Development of psoriasiform or eczematiform lesions has been reported in patients treated with anti-TNF therapy [25–28]. Although anti-TNF therapy is used to treat psoriasis, IBD patients can paradoxically develop these immune-mediated inflammatory skin lesions after initiating biologic therapy [29, 30]. While the timing of these skin lesions occurring after initiation of anti-TNF therapy and their resolution after discontinuation of therapy suggest that they are induced by the biologic agent, in some patients these inflammatory skin lesions may be an exacerbation of pre-existing psoriasis or de novo psoriasis [30].

Psoriasiform lesions that occur after initiation of anti-TNF therapy are thought to be an adverse effect of therapy because the majority of patients do not have a personal or a family history of psoriasis [31]. In a systematic analysis of cases of psoriasis induced by anti-TNF therapy for IBD, only 3/21 (14%) had a first- or second-degree relative with psoriasis [31]. The age at onset of psoriasiform and eczematiform lesions during anti-TNF therapy tends to occur in young adulthood [25, 31, 36], with a median age of 32 years (IQR 24–39) in the psoriasiform group and 31 years (IQR 23–39) in the eczematiform group (see Table 14.2) [25].

The majority of patients who develop psoriasiform and eczematiform lesions are females [25, 31, 32, 34, 36]. In a retrospective study consisting of 85 patients who had new onset or exacerbation of psoriasiform or eczematiform lesions while receiving anti-TNF therapy for IBD, Rahier et al. found that 42/60 (68%) in the psoriasiform group and 20/23 (87%) in the eczematiform group were females [25]. Guerra et al. and George et al. r eported a similar female predominance in their studies, 15/21 (71%) and 14/18 (78%), respectively [31, 32]. Similarly, in a systematic literature review consisting of IBD patients who developed psoriasis during anti-TNF therapy, 21/41 (64%) of the cases were females (see Table 14.2) [36]. This finding may be confounded by the fact that autoimmune diseases are generally more common in females and these inflammatory skin lesions are thought to be immune-mediated [31].

Cigarette smoking has been linked to the development of idiopathic psoriasis [37], and a similar association is thought to exist between smoking and anti-TNF-related psoriasiform lesions (see Table 14.2) [32, 38]. In a case control study consisting of 373 cases with new onset of plaque psoriasis, Wolk et al. found that smoking was associated with 70% increased risk for onset of psoriasis [37]. The ingredients in cigarettes are thought to be pro-inflammatory which can lead to immune dysregulation and the development of idiopathic psoriasis [37]. However, Guerra et al. found that smokers and nonsmokers were equally likely to develop anti-TNF-related psoriasiform lesions in their cohort [31]. In a retrospective case control study consisting of 18 anti-TNF-treated patients with psoriasiform lesions and 70 anti-TNF-treated patients without skin lesions, smokers were numerically more likely to develop psoriasis than nonsmokers, 7/18 [38.9%] vs. 13/70 [18.6%] (p = 0.13) [32]. Similarly, in a large retrospective cohort study where 42 cases of psoriasis were recorded among 402 anti-TNF-treated IBD patients, smoking was found to be an independent predictor of psoriasis (HR 2.37, 95% CI, 1.36–4.48; p = 0.08) [38].

Psoriasiform lesions may be more common in patients with CD than ulcerative colitis (UC) (see Table 14.2). In a case series by Guerra et al., 17/21 (81%) of patients with anti-TNF-related psoriasis had CD [32]. Rahier et al. also noted that majority of patients who developed psoriasiform or eczematiform lesions during anti-TNF therapy had CD, 52/62 (84%) and 17/23 (74%), respectively [25]. A similar finding was observed in a cross-sectional study by Hellstrom et al. where nearly 80% of patients who had eczema or psoriasiform lesions (new onset = 8, exacerbation of existing lesions = 6, existing lesions not worsened = 11) had CD [26]. In a retrospective case control study comparing demographic and clinical characteristics between 18 anti-TNF-treated patients with psoriasis and 70 anti-TNF-treated patients without psoriasis, those with upper tract CD were more likely to have psoriasis during anti-TNF therapy (39% vs. 5%, p = 0.001) [32]. This association may be confounded by the fact that patients with CD, particularly those with upper GI tract involvement, are more likely to receive an anti-TNF than patients with UC.

