not only on the biological agent, but also on patient-specific factors (Table 1; 10–19, e23, e24, e25, e60, e61, e62, e63, e64). As yet, there are no comprehensive systematic surveys covering all indications and groups of biological agents (13, 21, e19, e20, e21, e22, e23, e24, e25). The evaluation of incidence rates is largely limited by the fact that longer prescription periods, a larger number of indications, and thus higher prescription numbers are available for anti-TNF drugs than for newer biologics (for example, ustekinumab, vedolizumab) (21, 26, e27, e69, e43, e72, e73, e74, e75, e76, e77). This could lead to PR being underestimated for future biological agents, so this should be taken into account when interpreting Table 1.

Overview of common paradoxical reactions occurring during treatment with biological agents for chronic systemic inflammatory diseases
Table 1
Overview of common paradoxical reactions occurring during treatment with biological agents for chronic systemic inflammatory diseases

That PR do exist is confirmed by the evaluation of conventionally treated control collectives in which either no or very few PR were detected (16, 17, 20, e51, e60, e61, e62, e63, e64).

For example, in the product information documents of TNF inhibitors, infusion reactions are reported as very common (>1 : 10 for infliximab) and PSO lesions, rash, urticaria, alopecia, and eczema, etc., as common (1 : 10–1 : 100), although PR are not explicitly mentioned and no differentiation is made between paradoxical and allergic adverse reactions (e12, e13, e14, e15, e16).

The spectrum of important PR known to date is listed in Table 2. Apart from typical reported PR, such as PSO, arthralgias, or arthritis, many uncommon individual forms have been also been described (3, 12, 13, 14, 16, 21, 22, 23, e1, e2, e3, e11, e16, e17, e18, e19, e20, e21, e22, e23, e24, e25).

Semiquantitative spectrum of paradoxical reactions (PR) to biological therapy in chronic inflammatory systemic diseases
Table 2
Semiquantitative spectrum of paradoxical reactions (PR) to biological therapy in chronic inflammatory systemic diseases

Immunopathogenesis and differential diagnosis of paradoxical reactions in chronic inflammatory systemic diseases

Suspected PR must be distinguished from an infectious complication, change in disease phenotype, and extraintestinal manifestations (for example, an eye inflammation concomitant to IBD). A PR may also present as a significant deterioration of the underlying condition, change in clinical picture (for example, change from plaque PSO to pustular PSO), a new-onset of another disease, or a relapse (7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Systemic symptoms such as fever, lymphadenopathy, skin and eye lesions, as well as hepatosplenomegaly, in addition to sarcoidosis-like lung and skin changes, should in the first instance suggest infection, tuberculosis or lymphoma development. They should therefore first be excluded during biological therapy (7, 10, 14, 16, 20, 21, 22, 23) before the above criteria for PR are considered to be fulfilled (Box; 7, 10, 14, 16, 17, 18, 19, 20, 21, 22, 23).

New disease symptoms must be distinguished from deterioration of the underlying condition (review the disease activity) or loss of efficacy of the biological agent. For example, secondary loss of effect of the biological agent can develop if the drug is excreted secondary to protein-losing enteropathy, or if antibodies (also known as anti-drug antibodies [ADA]) are formed (1, 11, 18). If the clinical picture is unclear, the therapeutic levels of the biologic used or, with certain substances, the ADA may be measured to detect loss of active substance or a reduced effect due to antibody formation (1, 11, 17, 18, 19, 20, 21, 24, 25). With PR, the plasma levels of the biologics are usually within normal limits.

The problem is that in some patients the development of PR during biological agent use is varied and unpredictable. Even after a biological agent has been withdrawn or a switch to a biologic of a different class has been made, PR may still recur in genetically predisposed patients (10, 16, 17, e2, e4, e8, e11, e16). In the literature, even double and triple PR have been reported in individual patients (16, 17, 19, 20, 21).

