Omalizumab and adalimumab: a winning couple

Abstract

Introduction: We report a case of a young female patient, previously affected by psoriatic arthritis, and treated with adalimumab, who developed a chronic spontaneous urticaria and started a concomitant therapy with omalizumab. Methods & results: A 50% reduction of the Dermatology Life Quality Index (from 7 at baseline to 4 in weeks 12 and 24) and a complete reset of the Urticaria Activity Score for 7 days (from 27 at baseline to 0 in weeks 12 and 24) were recorded. During all treatment with omalizumab, administering of adalimumab was continued. Due to complete control of urticaria symptoms, the patient stopped treatment with omalizumab after 24 weeks. Conclusion: The combination of adalimumab and omalizumab could offer a favorable efficacy and safety profile. The synergistic action of the two biological drugs in reducing systemic inflammation could be responsible for a shorter time to obtain clinical response.

Chronic spontaneous urticaria (CSU) is per definition a disturbing and detrimental condition characterized by recurrent itching wheals that persist at least 6weeks, often associated with presence of angioedema. CSU is the most common subtype of urticaria affecting from 0.5 to 5% of the general population. Females are most commonly affected, and peak age of onset in adults is 20-40years (1). The pathogenesis is still not fully elucidated; however, multiple studies havesuggested a pivotal role of autoimmunity in up to 45% of cases (2). Second-generation H1-antihistamine therapy represents the key drugs for CSU patients, even if up to 50% of individuals may require additional therapy to relieve symptoms (3). The humanized IgG1k monoclonal antibody omalizumab targets the binding site on free IgE and was firstapproved in the USA in 2003 for allergy-induced asthma (4,5) and recently approved for patients affected by CSU aged 12years and older who are resistant to antihistamines. Real-world evidencehasprovided robust evidenceon the efficacy and safety of omalizumab in thepediatric and adult patient population affected by severe allergic asthma, and arecent report established significant improvement, good safety and tolerability profile in complex patients affected by CSU (6-8). Furthermore, omalizumab could also be considered in pregnancy, being classified as a category-B drug (9). Omalizumab exerts its action through selective capture of circulating free IgE, with consequent lowering of their level and downregulation of their receptors (FcεRI) on basophils and mast cells. These mechanisms could lead to a reduction of IgE-related responses and a lowering of the number of eosinophils, mast cells and basophils. In addition, drug-IgE complexes could be able to trap antigens and induce a reduction of IgE⁺ B cells and IgE synthesis (10). The fully humanized monoclonal antibody adalimumab is capable of both stopping cytokine signaling of soluble and transmembrane TNF-αand blocking TNFR1 (p55) and TNFR2 (p75) cell surface glycoprotein receptors (11,12). Adalimumab was initially approved for treatment of adult rheumatoid arthritis (RA) in 2002 in the USA and in 2003 in Europe. Adalimumab is now indicated for use in 12 different conditions, including adult and pediatric (>4years) chronic plaque psoriasis (PsO) and psoriatic arthritis (PsA) (13). Numerous PsO and PsA trials demonstrated the efficacy and safety of adalimumab as well as other immunomodulatory imide drugs (11). In addition, adalimumab is assigned to pregnancy category B. The etiological mechanism that induces the onset of psoriasis is unclear; however, immune dysregulation with abnormal secretion of cytokines and inflammatory mediators has been widely documented. Epidermal keratinocyte hyperproliferation and abnormal differentiation, local lymphocytic infiltration and angiogenesis are due to the crosstalk between cytokines and cells (14). TNF-αis one of the main proinflammatory cytokines involved in thepathogenesis of psoriasis. This cytokine interacts with different cell receptors, inducing an amplificated and pleyotropic inflammatory response and involving different pathways (15,16). Several studies have shown that the efficacy of adalimumab is due to its capability to induce a reduction in p38 MAPKand a reduction of IL-1b, IL-8, IL-17C and IL-20 (17). In recent years, sporadic cases regarding the sequential or combined use of biological drugs in patients suffering from various chronic inflammatory diseases have been described in the literature (18,19). We report a case of a young female patient suffering from psoriasis and urticaria in concomitant treatment with two different biologics.