Psoriasiform and eczematiform lesions appear to be reactions to the class of drugs rather than to the individual anti-TNF agent as these reactions have been reported with infliximab, adalimumab, and certolizumab pegol [25, 29, 31, 33, 39]. When analyzing more than 13 million reports from the Food and Drug Administration (FDA) Adverse Event Reporting System between 2004 and 2011, Kip and colleagues noted a total of 5432 cases of anti-TNF-related psoriasis (infliximab = 1789; adalimumab = 3475; certolizumab pegol = 168) [29]. The control drugs they selected in their analysis were propranolol and lithium, due to their recognized risk of psoriasis, and mesalamine [29]. Compared to control, the proportional reporting ratios of psoriasis for infliximab, adalimumab, and certolizumab pegol were 6.61, 12.13, and 5.43, respectively (p < 0.0001) [29]. As a class, the proportional reporting ratio of psoriasis for these TNF antagonists was 9.24 (p < 0.0001) [29].

Other reports have also demonstrated an association between various anti-TNF agents and inflammatory skin lesions [25, 39]. Of the 1004 IBD patients who were exposed to anti-TNF therapy, Afzali et al. identified 27 patients who developed psoriasiform lesions (infliximab = 8, adalimumab = 10, and certolizumab pegol = 9) [39]. In the Rahier study described previously, 62 patients had psoriasiform lesions (infliximab = 45, adalimumab = 15, certolizumab pegol = 2) and 23 patients had eczematiform lesions (infliximab = 15, adalimumab = 5, certolizumab pegol = 3) [25]. Adverse inflammatory skin lesions are likely seen more commonly with infliximab and adalimumab because of their increased market share compared to certolizumab pegol [25].

It remains unclear whether there is a dose-dependent risk between TNF antagonist and the development of dermatologic adverse events. Among 71 IBD patients who were receiving stable maintenance infliximab therapy, 9 (12.7%) were noted to have dermatologic adverse events (psoriasis = 2, non-psoriatic skin eruptions = 7) [40]. The median infliximab trough level in patients with dermatologic adverse events was higher compared to those without skin adverse events (13.3 μg/mL [IQR 8.8–17.4 μg/mL] versus 6.6 μg/mL [IQR 3.2–12.7 μg/mL]), respectively, (p = 0.058) [40]. However, in another retrospective cohort study where 264/917 (26%) of IBD patients on maintenance anti-TNF therapy developed dermatologic adverse reactions, trough infliximab levels were similar in patients with (4.2 μg/mL [IQR 2.6–5.8 μg/mL] and without lesions (4.0 μg/mL [IQR 1.6–5.9 μg/mL] [41].

Paradoxical de novo formation or worsening of psoriasiform lesions that occur during anti-TNF therapy is thought to be due to dysregulated interferon-α (IFN-α) production via plasmacytoid dendritic cell precursors (PDCs) [42, 43]. While there are certain genetic predispositions that are linked to classic psoriasis, including HLA-Cw6, HERV-K, as well as LCE3C and LCE3B deletions, it remains unclear which genetic pathways are responsible for anti-TNF-related psoriasiform skin lesions [44, 45]. In homeostatic conditions, TNF-α and IFN-α behave as opposite vectors in many innate immune responses [46]. When both cytokines are in balance, the result is an equilibrium allowing protective immunity [46]. TNF-α blockade results in uninhibited PDC production of IFN-α [29, 31, 33, 36, 43, 46]. When compared to primary plaque psoriasis, patients with anti-TNF-related psoriasis have been noted to have increased PDCs and IFN-α signaling demonstrated on histologic specimens [31, 42, 43, 47–49]. Furthermore, psoriasiform lesions have been shown to develop or worsen after injection of recombinant IFN-α [42]. IFN-α also heightens the expression of chemokine T cell receptors CXCR3, which increases T cell homing to the skin [31, 36, 43, 50]. Recruitment of CXCR3 T cells to the skin results in a T cell-mediated immune response with cytotoxic skin reactions that leads to the development of psoriasiform skin lesions [31].