A model explaining the majority of PR to TNF inhibitors is shown in the Figure. Not only can a biological agent reach the inflamed organ compartment, where it exerts its anti-inflammatory effect, but it also reaches healthy tissue, where it binds to target proteins, such as TNF-alpha, alters the cytokine balance (for example the ratio between interferon and TNF-alpha), activates dendritic cells, and can thus induce the PR (1, 2, 3, 11, 16, 21, 23, 24, 25, 26). The fact that biological agents often cause PSO lesions is due to the anti-TNF-alpha effect on the dendritic cells of the skin disinhibiting interferon-alpha formation and thereby triggering an excess production of IL-23. This ultimately causes hyperproliferation of skin epithelium by activating neutrophils via Th17 cells, on the one hand, and by enhancing IL-22 action on keratinocytes on the other (3, 17, 20, 25, 26, 27, e2, e5, e6). Similar immune mechanisms have also been reported for PR in other organ areas and, very rarely, in the inflamed organ system itself (progression of the underlying condition or primary failure of action) (12, 13, 14, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32; e6, e18, e23, e24).

Immunopathogenetic explanatory model illustrating the emergence of paradoxical reactions using TNF-inhibiting biological agents
Figure
Immunopathogenetic explanatory model illustrating the emergence of paradoxical reactions using TNF-inhibiting biological agents

The plasticity of PR suggests diverse aberrant immune pathways. Various immune phenomena can develop, depending on the biologic used. This means, on the one hand, that PR to anti-TNF-alpha antagonists (arthritis, PSO), for example, can be treated with ustekinumab, while PR induced by ustekinumab (for example, also arthritis or PSO), on the other hand, are treatable with TNF alpha antagonists (19, 21, 26, 27, 28, 29, e25).

Discussion and recommended action

Paradoxical reactions in dermatology

Many rare PR to various biologicals manifest frequently on the skin (Table 2) (3, 11, 12, 13, 16, 21, e2, e5, e6, e7, e19, e20, e50, e51, e52, e53, e54, e55, e56, e57, e77).

Pustular PSO is relatively common after the administration of TNF inhibitors for the treatment of plaque PSO. In this case, the plaques can either completely transform into pustular PSO (generalized or localized) or the pustules occur concomitantly (PSO cum pustulatione) (3, 12, 21, 26, e19, e20), which usually does not happen in a spontaneous setting. The exacerbation of plaque PSO as a diagnostic indicator and even the development of PSO arthritis in patients taking biological agents are also considered PR in principle.

In rheumatology, psoriasiform (PSO-like) eczematous skin changes are relatively common in patients taking TNF blockers, as well as those on IL-6 inhibitors (2, 3, 15, 16, e63, e67). Psoriasiform skin changes are particularly evident with anti-TNF treatment of IBD patients at 3.6/1000 – as opposed to 1.4/1000 person-years with conventional treatment, with patients with Crohn’s disease being more commonly affected (Table 1; 10–12, 17, 18, 19, 20, 21, e2, e5, e21, e71). Although PR are not reported in all reference citations, individual studies report of PSO-like skin changes with clinically and histologically classic PSO manifestations being induced in 3–16% of all treated patients with IBD who previously had healthy skin, (17, 18, 19, 20, 21, 28, e61, e63, e66, e71).

Whether a switch to IL-17 or IL-12/23 inhibitors is indicated in the event of psoriasiform skin changes in patients on TNF inhibitors has not yet been systematically investigated, but there are case reports of switching to ustekinumab after the development of psoriasiform changes (12, 26, 27, 28, 29). Ustekinumab has been used very effectively in patients with IBD suffering from anti-TNF-induced PSO (27). On the other hand, PR in the form of enterocolitis have also been reported to have developed in patients taking IL-17 inhibitors and ustekinumab for the treatment of PSO, PSO-arthritis and SPA (13, 21, 26, 27, 28, 29, 30, 31).

There are also reports of other rare dermatological symptoms (for example, pyoderma gangrenosum, erythema nodosum, hidradenitis suppurativa) developing under biological therapy that show the typical characteristics of a PR (Box, Table 2; 21, 29, 30, 31, 32, 33, 34, e6, e23, e54).

Paradoxical reactions in gastroenterology

Apart from PSO-like skin changes, arthritis and arthralgias, patients with IBD can also develop uveitis, scleritis, sarcoidosis, and pyoderma gangrenosum, among others, albeit less commonly (Table 1, Table 2). They must be distinguished from extra-intestinal manifestations and other causes.