Case report

A 21-year-old white female presented to our Dermatologic Unit for evaluation of recurrent episodes of urticaria and angioedema. Symptoms began to appear approximately 1year prior and had progressively worsened, with no associated, aggravating or relieving factors noted. Medical history was significant for psoriasis and PsA, lipoedema, insulin resistance and hyperinsulinemia, polycystic ovary, hiatal hernia, colitis and renal lithiasis. Her family history was positive for psoriasis, PsA and atopy. Her current medications included adalimumab for 2years, cetirizine, cyproterone, ethinylestradiol, glucophage and omeoprazole. Laboratory tests, including full blood count, liver and kidney function tests, electrophoresis, fibrinogen activity testing, parasitology testing, thyroid and antibody function tests, antinuclear antibody testing, extractable nuclear antigen panel, total IgE level, C1 esterase inhibitor test, markers of hepatitis B and C viruses and erythrocyte sedimentation rate were normal. The total IgE result was94.70IU/mlover a normal range of 0.0 to100.0. Increased C-reactive protein of 0.53 (normal range: 0 to0.5) was found. Skin tests (skin prick and patch testing) carried out due to the strong familiarity of atopy were negative. Diagnosis of CSU was confirmed by history, clinical and histological features (Figure 1and2). Omalizumab 300mg as an add-on to H1-antihistamines was administered by subcutaneous injection every 4weeks for 6months. Clinical assessment of theUrticaria Activity Score for 7days (UAS-7) and Dermatology Life Quality Index (DLQI) were performed at baseline, 12 weeks and 24weeks of treatment. A dramatic improvement in urticaria symptoms was recorded from the first weeks of therapy, with a 50% reduction of the DLQI (from 7 at baseline to 4 in weeks 12 and 24) and a complete reset of the UAS-7 (from 27 at baseline to 0 in weeks 12 and 24). During all treatment with omalizumab, administering of adalimumab 40mg every other week was continued as indicated for PsA. Due to complete control of urticaria symptoms, the patient stopped treatment with omalizumab after 24weeks. No adverse event was reported. 6months after treatment discontinuation, the patient remained urticaria free.

Figure 1. Urticarial clinical and histopathological features. Presence of numerous wheals on the extremities of the patient before the anti-IgE treatment.

Figure 2. Urticarial clinical and histopathological features. A and B. The skin samples show mild edema of the superficial dermis associated with perivascular inflammatory infiltrate (hematoxylin-eosin stain; original magnification 100x). C. In this higher magnification of A. , it is possible to observe neutrophils filling vessels of the upper dermis (blue arrows) and an isolated perivascular mast cell (black arrow; hematoxylin-eosin stain; original magnification 400x). D. In this higher magnification of B. , interstitial eosinophils are prominent (green arrows; hematoxylin-eosin stain; original magnification 400x).

Discussion

Autoimmune diseases have been on the rise throughout westernized societies over the past decades, affecting young women, above all those with a positive family history and a genetic predisposition, as in our patient. According to the theory of ‘overlapping autoimmune diseases’, autoimmune disorders occur at increased frequency in patients with known and pre-existing autoimmune disease (2). As reported by Kolkhir et al., numerous autoimmune conditions, including insulin-dependent diabetes mellitus, RA, celiac disease, Graves’disease, vitiligo, pernicious anemia, Hashimoto’sthyroiditis and psoriasis have been associated with chronic urticaria (20). No specific provoking factor for CSU has been identified yet. Although the mechanisms at the basis of CSU remain to be completely clarified, it seems plausible that both autoimmunity (IgG-related condition) and autoallergy (IgE-mediated condition) can act together for the onset of CSU and increase the susceptibility to the development of other autoimmune diseases (2). Our patient can be defined as an early responder, as significant clinical efficacy was observed in the first days after administration of omalizumab, associated with a dramatic reduction in UAS-7 in the first month of therapy (21). In our case, omalizumab was shownto be particularly effective, even if the IgE levels were at the upper end of the normal range. This could be due to the presence of autokinergic IgE, autoantibodies capable of evoking a powerful inflammatory response, not always traceable in common laboratories (22). Cytokinergic IgE represents a subpopulation of antibodiesthat are capable of binding the FcεRI even in the absence of the antigen, inducing the activation of inflammation(23). Omalizumab blocks the Cε3 domain of free IgE, inhibiting the interaction to its high-affinity receptor and downregulating its expression on mast cells and basophils (24). This latest mechanism of the drug prevents large aggregates of FcεRI, blocking the activation of mast cells and the release of inflammatory cytokines. Adalimumab is a human monoclonal antibody that blocks soluble and membrane-bound TNF-α, a pivotal mediator involved in inflammatory conditions, including autoimmune disorders, cancer and allergy. By targeting TNF through its receptor TNFR2, adalimumab has shown to neutralize TNF proinflammatory activities and to determine tolerance by stimulating regulatory T (Treg) cells in model of RA (25). Upon activation, the pleiotropic cytokine exerts through two signaling cascades: NF-κ-light-chain-enhancer of activated B cells and MAPK(25). The latter would be effectively reduced by adalimumab, as demonstrated in lesional psoriatic biopsies. Through epidermal p38 MAPK blockade, adalimumab may inhibit keratinocytic infiammation and proliferation and thereby stop their crosstalk with the cells of theimmune system (26). Moreover, TNK blockade may inhibit multiple kinases and signal pathways, including p38 MAPK, a crucial kinase for IgE class switch recombination (27). Therefore, by reducing theIgE level, adalimumab and the other TNF antagonistmay induce antiallergic effects (25). However, omalizumab could contribute to this mechanism of action by further reducing the number of circulating free IgE and, as suggested by Gadir et al., by increasing Treg cell activity due to the reversal of their Th2 cell-like program (28). Only two reports regarding concomitant use of biologics in complex patients have been described to date. In one report, two young female patients (25 and 35years old) were treated with adalimumab for psoriasis for 64months and 9months, respectively. After the appearance of urticaria, they underwent concomitant treatment with omalizumab for 9 and 8months, in the absence of side effects (18). In the case reported by Ghazanfar and Thomsen, a 64-year-old female patient was treated with omalizumab for CSU and currently with etanercept for RA. The combined treatment lasted for 3 months without the occurrence of adverse events (19). As in the cases mentioned previously, our patient required a very short course of treatment with omalizumab (6months) compared with the average (the mean±SD omalizumab treatment duration was 9.1±3.8months) (29). One may speculate that the synergistic action of the two biological drugs in reducing systemic inflammation could be held responsible of the shorter time required to obtain clinical response. The median time to obtain a good control of urticaria symptoms (UAS7 ≤6) was 6weeks and median time to achieve a UAS=0 was 12 or 13weeks (ASTERIA I and GLACIAL).

