Anti–TNF-α therapy has been increasingly associated with drug-induced autoimmune diseases, such as cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus, and interstitial lung disease.10,13-16
Vasculitis is the most common autoimmune disease that results from anti–TNF-α therapy.8,9
To date, 213 cases of TNF-induced vasculitis have been reported in the medical literature: 39 in a nationwide series in France, 139 in Spain, and 35 in the United States that were derived from the Adverse Events Reporting System of the US Food and Drug Administration.8-11,14
To our knowledge, the current study is the first single-center series describing vasculitis associated with anti–TNF-α therapy in a US cohort. presents a comparative analysis of 8 patients in the current study with 118 previously reported cases.
In our series, the patients had similar demographic characteristics (age and sex) compared with previously reported patient characteristics.9-11
In addition, most (4/8; 50%) of the patients had RA, which is also in keeping with previous reports.9
Although the spectrum of vasculitis was broad, there was a notable predominance of cutaneous involvement (5/8; 63%), with palpable purpura being the most common cutaneous lesion. Although less common, other cutaneous features included ulcerations, blisters, and erythematous macules. An important finding was the presence of systemic vasculitis in an equally large number (5/8; 63%) of patients. Peripheral neuropathy and renal vasculitis were the most frequent types of systemic vasculitis present in these patients. This clinically significant finding was consistent with those reported in both the Spanish- and French-language medical literature.9,10
Histologic examination was performed for all confirmed cases of vasculitis in our study. The histologic confirmation of diagnosis differs from findings reported for the Spanish and French studies, neither of which required confirmatory histologic evidence for all reported cases of vasculitis.9,10
The most common biopsy performed in our study was a skin biopsy (5/8; 63%). Other biopsies were nerve (3/8; 38%) and kidney (1/8; 13%). In our study, patients with cutaneous small-vessel vasculitis had histologic features of leukocytoclastic vasculitis (5/5; 100%). The predominance of this histologic feature on cutaneous biopsy specimens is similar to that in findings reported in other series.9,10,14
However, in addition to reporting cases of leukocytoclastic vasculitis, Ramos-Casals et al9
and Saint Marcoux and De Bandt10
reported cases of necrotizing vasculitis on histologic examination of cutaneous lesions (although the term necrotizing vasculitis
was not defined in these reports). Our histologic finding of mononeuritis multiplex and IgA nephropathy on nerve and kidney biopsy specimens, respectively, was consistent with similar findings in the French study.10
An important clinical question is whether patients can subsequently be treated with alternative anti–TNF-α agents after development of vasculitis induced by anti–TNF-α therapy. In our group of 8 patients, none was rechallenged with another anti–TNF-α agent. However, in another study that analyzed data from the US Food and Drug Administration database, relapses occurred in 6 of 9 patients (67%) who were rechallenged with the same anti–TNF-α agent.14
This rate of recurrence differs substantially from the 33% recurrence rate found in the French study.10
The lower relapse rate reported in the French study may be attributable to the fact that patients were rechallenged with an alternative anti–TNF-α agent. In our study, we were unable to elicit why none of the 8 patients were rechallenged with an alternative biologic agent.
It can be challenging to determine causality in cases of vasculitis associated with anti–TNF-α therapy. However, the resolution of vasculitis after drug therapy discontinuation and adjuvant treatment is often helpful in supporting the etiologic role of anti–TNF-α therapy in the development of vasculitis. In our study, 7 of 8 patients (88%) had at least partial resolution of their vasculitis after drug therapy discontinuation. The mean time to resolution was 6.9 months. Unfortunately, we found no comparative data in the medical literature. To provide an objective assessment of causality, we used the Korean algorithm12
to further support our data (). The Korean algorithm consists of 8 questions on adverse drug reactions, with scores of 9 or higher being “certain” for a reaction, 6 to 8 “probable/likely,” and 3 to 5 “possible.”12
Seven of 8 patients in our study had “certain” reactions (all 7 had scores of 9), and 1 patient had a “probable/likely” reaction (score of 6).