Diagnosi s of anti-TNF-related psoriasiform skin lesions requires a thorough history, physical exam, and possible skin biopsy. It is crucial to exclude trauma, mechanical stressors, infection, and other medications including beta-blockers, lithium, nonsteroidal anti-inflammatory drugs, tetracycline, and antimalarials as causative agents [33, 51]. Skin lesions that arise during anti-TNF therapy should be evaluated by a dermatologist. Lesions that arise in unusual locations such as on the face or at flexor surfaces may warrant skin biopsy [33]. Biopsies with immunohistochemical staining from the anti-TNF-related psoriasiform lesions show increased concentration of IFN-α in perivascular lymphocytic infiltrate and dermal vasculature [36]. Other histological findings include epithelial hyperplasia with acanthosis and hyperkeratosis with increase cell turnover, parakeratosis, lymphocytic infiltration of the epidermis, and dilated capillaries (see Fig. 14.3) [30, 31, 33].

Managemen t of anti-TNF psoriasiform lesions generally does not require cessation of anti-TNF agent [36]. For mild disease with lesions encompassing less than 5% of total body surface area, the anti-TNF agent can be continued [31, 33, 36]. Treatments of mild psoriasiform lesions include topical corticosteroid, emollients, keratolytic therapy, vitamin D analogs, and/or ultraviolet phototherapy [31, 33, 36]. In the case series of Guerra et al., 17/21 patients (81%) continued the anti-TNF agent and had resolution of psoriasiform lesions using topical corticosteroid with or without ultraviolet phototherapy [31]. Duration of therapy before response typically ranges from 1 to 3 weeks [31]. In a systematic review consisting of 222 cases of anti-TNF-related psoriatic lesions, Denadai et al. found that 64/87 (74%) had resolution of psoriatic skin lesions without having to withdraw the anti-TNF agent [33].

In refractory disease or in cases of severe disease with greater than 5% of total body surface area involved, discontinuation of anti-TNF agent may be necessary [31, 33, 36]. In a retrospective study consisting of 85 patients (69 with CD, 15 with UC, and 1 with indeterminate colitis), 29 (34%) patients discontinued anti-TNF therapy due to uncontrolled skin lesions [25]. In a review published by Denadai et al., 86 patients had their anti-TNF agent discontinued, and a large number of these patients, 71/86 (83%), subsequently had resolution of their skin lesions [33]. In addition to topical therapies and phototherapy as described above, systemic treatments such as retinoids, methotrexate, or cyclosporine may also be necessary in these complicated cases [31, 33, 36].

Recurrence of psoriasiform lesions can occur after reinitiating or switching anti-TNF therapy [27, 31, 33]. In the case series by Guerra, 4/21 (19%) patients had their anti-TNF therapy discontinued: One patient had complete response after discontinuation and no recurrence of psoriasis after reintroduction of the same anti-TNF therapy. The other three patients had partial response after discontinuation of the drug (two patients had discontinued anti-TNF therapy permanently; the third patient who had palmoplantar psoriasis was managed with topical corticosteroid and then had mild recurrence after anti-TNF therapy was reintroduced, and the psoriasiform lesions were successfully controlled with topical corticosteroid) [31]. In a single-center observational retrospective study, 59/583 (10.1%) IBD patients had psoriasiform lesions emerge on anti-TNF therapy [27]. Twenty-one of 59 patients (35.6%) switched to another anti-TNF therapy and over half of these patients (12/21, 57%) had recurrence of psoriasiform lesions [27]. Similarly, in the review published by Denadai et al., of the 29 patients who switched anti-TNF agents, 21 (72%) had recurrence or aggravation of their psoriasiform lesions [33].