A severe form of PR is the manifestation of enterocolitis during treatment with biological drugs. This is very similar to IBD, although not identical. It is another example of drug-induced bowel inflammation (13, 21, 26, 27, 28, 29, 31, 32). At least 158 cases of new-onset enterocolitis have been reported in the RA and JIA registers of the U.S. FDA, the majority during treatment with etanercept (82%); and more recently, some in connection with IL-17A inhibitors too (13, 21, 32, 33, 38, e18, e22, e23, e25, e58, e60, e65, e70). Basically, it also applies for IBD that a new relapse can be triggered instead of therapy-induced remission (26, 29, 31, 32, 33, 34, e22, e23, e24, e25). However, in the majority of these bowel inflammations, the relapse can be successfully treated by drug withdrawal or switching to another anti-TNF antibody or to ustekinumab or vedolizumab, in addition to conventional therapy for IBD (13, 27, 28, 29, 34, 35, 36, e22, e23, e24, e25, e26, e27).

Paradoxical reactions in rheumatology

Biological agents are prescribed above all for severe exacerbations, in combination with methotrexate in RA and almost exclusively as monotherapy in SPA (2, 7, 16, 36, 37, 38, e1, e8, e28, e29, e30, e31, e32, e33, e34, e35, e36, e37).

PR have been reported in all indications and for almost all classes of biological agents across their entire range (Table 2) (1, 2, 3, 10, 11, 12, 16, 28, 36, e28, e29, e30). Given their long period of availability following early marketing approval, etanercept, infliximab, and adalimumab have more comprehensive data available on PR in patients with RA, SPA, and PSO arthritis, as well as on their respective treatments (16, 36, 37, 38, e1, e8, e28, e29, e30, e31, e32, e33, e34, e35, e36, e37). In general, different immunophenomena due to TNF inhibitors are seen in patients with seropositive RA than in those with spondyloarthritis. The latter patients show more similarities with CED and PSO patients, with clustered occurrence of uveitis as well as actual CED and PSO, whereas in RA humoral immunoreactions, such as autoantibody formation, lupus-like diseases or vasculitis, are significantly more frequent (37, 38, 39, 40, e29, e30, e31, e32, e33, e34, e35, e36, e37).

The autoimmune phenomena observed in RA patients on TNF inhibitors often regress once therapy is interrupted (2, 16, 22, 36, 37, 38, 39, e1, e8, e33, e34). Therapeutically, rituximab is especially indicated for patients presenting a humoral immunoresponse, although tocilizumab, anakinra, or a Janus kinase (JAK) inhibitors may also be used (39, 40). Concomitant methotrexate therapy may reduce PR induced by biologics (19). Any known risk for autoimmune phenomena should be taken into account when selecting a biological agent. For example, etanercept and TNF antibodies should not be chosen after a history of uveitis associated with familial multiple sclerosis (36, 37, 38, 39, e35, e36, e37, e38, e39, e40).

Treatment options for paradoxical reactions

Whether extension or change of therapy is indicated will depend on the underlying condition, the type, severity, and extent of the PR, and the therapeutic alternatives.

In the event of life-threatening or organ-threatening reactions, such as lupus-like glomerulonephritis or encephalitis, biological therapy must be discontinued and steroid therapy started at 1–2 mg/kg. Most patients respond well to this approach, so any stronger immunosuppression (e.g. with cyclophosphamide) can be avoided (2, 10, 11, 12, 13, 21, 22, 23, 24, 26, 27, 28, 29, 30, e1, e10, e16, e17, e18, e28, e29, e30). With life-threatening PR, the patient should not, if possible, be re-exposed or switched to an agent of the same class (for example, switching from infliximab to adalimumab) (2, 10, 11, 12, 21, 22, 23, 24, 29). However, re-exposure or a switch may well be considered for mild and moderate forms (16, 17, 18, 19, 21, 40, e1, e10, e23, e24, e25, e26).

With severe PR, the biological agent should be withdrawn (if the underlying disease is in remission) or therapy should be switched to a different class of agents (if the underlying condition is active), for example in the case of SPA treatment, from a TNF inhibitor to an IL-17 inhibitor (3, 19, 20, 21, 26, 28).

Mild to moderate PR in patients receiving TNF antagonists can often be successfully treated by discontinuing them or switching to another TNF inhibitor, ustekinumab, or IL-17A antagonist (1, 2, 3, 21, 22, 23, 26, 29, e16, e18, e20, e23). Switching to a different TNF inhibitor carries a certain risk of recurrence, depending on the clinical picture (for example, 50–60% in patients with PSO) (10, 13, 15, 16, 17, 21, 28, e18, e53, e57, e64).

