Adverse cutaneous reactions to anakinra in patients with rheumatoid arthritis: clinicopathological study of five patients

Abstract

Background Anakinra, a recombinant human form of interleukin-1 receptor antagonist, is used to treat patients with active rheumatoid arthritis (RA). Objectives To report five patients with cutaneous adverse drug reactions due to anakinra and to evaluate the histopathological and immunohistochemical findings with the aim of understanding the possible mechanisms involved. Methods Five patients of a series of 10 patients with RA undergoing treatment with anakinra in a clinical trial presented inflammatory lesions at the anakinra injection sites. In each case, clinical features were recorded and skin biopsy specimens were obtained. In one patient sequential biopsy specimens were obtained from skin lesions at different stages of development. Tissue sections of the biopsy specimens were stained with haematoxylin and eosin and May-Grünwald-Giemsa, and were immunoreacted with antibodies to leucocyte common antigen, CD68, CD3, CD45RO, CD20 and CD45RA. Results The onset of reaction was within the first month of treatment and appeared as well-defined erythema and oedema involving the injection sites. In two patients the treatment had to be discontinued because of the skin reaction, and in one patient it was associated with systemic involvement. All biopsy specimens exhibited marked dermal oedema and a lichenoid dermal infiltrate composed mainly of lymphomononuclear cells with prominent populations of eosinophils and large CD68+ dermal macrophages and an increase in the number of mast cells, which were spindle shaped in a significant proportion. Conclusions Cutaneous toxicity is a frequent, usually well-tolerated complication of treatment with anakinra in patients with RA, although in some cases it can be associated with systemic involvement. The most relevant histopathological findings include dermal oedema and a lichenoid, perivascular and periadnexal predominantly lymphomononuclear infiltrate, with many eosinophils and the presence of enlarged CD68+ macrophages. These findings resemble those seen in skin reactions in patients receiving chemotherapy and colony-stimulating factors. We also found an increase in mast cell numbers that could be a specific effect of anakinra.

Cytokine inhibitors and pain control

“…Recently, a selective IL-1 receptor antagonist that differs from naturally occurring IL-1ra by the presence of a methionine group named Anakinra (Amgen Inc.) was developed. Anakinra was tested in models of inflammatory diseases and is under clinical evaluation (55,56) . Besides IL-1β, TNF has also become a target for the treatment of inflammatory diseases including arthritis.…”

Anaphylaxis to anakinra in a pediatric patient with systemic juvenile idiopathic arthritis successfully treated with canakinumab: a case-based review

“…The patient was switched to an alternative anti-IL-1 agent (canakinumab) without subsequent reaction. Although rare cases of hypersensitivity related reactions to anakinra have been reported [4][5][6][7][8], to our knowledge, this is the first report of anaphylaxis in a pediatric patient with sJIA who was safely switched to alternative anti-IL-1 therapy.…”

Unerwünschte Arzneimittelreaktionen auf Biologika

“…Durch eine andere Injektionstechnik konnten einige Patienten reexponiert werden, bei einem trat ein disseminiertes Exanthem auf. Histologisch fanden sich überwiegend diffus und perivaskulär angeordnete vermehrt Eosinophile und lymphatische Zellen, 90 % waren CD3+-Lymphozyten [43]. Eine sehr seltene UAW der Haut ist die interstitielle granulomatöse Arzneimittelreaktion.…”

“…Derartige, fern von der Injektionsstelle aufgetretene Plaques wurden für TNF␣-Antagonisten (Infliximab, Adalimumab) sowie für Anakinra beschrieben [44], aber auch nach vielen anderen Substanzen. Unter anderem auf Xenobiotika wie Ganciclovir [45] sowie auf Calciumantagonisten, ACE-Hemmer, Furosemid und Betablocker und weitere Medikamente wurde diese, wahrscheinlich als individuell zu interpretierende Reaktionsform auf unterschiedliche Arzneimittel beobachtet [43]. [48].…”

“…Lokalreaktionen auf die subkutan applizierten BRM sind sehr häufig und kön-nen gelegentlich durch Änderung der Injektionstechnik vermieden werden. Bei leichten Reaktionen kann die Therapie versuchsweise fortgesetzt werden, allerdings wurden vereinzelt streuende Exantheme beobachtet [43]. <<<…”