Early recognition and prompt initiation of therapy is essential in management of anti-TNF-associated psoriasiform lesions. Except in cases where the psoriasiform lesion is severe or extensive, topical treatment is the therapy of choice, and discontinuation of the biologic agent may not be necessary. Patients who are rechallenged with the same or a different anti-TNF agent need to be monitored closely as recurre nce of psoriasiform lesions frequently occur (see Table 14.3) [33].

Lupus-like syndrome (LLS), a rare autoimmune disorder, is a recognized adverse reaction to anti-TNF therapy in IBD patients [52]. Compared to systemic lupus erythematosus (SLE), patients with LLS tend to be older with mean age of 46–51 years, and with slight female predominance [53–55]. LLS is generally characterized by arthralgia, myalgia, fever, arthritis, and serositis [52, 55]. While malar rash, photosensitivity, and oral ulcers are less common in LLS [55], skin involvement and photosensitivity are common in patients who develop LLS after anti-TNF therapy [54, 56, 57]. However, central nervous system and renal involvement are rarely seen in LLS [55, 56].

Patients who have received anti-TNF therapy are at high risk of developing autoantibodies [57, 58], but the rate of LLS is generally low at 0.5–1% [59, 60]. In the ACCENT I trial consisting of 573 patients randomized to placebo or infliximab, positive antinuclear antibodies (ANA) and double-stranded (ds) DNA were more common in patients on infliximab than those on placebo, 56% and 34% vs. 35% and 11%, respectively [12]. However, only two patients in the infliximab groups with positive autoantibodies developed LLS [12]. Similarly, in a multicenter, longitudinal, observational study where 286 patients had autoantibodies assessed both before and after at least 6 months of infliximab treatment, only one patient (0.35%) in this cohort was diagnosed with LLS [57].

Autoantibodies are also common after treatment with adalimumab. In a case series consisting of 180 IBD patients treated with an anti-TNF therapy (infliximab or adalimumab, or infliximab and adalimumab consecutively), 44.4% were found to have antinuclear antibody (ANA) titers ≥1:240, and 15.6% had dsDNA serum levels ≥9 U/mL [52]. Only 1.1% of these patients, however, had severe LLS requiring immediate discontinuation of anti-TNF therapy. Severe LLS was defined as severe arthralgia including joint swelling and/or additional LLS-related symptoms requiring immediate disconti nuation of anti-TNF therapy and initiation of corticosteroids and/or immunosuppressive therapy [52]. Biegel et al. observed that the ANA and dsDNA titers positively correlate with clinical severity of LLS [52].

Onset of LLS has been reported to range from 10 days to 54 months after initiation of anti-TNF [60]. In a case series of 92 patients who developed SLE or LLS after anti-TNF therapy (infliximab = 40, etanercept = 37, and adalimumab = 15), the mean latency of onset was 41 weeks after anti-TNF therapy [54]. Clinical and immunologic data were available in 72 of these patients: 68 (94%) had positive autoantibodies, 57 (79%) with positive ANA, 52 (72%) with dsDNA antibodies, 8 (11%) with antiphospholipid antibodies, and 7 (10%) with anti-Smith antibodies [54]. Sixty-four (89%) patients had cutaneous features, 28 (39%) had musculoskeletal manifestations, and 21 (29%) had systemic symptoms including fever, malaise, and asthenia [54]. SLE cutaneous features including malar rash, photosensitivity, and/or discoid lupus were seen in 48 (67%), arthritis in 22 (31%), cytopenia in 16 (22%), serositis in 9 (12%), and nephropathy in 5 (7%).

