Several lines of evidence pointing to the immunomodulatory effects of TNF-α blockades have been accumulating with the increasing use and longer follow-up of treatment with TNF-α antagonists. Testimony of autoimmunity triggered by TNF-α blockers includes 92 reported cases of lupus, 113 patients with vasculitis and 24 cases of interstitial lung diseases [2]. The ability of TNF-α to induce autoantibodies in a large proportion of patients was established in several studies [31-33].

Our cases represent untoward immunomodulation triggered by infliximab that had brought about the desired therapeutic effects on the existing disease symptoms for which it had been prescribed. The first case was a patient with longstanding ankylosing spondylitis who acutely developed Crohn's disease. Endoscopic studies in patients with ankylosing spondylitis have demonstrated the presence of intestinal inflammation in up to 60% of them, particularly in those with active peripheral joint disease[34]. One prospective follow-up of patients with juvenile onset disease who initially presented with peripheral rather than axial joint disease also showed that intestinal inflammation increases the likelihood of progression to axial disease [35]. Our patient was probably predisposed to develop inflammatory bowel disease, but the fact that it developed with the introduction of infliximab, by itself indicated for Crohn’s disease, despite highly satisfactory control of his ankylosing spondylitis, strongly suggests a triggering effect of the drug. Interestingly, etanercept, a soluble receptor of TNF-α has been implicated in the onset of 6 cases of Crohn's disease [36-39] -3 of them in patients with ankylosing spondylitis [39]. The second case was a patient with very long-standing ankylosing spondylitis who developed palmo plantar psoriasis shortly after beginning a course of infliximab. There have been several reports in the medical literature of new-onset psoriasis or worsening of pre-existing skin diseases in patients treated with TNF-α inhibitors for psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease. Interestingly, infliximab is efficacious in treating skin psoriasis. A great proportion of the patients described in the literature presented with palmo-plantar psoriasis, although all forms of psoriasis were described [2, 3, 5-30]. It has been suggested that palmo plantar psoriasis may be induced by an abnormal expression of TNF-α in the eccrine palmar sweat gland and duct [40]. Although TNF-α is a well-documented contributor to the psoriatic skin lesion, another important pathway for triggering common human autoimmune disease involves plasmacytoid dendritic cell precursors and type 1 interferon (INF) production. TNF-α regulates INF-α production and neutralization of endogenous TNF-α may promote INF-α production by plasmacytoid dendritic cells inducing psoriatic plaques [41]. Our third case was a woman with long-standing psoriasis who developed peripheral arthritis during treatment with infliximab. The differential diagnosis of this case includes infliximab-induced lupus and psoriatic arthritis. The fact that the arthritis subsequently responded to the infusion of infliximab and that the anti-dsDNA result was negative support the likelihood of the seronegative arthritis having been triggered by infliximab.

Another plausible explanation for the undesired evolution of our three cases may involve the effect of TNF-α antagonists on the risks of infection. TNF-α blockers have been implicated in the reactivation of a variety of infectious diseases, including mainly intracellular pathogens, such as Mycobacterium tuberculosis and others [42]. Immune activation by bacteria was shown to have acrucial role in the development of the disease in both reactive arthritis (ReA) and in the HLA-B27 transgenic rats model [43]. There is evidence that this is related to an abnormal persistenceof intracellular pathogens, at least inReA [31]. Recent studies indicate that othersubtypes of SpA may also have an impairment of certain aspectsof the innate immune defense, particularly with regard to theexpression of scavenger receptors [44, 45]. However, whereas SpAhas traditionally been associated with urogenital infection withchlamydia or gastrointestinal infections with Gram-negativepathogens, such as salmonella, shigella, campylobacter, and yersinia [46],treatment with anti-TNF-α blockers may affect the intestinal flora by inducing a change in the predominant manifestation of spondyloarthropathies.