Conclusion

In our case, the clinical history and the follow-up period suggested that the combination of the two drugs could be more effective than the single biological medicine. However, immunohistochemical and molecular studies will be needed in the near future to understand the difference between the two approaches. In patients of childbearing age with at least two autoimmune diseases or with predisposing factors (e.g., female sex, familiarity or with predisposing genetics), it is mandatory to establish therapeutic strategies aimed at minimizing side effects and increasing the therapeutic profile of drugs: the choice must be made taking into account the different pathogenesis of diseases, the mechanism of action and the safety profile of the chosen drugs. Adalimumab and omalizumab offer a favorable efficacy and safety profile over time and the possibility of pregnancy in young patients. With our report, we add to the literature our experience regarding the concomitant use of omalizumab and adalimumab in a young female patient affected by both PsA and CSU, with a favorable outcome and no adverse events. Further immunohistochemical and molecular studies are needed to investigate possible benefits of single or combined combination treatment with biologics in complex patients.

Summary points

• Autoimmunity and autoallergy can act together for the onset of chronic spontaneous urticaria (CSU) and increase susceptibility to the development of other autoimmune diseases.
• Omalizumab is a humanized monoclonal antibody for the treatment of CSU that targets the binding site on free IgE.
• Adalimumab is a recombinant, fully human, monoclonal antibody capable of stopping TNF-αand indicated to treat 12 different conditions, including chronic plaque psoriasis and psoriatic arthritis. TNF blockade may inhibit multiple kinases and signal pathways, including p38 MAPK, a crucial kinase for IgE class switch recombination. Therefore, by reducing the IgE level, adalimumab and the other TNF antagonist may induce antiallergic effects25.
• Omalizumab could contribute to this mechanism of action by further reducing the number of circulating free IgE and by increasing Treg cell activity due to the reversal of their Th2 cell-like program.
• The synergistic action of the two biological drugs in reducing systemic inflammation could be held responsible for a shorter time to obtain clinical response in CSU.
• The combination of adalimumab and omalizumab could offer a favorable efficacy and safety profile.

Author contributions

L Diluvio wrote the main manuscript, and L Vollono and A Zangrilli contributed substantially to the acquisition of data and information. All authors reviewed the manuscript. All authors read and approved the final version of the manuscript.

Financial and competing interests disclosure

L Bianchi was consultant and speaker for Novartis and Abbvie. The publication of this research was supported by Novartis Farma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained verbal and written informed consent from the patient for the inclusion of her medical and treatment history within this work.

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