Patients who develop autoantibodies and LLS tend to be older and of female gender [53–55, 61, 62]. When Beigel et al. examined factors associated with the development of LLS in IBD patients treated with an anti-TNF therapy, they found that increased age is a risk factor for developing ANA titers ≥ 1:240 (odds ratio 1.06, 95% CI 1.03–1.09, P < 0.001) and for developing LLS (odds ratio 1.08, 95% CI 1.03–1.13, P = 0.002) [52]. Moulis et al. analyzed 39 LLS cases associated with anti-TNF therapy, the majority of patients who were affected were females with a female to male ratio 10:1 [62]. Similarly, in the case series by Ramos-Casals et al. where epidemiologic data was available for 62 patients who developed LLS after anti-TNF therapy, there was a female to male ratio of 5:1 [54]. These findings are similar to the female to male ratio in patients with SLE. A meta-analysis consisting of 16 studies with a total of 11,934 SLE patients demonstrated an average female to male ratio of 9:1 [63]. SLE is more prevalent in women because of differences in the metabolism of sex hormones [64].

The two antibodies ANA and dsDNA, part of the immunologic criteria for SLE, have been examined as potential predisposing factors for the development of LLS [52, 54]. In the case series by Ramos-Casals et al., 72 patients with anti-TNF therapy-related lupus met SLE criteria; 57 (79%) and 52 (72%) of these patients were found to have positive ANA and dsDNA, respectively [54]. However, the threshold titers used for positivity of these two antibodies were not reported [54]. In another case series published by Biegel et al. consisting of 180 IBD patients treated with an anti-TNF therapy, dsDNA antibody values ≥9 U/mL were shown to be associated with the development of LLS (P = 0.02) [52]. In this cohort, no association was found between ANA titer ≥ 1:240 and development of LLS [52].

Given the low incidence of LLS and limited data, it remains unclear whether concomitant immunomodulator is protective against autoantibody formation and development of LLS. In the case series published by Biegel et al. described previously, concomitant immunomodulator was shown to be protective against ANA formation (p = 0.05) and LLS development (p = 0.04) [52]. Others have found that ANA and dsDNA can be detected in CD patients despite being on concurrent immunomodulator while receiving infliximab, but how this rate compares to those who are not on concurrent immunomodulator is unclear [12, 58].

The pathophysiology of anti-TNF therapy-induced LLS is not clearly defined, but several hypotheses have been proposed on the development of autoantibodies. Anti-TNF therapy induces apoptosis in inflammatory cells; the release of antigenic particles during this process may stimulate autoantibody formation in susceptible individuals and may lead to the development of LLS [60, 65]. This hypothesis is supported by the finding of increased plasma nucleosome levels after infliximab treatment [66]. Another hypothesis is that patients on anti-TNF therapy are prone to infection which would activate polyclonal B lymphocytes to stimulate autoantibody production [60]. A third potential mechanism by which TNF antagonists could induce autoantibody formation is by humoral autoimmunity activation via inhibition of cytotoxic T-lymphocyte response [60].

Diagnosis of LLS requires early recognition of a constellation of symptoms including arthralgia, joint swelling, myalgia, rash, erythema, fever, and/or serositis in patients treated with anti-TNF therapy [52, 55]. In patients with only joint manifestations, the differential diagnosis includes delayed hypersensitivity reaction to infliximab, type 1 or 2 arthritis related to underlying IBD, and other causes. Oral ulcers and classic malar rash associated with SLE are less common in LLS, but patients with LLS can present with an erythematous purpuric rash and photosensitivity [54, 56]. LLS rarely involves the central nervous or the renal systems [55, 56]. Although there are no diagnostic criteria for LLS, the diagnosis of LLS is generally made based on clinical features as described previously, the presence of ANA and anti-dsDNA autoantibodies, and notable improvement of symptoms within days or weeks after the offending drug is discontinued. The ANA and anti-dsDNA titers used in the report by Biegel et al. for the diagnosis of LLS were ≥1:240 and ≥9 U/mL though different thresholds for autoantibody positivity have been used in other studies [52, 58].