Henoch-Schönlein purpura in a patient with rheumatoid arthritis receiving etanercept

ARTICLE

Auteur(s) : Akihiko Asahina¹, Noboru Ohshima¹, Hisanori Nakayama², Akira Shirai¹, Takuo Juji³, Toshihiro Matsui²

¹Department of Dermatology
²Department of Rheumatology
³Department of Orthopedics, Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan

We report the case of a 61-year-old woman with a 28-year history of severe rheumatoid arthritis (RA), who developed Henoch-Schönlein purpura (HSP) while receiving etanercept. Since her RA condition was unstable despite the administration of prednisolone (PSL) at 7 mg/day and leflunomide at 20 mg/day, she started etanercept at 25 mg twice weekly. Six months later, she noticed purpuric papules and macules on both legs (figure 1A). Histopathology showed leukocytoclastic vasculitis of small vessels in the upper dermis (figure 1B), with IgA deposition by direct immunofluorescence (figure 1C). Routine laboratory examinations showed leukocytosis (10,950/μL) with elevated CRP (3.18 mg/dL), rheumatoid factor (68 IU/mL), and complement (CH50: 55 U/mL, C3: 160 mg/dL, C4: 25.8 mg/dL). Serum IgG and IgA levels were high (2,690 mg/dL and 1,060 mg/dL, respectively). ANA was positive (1:80), but anti-dsDNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies, and circulating immune complexes were not detected. Serum anti-streptolysin O was negative. She showed normal renal findings, and the fecal occult blood test was negative. She discontinued etanercept, and started dapsone at 75 mg/day, followed by a tentative increase of PSL up to 30 mg/day. While the HSP eruptions disappeared, RA flared up with elevated CRP (9.14 mg/mL) after tapering PSL to the baseline. She then received an intravenous injection of tocilizumab at 530 mg (8 mg/kg), and soon her RA condition was successfully improved. She is currently being treated with tocilizumab on a monthly basis, without dapsone.

A growing number of reports indicate the development of autoimmune processes during TNF-targeted therapies. Cutaneous vasculitis is the most common, and the majority of patients have RA as the underlying disease [1]. Although severe RA may be associated with leukocytoclastic vasculitis of small and medium-sized vessels by itself, and TNF-targeted therapies are sometimes effective for refractory vasculitis associated with RA, some observations support the causal relationship of anti-TNF-α agents in the development of vasculitis. They include the temporal order between inhibitor administration and the occurrence of vasculitis, the spontaneous improvement after discontinuation of the inhibitor, and a positive re-challenging phenomenon [1]. Some cases showed occurrence with both etanercept and infliximab [1]. Our case is particularly significant in that HSP is distinct from RA-associated vasculitis. We have identified at least four cases of definite or probable HSP occurring during TNF-targeted therapies, and all were in rheumatological journals [2-5]. More cases of HSP may have been overlooked, or may have been reported simply as leukocytoclastic vasculitis without demonstrating IgA deposition, or as cases of IgA glomerulonephritis.

As possible underlying mechanisms of vasculitis, anti-TNF-α-TNF-α immune complexes may be deposited in small capillaries and trigger a type III hypersensitivity reaction. Anti-TNF-α agents may inhibit Th1 functions and favor the activation of antibody-mediated immune mechanisms. Some cases of vasculitis may lie in the spectrum of lupus-like syndromes triggered by anti-TNF-α agents. In cases of HSP, anti-TNF-α agents may induce infection to trigger the onset of HSP. Our patient, however, had no preceding infection. We also postulate a possible involvement of interferon (IFN)-α, since viral infection, a well-known trigger of HSP, serves as a stimulator of plasmacytoid dendritic cells. It has recently been shown that anti-TNF-α agents induce an increase of IFN-α production by plasmacytoid dendritic cells, contributing to the onset of lupus-like syndromes and the paradoxical induction of psoriasiform or palmoplantar pustulosis-like eruptions [6].

Finally, our patient urgently required RA control after the discontinuation of etanercept. It was considered prudent not to reintroduce etanercept or switch to other anti-TNF-α agents. Tocilizumab has not been shown to increase the risk of vasculitis, and it may be a good alternative agent when anti-TNF-α agents are contraindicated, as demonstrated in our case.

Acknowledgements

References

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