The confounding bias of vasculitis occurring in patients with severe RA and the treatment of severe RA with anti–TNF-α therapy make it challenging to decipher the phenomenon responsible for vasculitis in these cases.17
Both RA and IBD can be associated with vasculitis, and therefore we cannot exclude the possibility that vasculitis was associated with these underlying conditions. However, in our study, the absence of clinical features such as articular flare, which one would expect in active RA,17
led to a favored diagnosis of anti–TNF-α therapy–induced vasculitis. In addition, the underlying disease (ie, RA) was medically managed and under control as determined by the rheumatologist. Similarly, the absence of diarrhea or abdominal pain in patients treated for IBD, as well as evaluation by a gastroenterologist who deemed the IBD to be quiescent at the time of vasculitis, supported our diagnosis in those cases.
The development of autoantibodies, such as antinuclear antibodies and anti–double-stranded DNA antibodies, in patients treated with anti–TNF-α agents is well recognized in the medical literature.2,18
Both antinuclear antibodies and anti–double-stranded DNA antibodies can be induced in patients with RA and Crohn disease treated with infliximab. With the anti–TNF-α agents, induction of antinuclear antibodies occurs in 23% to 57% of patients, whereas induction of anti–double-stranded DNA antibodies occurs in 9% to 33% of patients.4
Although the occurrence of these autoantibodies is not infrequent, a well-defined association has not been characterized between the induction of autoantibodies and the subsequent development of vasculitis associated with anti–TNF-α therapy. Our study did not address the development of autoantibodies in patients in whom vasculitis developed after anti–TNF-α therapy.
It is unclear why benign limited cutaneous vasculitis developed in some patients, whereas systemic involvement developed in others. However, this discrepant course of illness suggests a potential role for individual genetic susceptibility, which would explain why some biologic agents are successful in treating systemic vasculitis, yet these same agents paradoxically trigger vasculitis in other patients being treated for an underlying rheumatic or systemic autoimmune disease. Although the pathogenesis of vasculitis associated with anti–TNF-α therapy remains unknown, the development of antibodies against anti–TNF-α agents could lead to an immune complex–mediated hypersensitivity vasculitis.5
Another hypothesis suggests that inhibition of TNF-α promotes the expression of type 1 interferon by altering the balance between TH
1 and TH
2 cytokine production, leading to the induction of autoimmune diseases such as lupus erythematosus, dermatomyositis, and vasculitis.19,20
Although injection site reactions after anti-TNF therapy have been implicated as playing a role in direct antigen-mediated hypersensitivity vasculitis,9
none of the 8 patients in our cohort had a documented injection site reaction before the development of vasculitis.
Our study has several novel features that augment previous reports describing vasculitis associated with anti–TNF-α therapy. As mentioned, to our knowledge, the current study is the first single-center series describing vasculitis associated with anti–TNF-α therapy in a US cohort. We required strict inclusion criteria that consisted of confirmed histologic evidence of vasculitis (in contrast, only 87 of the 118 patients [74%] described by Ramos-Casals et al9
had histologic confirmation of vasculitis). We also used an objective assessment algorithm (Korean algorithm12
) in our patient cohort to corroborate a diagnosis of vasculitis associated with anti–TNF-α therapy. Whereas most of the patients described by Ramos-Casals et al9
had RA (99 of 118 patients [84%]), 4 of our 8 patients (50%) had IBD; this discrepancy may have been due to the large IBD clinic at our institution. Moreover, we found a higher rate of peripheral nerve involvement by vasculitis (4 of 8 patients [50%]) compared with that reported by Ramos-Casals et al9
(18 of 118 patients [15%]) and by Saint Marcoux and De Bandt10
(10 of 39 patients [26%]). Finally, although the report of Ramos-Casals et al9
does not provide information on the exact time to resolution of vasculitis in their 118 cases, we report a mean time of 6.9 months to resolution of vasculitis after cessation of anti–TNF-α therapy; this information can help health care professionals counsel their patients about the prognosis of vasculitis associated with anti–TNF-α agents.
Our study is limited by its retrospective nature. In addition, confounding factors make it challenging to correctly diagnose vasculitis attributable to anti–TNF-α use (eg, underlying disease that can cause vasculitis, other causes of vasculitis, and clinical mimickers of vasculitis). To limit the effect of such confounders, we excluded patients who lacked histologic confirmation of vasculitis and whose diagnosis of vasculitis was questionable. Similarly, causality was difficult to assess because rechallenge with the same or alternative anti-TNF agents was not performed in our patients. Finally, there is a referral bias inherent in our institution's status as a tertiary care academic medical center because of the complexity of cases referred there. As a result, our cohort is not representative of a general US-based medical practice.