Mild PR (unremarkable PSO, arthritis) can often be adequately controlled symptomatically (external medicines, non-steroidal anti-inflammatory drugs (NSAIDs), joint injections), and in pustular PSO also with the help of retinoids or by adding methotrexate. The biological agent can then be continued (2, 17, 18, 19, 21, 40).

Patients who have a paradoxical reaction to biologics should be treated, where indicated, with conventional drugs (for example, steroids) or by applying therapeutic principles that do not induce PR (Janus kinase inhibitors) (10, 11, 12, 13, 21, 29, 35, 40, e1, e2, e24).

Conclusions

PR should be explicitly recorded in biologic registers. We advise reporting possible PR as adverse drug reactions, not least to provide a better basis for estimating incidence rates in real-world care settings.

In addition, samples from affected patients should be preserved in a biobank to identify possible genetic predisposition patterns by cluster analysis and to provide individualized treatment options in the future to avoid PR (18, 25, 36, e35, e65, e68).

Conflict of interest statement
University Lecturer Dr. Sander received consultancy payments from Swedish Orphan Biovitrium and EUSA Pharma. He received lecture fees from AbbVie, Janssen Cilag and EUSA Pharma. He served as a paid expert consultant for Hogan Lovells International LLP in a matter related to the topic.

Prof. Sticherling received research support from Novartis Pharma. He has been reimbursed for presentations by Abbvie, Almirall, Boehringer, Celgene, Janssen Cilag, Pfizer, Novartis, Leo, Sanofi and UCB. He received reimbursement of congress attendance fees and travel costs from Abbvie, Janssen Cilag, Novartis and UCB. He is a member of the Advisory Boards of Abbvie, Amgen, Biogen, Celgene, Janssen Cilag, Leo, Lilly, Pfizer, Novartis, Sanofi and UCB. He is also a member of the Scientific Advisory Board of the German Psoriasis Association.

Prof. Raithel received lecture fees from Janssen Cilag and the Falk Foundation.

Mr. Kremenevski confirms that there are no conflicts of interest.

Manuscript received on 1 July 2021, revised version accepted on 24 November 2021

Translated from the original German by Dr. Grahame Larkin, MD

Corresponding authors
Prof. Martin Raithel MD, Igor Kremenevski

Malteser Waldkrankenhaus St. Marien, Gastroenterology, Interventional Endoscopy, Hemato-Oncology, Diabetes and Metabolic Diseases, Rathsberger Str. 57, 91054 Erlangen, Germany

martin.raithel@waldkrankenhaus.de

Cite this as:
Kremenevski I, Sander O, Sticherling M, Raithel M: Paradoxical reactions to biologicals in chronic inflammatory systemic diseases. Dtsch Arztebl Int 2022; 119: 88–95. DOI: 10.3238/arztebl.m2022.0067

Supplementary material

eReferences:
www.aerzteblatt-international.de/m2022.0067

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Malteser Waldkrankenhaus St. Marien, Gastroenterology, Interventional Endoscopy, Hemato-Oncology, Diabetes and Metabolic Diseases, Erlangen, Germany: Igor Kremenevski, Prof. Martin Raithel MD
The Policlinic of Rheumatology & Hiller Research Unit at the Heinrich-Heine University Düsseldorf, Germany: University Lecturer Dr. Oliver Sander MD
Dermatology Department of the University of Erlangen, Psoriasis Center Erlangen, German Center for Immune Therapy, Erlangen: Prof. Michael Sticherling MD
Immunopathogenetic explanatory model illustrating the emergence of paradoxical reactions using TNF-inhibiting biological agents
Figure
Immunopathogenetic explanatory model illustrating the emergence of paradoxical reactions using TNF-inhibiting biological agents
Overview of common paradoxical reactions occurring during treatment with biological agents for chronic systemic inflammatory diseases
Table 1
Overview of common paradoxical reactions occurring during treatment with biological agents for chronic systemic inflammatory diseases
Semiquantitative spectrum of paradoxical reactions (PR) to biological therapy in chronic inflammatory systemic diseases
Table 2
Semiquantitative spectrum of paradoxical reactions (PR) to biological therapy in chronic inflammatory systemic diseases
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